Metabolism Review Notes.docx

Metabolism Review Notes (Lectures) Gut Motility Learning Objectives Describe the movements of the oesophagus, stomach and intestine during hunger and after eating. Explain basic elements of the peristaltic reflex. Describe the process of gastric emptying. State the approximate gastrointestinal transit times. Describe the propulsive and non-propulsive movements of the small and large intestines. Describe the process of defaecation. Extrinsic innervation of the gut Parasympathetic: vagus (from the NTS nodose ganglion) and pelvic nerves (sacral region of spine) Sympathetic: prevertebral ganglia (greater splanchnic nerve, lumbar colonic nerve, hypogastric) Dominant controls systems in the GI tract are: CNS controls (vagus) in the oesophagus. Myogenic, ENS and CNS (vagal control) in the stomach ENS control in the small intestine ENS and myogenic control in the large intestine ENS and CNS (spinal) control of the rectum and anus. Enteric Nervous System The enteric nervous system controls GI motility, local blood flow and trans mucosal movement of fluids. It contains sensory elements, interneurons and motor neurons. Works with the CNS. Diagram: blue motor nerves that contract or relax muscle located in myenteric plexus. Interstitial cells of Cajal (ICCs) Exist around myenteric plexus (within muscle in stomach, colon), submucosal plexus (colon) They cause spontaneous phasic muscle contractions through creating electrical slow waves. Muscle is arranged as a functional syncytium, allow waves to spread over large distances (!) Influence ability of hormones/neurotransmitters to induce movements. Hunger Migrating Motor Complex Occurs during hunger: there is a large contraction every 90-120 minutes that originates in the stomach (vagus-dependant) or in the small intestine (vagus independent). This contraction builds up in three phases: Phase I + II: build-up of irregular contractions. Phase III: high amplitude, big contraction Works to clear undigested material, prevent bacterial growth and give sensation of hunger Food Intake Consists of three phases: cephalic (thought, sight, smell, taste) prepares GI tract Gastric (satiation, early digestion, gastric emptying) triggered by mechanical effect. Intestinal phase (feedback and satiation) triggered by chemoreceptors in small bowel. Peristalsis Oesophagus: Swallowing of food: first peristaltic wave. As the bolus moves down and gets stuck, stretch receptors are stimulated which causes a second wave to occur. The second wave is therefore a back-up, driven by ENS (if bolus get’s stuck) Enteric sensory neurons (contain mechanical and chemo sensitive receptors) detect intraluminal stimuli and initiate peristalsis, plus increased secretion and vascular flow. Information transmitted to motor neurons (through Ach, NO, ATP) There is an ascending wave of peristalsis (contraction: causes excitatory neurotransmission to muscle: ACh) and descending wave of peristalsis (relaxation: inhibitory neurotransmission: NO). The stomach Stomach: fundus, body, antrum and pylorus. Contraction: ICCs generate slow waves, which propagate from dominant pacemaker in corpus (body). There is a higher frequency (greater contraction) @ greater curvature. Proximal Area: (fundus and body): thin wall, contracts weakly and infrequently: stores food because of receptive relaxation (reflex in which fundus dilates when food is passed down pharynx). Adaptive relaxation: stomach dilates in response to small increases in intra-gastric pressure (food enters) Distal Area: Has a thick wall with strong and frequent peristaltic contractions that mix and propel food into the duodenum. First phase is propulsion; second phase is emptying. Large particles are send back to the antrum (this is the third phase: retropulsion) (!) Movements of antrum enables powerful contractions against a closed pylorus: further breakdown Regulation of rate of expulsion: Depends on: Physical Properties Neuronal and Hormonal Feedbacks Nutritional Value, Content (may be slow if high nutrient density: no overloading) Emptying of liquids: exponential. Large solid particles suffer a lag phase. Larger volume of liquid = faster emptied Relieving the pressure: Increased pressure due to a build-up of gas is picked up by stretch receptors, which send a signal to the vagus to evoke a transient lower oesophageal sphincter rexation: allows the pressure to be released. Avoids early satiety. Occurs mainly after a meal (MMC abolished). Signalling upper GI tract during and after food intake Duodenal and Jejunal Breaks (top right): after a certain amount of food is let through pyloric sphincter, vagal afferents signal the motor nuclei (brainstem) vagal efferents to reduce contractions, reduce opening of pyloric sphincter and enhance relaxation. The Ileal Brake: Fat reaches the ilium and sends a signal to break/slow down gastric digestion. Ileal break: mediated by peptide YY. Glucagon-like peptide-1, oxyntomodulin. Conditions that are involved with the described movements: Gastro-oesophageal reflux: failure to clear acid/dysfunctional lower oesophageal sphincter. Early satiety/nausea: incomplete gastric accommodation. Neuropathy: diabetes, dysrhythmia: nausea (gastroparesis), obesity: poor feedback control. Colon and Rectum Ascending: mixing, absorption, fermentation. Slow transit. Rich in living bacteria. It is a site of fermentation and absorption of water ions, nutrients. Formation of haustra: increases surface area. Retropulsion, segmentation: movements that churn and slow the transit. Movements controlled by ICCs and local mediators (5-HT). 5-HT3 receptor antagonist: could lead to constipation. Transverse: absorption, relatively rapid transit. Descending: storage, slow, partly involuntary transit. A series of mass movements usually persists from 10-30min, they cease but return every 12 hours. Rectum to Anal Movements 1) As contents push rectum, pressure increases passively. Active contraction: can cause further P. The external sphincter contracts and the internal anal sphincter relaxes (first part in image) 2) Contents continue to enter rectum, triggers conscious urge to defecate. Defecation Histology of the Gut (Notes in microanatomy) Learning Objectives Outline the basic components that make up the wall of the alimentary tract. Define the acronyms MALT and GALT. Describe variations in the basic wall plan at sites (i.e. junctions, retroperitoneal regions). Describe the changing nature and function of the mucosae in the alimentary tract. Explain how the mucosa of the small intestine is adapted to increase its surface area for absorption. Outline the cellular composition of the epithelia in each part of the alimentary tract. 1. Alimentary Tract: Oral Cavity: Stratified squamous epithelium, salivary glands, specialised structures (e.g. teeth) Simple Passages (Oesophagus, anus): Stratified squamous, transport of food/waste. Digestive Tract (Stomach, intestines): Mucosal and accessory glands (pancreas, enterocytes, liver) Fragmentation Digestion Absorption Elimination 2. The Gut Wall Basic Plan 1. Mucosa: varies with region and function: contains epithelium, LP, MM. 2. Submucosa: Is a thick fibrocollagenous layer that serves to absorb shock. Contains vessels and nerves (and submucosal neural plexus) 3. Muscularis Propria/Externa: Inner circular and outer longitudinal (some alterations. 4. Adventitia/Serosa: found where gut is retroperitoneal (behind the peritoneum): most of oesophagus, duodenum, ascending and descending colon, rectum. Enteric NS: Autonomous ganglia that receive signals from (para) sympathetic nervous systems and spinal sensory afferents. Submucosal plexus: innervating muscularis mucosae, mucosal glands. Mye8nteric plexus: innervating muscularis Propria. 3. MALT/GALT Mucosa (or Gut) associated lymphoid tissue: consist of lymphoid follicles, lymphocytes and plasma cells in the LP, and intraepithelial lymphocytes. Exist to control microbial activity. 4. Oesophagus Mucosa: Has stratified squamous epithelium, non-keratinised. Submucosa: Mucous glands, blood vessels, nerves and ganglion cells, lymphoid tissue. Muscularis Propria: Top 1/3 skeletal- swallowing. Bottom 1/3 smooth – peristalsis Oesophagogastric Junction: change in mucosa from stratified squamous to simple columnar/glandular mucosa (stomach). Occurs at an acute angle. Intra-abdominal pressure in oesophagus greater than intragastric: unidirectional peristalsis. 5. Stomach Glandular mucosa: glands/gastric pits that produce gastric juice (gastric acid, intrinsic factor, pepsinogen). Endocrine cells regulate functions in gastric pits, stem cells repair Churning: mechanical and gastric juice: chemical digestion. The mucosa: protected by a thick alkaline mucous layer that is secreted by cells of the columnar surface and mucous neck cells. Bolus chyme. (Part of stomach: cardia, fundus, body and pylorus covered in another lecture. 6. Small Intestine Gastroduodenal junction: pyloric sphincter occurs (circular MM thickens). Increasing SA for absorption: Plicae circulares: circular folds including submucosa in jejunum and ileum. Villi: extension of mucosa, at bases of intestinal glands (crypts of Lieberkuhn). Have a main core that consists of lamina Propria (contains areolar c.t, smooth muscle from MM, GALT, capillaries, central lacteal, nerve fibres). Microvilli: apical processes, ‘bush order’ = aids terminal digestion of proteins and carbohydrates, peptidases and disaccharides. 7. Large Intestine Absence of villi: only tubular glands in mucosa. Have more goblet cells compared to enterocytes. Outer longitudinal muscularis propria organised in 3 bundles: taeniae coli: act to sacculate colon: forming haustra. Descending and ascending colon are retroperitoneal: covered by adventitia. The rest is covered by the serosa. Large intestine contains: Tubular glands in mucosa GALT (Gut associated lymph) in LM. Circular Muscle Layer Three longitudinal muscle bands: taeniae coli. Mucosa: typical mucosa with tubular glands, numerous goblets cells absorptive enterocytes. (Rest covered in microanatomy practical). Body Fluid Compartments and Water Balance Learning Objectives Titles 1. Name main fluid compartments of the body: comment on volumes and cations. Water gain: food (30%), drink (60%), total (90%), metabolism (10%) Water loss: urine (60%), faeces (4%), insensible losses (28%), sweat (8%) Rates of fluid movement in digestive system Ingested water ~ 2 litres, Liver and pancreatic secretions ~ 2 litres, Salivary gland secretions ~ 1.5 litres, Secretions by glands of stomach and small intestines ~ 3.5 litres. Small intestine absorbs ~ 8.5 litres Colon ~ 400ml, Faeces ~ 100ml Components of the body fluid compartments Analogy: The cell is an island. The sea is NaCL (ECF). On the island there is a banana tree made up of lots of potassium and phosphate (see diagram in LO 3) 2. Distinguish between terms osmolarity and osmolality Solutes: electrolytes (inorganic) and non-electrolytes (glucose, lipids, creatinine, urea). Osmotic Pressure: process that controls movement of solvents (water) across a membrane. Osmolarity: osmoles/solutes per litre (Osm/L) Osmolality: osmoles/solutes per kg (Osm/kg) (preferred). 3. Understand how water and solutes are transported across cellular membrane. Plasma and interstitial fluid are in equilibrium. 4. Explain how total body water and total body sodium are regulated Sodium and water homeostasis Na+ is an extracellular cation. Determinant of plasma, ECF osmolality: where Na goes water follows. Regulated by CNS, hormones, kidneys 1. CNS and thirst mechanism - Subfornical Organ (SFO) - Organum Vasculosum of Lamina Terminalis Structures: extensive vasculature, lack of blood brain barrier. Link the CNS and peripheral blood flow. Main stimulus: increase in plasma osmolality Increase in plasma osmolality of 1%-2% or a decrease in plasma volume of 10% - 15%. Thirst centre: anterior hypothalamus. 2. Hormonal Regulation of Low Plasma Vol. Antidiuretic hormone (ADH): Released from posterior pituitary (plasma osmolality detected by osmoreceptors, plasma volume by baroreceptors of great veins or right atrium. ADH: cells of the distal tubule and collecting duct are made permeable to water. Target aquaporins. Aldosterone: Released from adrenal cortex when “reduced Na+” or “increased K+”. Targets Na+/K+ ATPase and epithelial Na+ channel (ENaC) are cellular targets of aldosterone. 3. Hormonal Regulation of High Plasma Volume: Atrial natriuretic peptide (ANP) cardiac atria release when increased blood volume (stretch). Produces effects, which bring blood volume, back towards normal including increased Na+ secretion. Targets the JGA of kidney, the hypothalamus and adrenal cortex. 5. State typical values for osmolality of urine and daily urine production. In the kidney: 80% of water is reabsorbed in the proximal tubule 24-hour urine osmolality: 500 and 800 mOsm/kg Random urine osmolality: 50 to 1400 mOsm/kg 12-14 hours of fluid intake restriction: greater than 800 mOsm/kg EXTRA: Lactose intolerance: Most of the world’s population. Mutations in gene coding for lactase or sodium-dependent glucose transported means lactose is not digested. It ferments and causes symptoms. EXTRA: Plasma Osmolality Normal plasma osmolality: 0.3 Osm/kg Agents with > 600-mOsm/kg crenation (hypertonic) Agents with < 150-mOsml/kg haemolysis (hypotonic) The gut introductory lecture (No notes required) Digestion and Absorption Learning Objectives List the main energy sources present in food. Describe the roles of the salivary glands, stomach, liver, pancreas and small intestine in the digestion of carbohydrates, lipids and proteins. Distinguish between portal and lymphatic routes of nutrient transport. Describe the main characteristics of the transport systems for amino acids and monosaccharaides. Explain how digested lipids are absorbed by the intestinal epithelium. Describe how the lipids are transported out of the enterocyte. 1. Mouth Salivary Glands Parotid Glands: serous saliva (watery: rich in amylase): for breakdown of food. Sublingual and Submandibular: mucous and serous secretions (proline rich proteins). Is a lubricant and plays a role in protections vs microbes. Structure: Have a serous acinus (contain amylase in zymogen granules) and a mucous acinus. They secrete an average of 1.5L of saliva/day Ionic composition altered at striated, excretory ducts (HCO3). Controlled mainly by parasympathetic signals from superior and inferior salivatory nuclei (release Ach on M3 receptors) Amylase: Acts on 1,4 glycosidic bonds in starch (does not break down terminal 1,4 or branch 1,6 bonds) di, trisaccharides (maltase) and branches oligosaccharides. Stops @low ph. 40% of starch is converted. 2. Stomach (Structure covered in pervious lecture) Gastric Juice: 2L per day. Contains HCL, salts, pepsin, mucus, water, intrinsic factor, bicarbonate. High potassium (higher than in plasma): prolonged vomiting causes hypokalaemia. Gastric Pits: contain various cells. Mucous Neck Cell: cover epithelium mucous Stem Cell: repair damaged epithelium Parietal Cell: secrete HCL Chief Cell: secrete pepsinogen Endocrine Cell: Release hormone molecules Control of Gastric Acid Secretion: Driven by gastrin, released from G cell (antral region) in response to presence of peptide. Stimulates CCKB receptors on parietal cells to release HCL/acid/H+. Stimulate CCKB receptors on enterochromafin like cells (ECL): release histamine (stimulates acid secretion from parietal cells) Inhibitory: release of somatostatin from D cells inhibits G cells, ECL cells and parietal cells Excitatory: vagal to G cells, ECL, parietal Pepsin: Secreted as inactivated pro-enzyme pepsinogen (from chief cells). Secretion promoted by gut hormones. Gastrin, secretin (duodenal S cells), acid in the gastric mucosa and Ach (parasympathetic) Pepsinogen pepsin: by the cleaving of acid liable linkages (lower pH the faster pH3>). Pepsin also converts pepsinogen. Catalyses the hydrolysis of peptide bonds. 3. Pancreas - Secretes up to 1.5L/day - Secretions contain: Aqueous HCO3 (neutralise chime, promoted by secretin, acid) Enzymes: promoted by CCK: released from duodenum I cell by fat and peptide. Also by Ach: neuronal b ENS/vagovagal). Gastopancreatic: increase in pancreatic secretion induced by distention of the corpus of the stomach. Duodenopancreatic: Food entering duodenum. Pancreatic Enzymes: Inactivated enzymes: include trypsinogen, chymotrypsinogen etc.… Trypsin: trypsinogen trypsin (duodenum) by enteropeptidase. Trypsin: conversion of more trypsin. Trypsin also converts chymotrypsinogen to chymotrypsin, procarboxypeptidase carboxypeptidase Trypsin Inhibitor: found in pancreatic juice, prevents premature activation in pancreatic ducts. Activated enzymes: secreted in activated form Examples: pancreatic amylase, pancreatic lipases. They are very active: can digest all proteins and sugars in absence of gastric/salivary activity. Bile Salts and Fat Digestion: Bile salts are synthesized from cholesterol (cholic acid and chenodeoxycholic acid). Promotes emulsification of fat into droplets. They are secreted from hepatocytes into canaliculi and ducts, stored in gall bladder, stimulated by CCK, gastrin and acetylcholine. They are reabsorbed in the ileum and send back to the liver through the hepatic portal vein: enterohepatic circulation of bile. 4. Small Intestine Duodenum: Bruner cells: found under the sphincter of Oddi. Produce a mucus-rich substance with bicarbonate to protect the duodenum and provide alkaline to neutralise gastric juice. Ileum: Peyers Patch: important part of lymphoid tissue that monitors/prevents growth of microbes. Jejunum: Area in between the duodenum and ileum. Fat Breakdown: Breakdown of emulsified fats: Micelles: nanometre particles of lipid digestion. Micelles: consist of two monoglycerides due to the action of ester hydrolase (+ colipase peptide) on triglycerides. Cholesterol is also broken down by cholesterol esterase. Fat Absorption: Micelles move through the brush border: fatty acids, cholesterol and phospholipids are absorbed. Bile salts are retained in lumen and only reabsorbed in lumen. Enterocyte: Fatty acid binding protein: transports fat to sER where they are remade to triglycerides, cholesterol ester or phospholipids. These are then packaged into chylomicrons. These are secreted into the lacteal of lymph circulation. Rejoins venous circulation at subclavian vein. Carbohydrate digestion: Lactase: lactose glucose + galactose. Sucrase: sucrose fructose + glucose (Two examples, there are many more) Transport in small intestine: Glucose and Galactose: Na+/Glucose co-transporter in the apical membrane (SGLT1) Fructose: Facilitated transporter in apical membrane (GLUT5) All three: Facilitated sugar transported in basolateral membrane (GLUT2) carries all 3. Peptide digestion: Also move across brush border Amino Acid Absorption: ~90% of a.a that enterocytes transported across basolateral membrane, 10% serves intracellular protein synthesis. 5 Transporters: 3 Na+ dependent, 2 Na+ independent. Hepatic Portal System: drains nutrients and transfers them to liver. Gastric Secretions Learning Objectives Define peptic ulcer and describe the symptoms of ulceration. Describe the most common cause of peptic ulcer and how this cause is eradicated and a cure effected. Important group of ulceragenic (ulcer causing) drugs. Comment on possible mechanism which may underline this effect. Explain the mechanism of action of a named proton pump inhibitor used in the treatment of ulceration. Outline the use of H2 blocking drugs in the treatment of gastric ulceration. Describe the therapeutic treatment of gastro-oesophageal reflux disease (GORD). 1. Salivary Secretions Amylase: An enzyme, polysaccharides disaccharides Lysozyme: Enzyme that lyses bacterial membranes Bicarbonate: A buffer that neutralizes food and bacterial acids Growth factors: Stimulate epithelial proliferation to protect the oesophageal epithelium from breaking down. Transcobalamin II: Binds to vitamin B12: prevent breaking down stomach 2. Gastric Luminal Secretions Mucous: most common on luminal surface, extend down into glands as “neck cells” Secrete bicarbonate rich mucus: coats and lubricates gastric surface (protects) Acid: HCL from parietal cells, activation of pepsinogen pepsin, inactivation of bacteria. Proteases: Pepsinogen: inactive zymogen from mucous cells and chief cells. Activated by low pH into active pepsin which digests proteins. There is also chymosin: coagulates milk protein Lipase: initiates triglyceride digestion. Intrinsic factor: glycoprotein from parietal and chief cells: binds vitamin B12 in intestine so that it can absorbed. Gastric Epithelial Cells: Green circle: active transport protein (proton pump). Pumps out hydrogen ions in exchange for potassium ions (electrically neutral). Bicarbonate can diffuse out of the cell back into the plasma. This leads to an increase in pH away from the stomach. Chloride shift to keep this electrically neutral (this is also done by an active transport protein). Gastric pits contain canaliculi (secretory network in the parietal cell) that transport hydrogen ions/acid to the top of the cell so that it can be secreted through the mucus layer into the lumen. It prevents the parietal cell from being damaged. 3. Feedback Control of Acid Secretion Vagus: Integration into the enteric nervous system, post-ganglionic nerves innervate. Secretes Ach via the M3 muscarinic receptor to control secretion on the parietal, ECL, D cell (inhibitory). Also innervates G cell via GRP receptor. ECL Cell: releases histamine. Acts on the histamine H2 receptor on the parietal cell: secretion. Histamine secretion stimulated by somatostatin from D cell. Somatostatin: come from D cells. Connects to the G cell via SRR, inhibts secretion. G-Cell: Secrete gastrin that connects to parietal cell through CCK receptor, increases secretion. Caused by the digestion of proteins and amino acids. D Cells: Inhibits parietal cell through a paracrine pathway on the SSR receptor. It is inhibited by the vagus nerve via the M3 muscarinic receptor. Neural Control of Gastric Secretion. Three phases of control and where they are mediated. Cephalic: (responds to sight, smell, taste, thought of food). 30% of acid secretion: before food enters stomach. Sensory/mental inputs converge on hypothalamus, relays signals to medulla oblongata. Vagus fibres stimulate parasympathetic NS of stomach: stimulates secretion (via parietal and G cells). Gastric: Swallowed food activates gastric activity by stretching the stomach. Vasovagal reflex distention activates an afferent pathway: dorsal nucleus of vagus nerve: stimulates acid secretion. Local ENS pathway: activated ENS to release ACH: stimulates parietal cells. Proteins broken down into peptides: also, activates G cells to secrete more gastrin, accelerates protein digestion. Stimulates ECL to produce histamine (looked at above). Intestinal: 5-10% of gastric secretion. Duodenum responds to arriving chyme. Acid and semi-digested fats in duodenum trigger enterogastric reflex. Sends signals to medulla, inhibits vagal nuclei, stimulate sympathetic neurons, sends inhibitory signals to stomach. Peptic Ulcer Disease Main cause: Helicobacter Pylori. Mechanism: Pylori thrives in environment of epithelium. Produces ammonia, acidifies the stomach (more comfortable for organism) (Urea NH4). This destroys the mucous layer so acid can act on the epithelium. Around 50% of world population is infected. Diagnosed through the urea breath test. Treatment: Combination therapy consists of antibiotics and PPI (proton pump inhibitor). Further Therapy of Peptic Ulcer Disease: Histamine (H2) receptor antagonists: cimetidine, ranitidine, famotidine. Proton Pump Inhibitors: Omeprazole (blocks the proton pump). Large spectrum of drugs. Gastro-Oesophageal Reflux Disease (GORD) Reflux: Retrograde flow of gastric contents into oesophagus causes reflux (not GORD) GORD = retrograde flow causes troublesome symptoms, occurs in 10-20% of population. This is not caused by HCL secretion: caused by: Excessive reflux of normal gastric juice (TLOSRs) Weakened oesophageal epithelium. Hypersensitivity of oesophageal pain sensing nerves. Treated with PPIs, neurological drugs (baclofen: reduces TLOSRs). Glycolysis and Glucose Oxidation Learning Objectives Outline the mechanism of glucose uptake into cells. Distinguish between the facilative glucose transporters (GLUT's) with respect to tissue distribution and kinetic characteristics Understand how the pentose phosphate pathway links with glycolysis and its role in providing NADPH and ribose 5-phosphate. Understand the significance of the regulatory and kinetic characteristics of glucokinase and hexokinase: tissue locations and physiological roles. Phosphofructokinase is the major control point of glycolysis. Specify how it responds to cellular messages. Understand that glycolysis can produce ATP by substrate level phosphorylation. Understand how glycerol and fructose enter the glycolytic pathway. Outline the potential fates of the pyruvate produced by glycolysis. Understand the physiological importance of PDC. Understand the regulation of PDC by allosteric mechanisms and by reversible phosphorylation. 1. Glucose Hypoglycaemic: to little glucose in blood. Hyperglycaemic: too much glucose in blood. Average 4g of glucose circulating, brain uses about 60%. Glycolysis: breakdown of sugar Pentose Phosphate: important pathway for anabolism. Gluconeogenesis: making of sugar. Glucose uptake: Facilitated transport. 12 Glucose transporters (GLUT) GLUT 1: Constitute (Low Km = easily saturated) provides cells with glucose GLUT 2: Liver/pancreas (High km = works with high conc to allow response/sense to high/low levels). GLUT 4: Glucose muscle and adipose (controlled by insulin), Low Km. Role of Hormones: Pool of GLUT4 in vesicles. They are recruited to the membrane when insulin is present/increased secretion. Also promoted during exercise. 2.1 Glycolysis: Hexokinase and Glucokinase (1) In this step, glucose is converted to glucose-6-phosphate (irreversible). It uses up one ATP (catalysed by the enzyme hexokinase. This step is sensitive to feedback inhibition, which means that if there are enough glucose-6-phosphates produced hexokinase is inhibited. Glucokinase: another enzyme that catalyses this step in the liver and pancreas. Not sensitive to feedback inhibition (and his a higher km), ensures that the liver and pancreas (through beta cells) can sense and control amount of glucose. Glucokinase Regulatory Protein (GKRP): controls their location. In high sugar, it is promoted to regulate GKRP. (2) Isomerisation: The process of rearranging a molecule to rearrange the energy. In glycolysis glucose-6-phosphate is rearranged to fructose-6-phosphate: makes the steps chemically easier. 2.2 Glycolysis: Phosphofructokinase-1 (3) Phosphofructokinase-1 removes a phosphate group from ATP and gives it to fructose-6-phosphate to make fructose-1, 6-biphosphate (irreversible). High levels of ATP and citrate inhibit this step (the cell no longer needs to make ATP) = markers of energy need. Phosphofructokinase-2: Acts on fructose-6-phosphate to form fructose-2, 6-biphosphate: this is done if the level of fructose-6-phosphate is too high. 2.3.Glycolysis: 6 Carbons to 3 Carbons (4): Fructose-1, 6-bipshosphate is cleaved to give two 3C products: Dihydroxyacetone Phosphate (Rearranged into: G3P) Glyceraldehyde-3-Phosphate: Used to continue the process. Up to this point: glycolysis has only used ATP. (5) Both glyceraldehyde-3-phosphate are oxidised to form 1,3-biphosphoglycerate by a glyceraldehyde phosphate dehydrogenase: in this step NAD+ is made to NADH. (6) In the next step, phosphoglycerate kinase transfers a phosphate from 1,3-biphosphaglycerate to ADP to form ATP and 3-phosphoglycerate. (7) Phosphoglycerate phosphoenolpyruvate (PEP). PEP is an unstable molecule that through pyruvate kinase donates a phosphate to ADP to form ATP and pyruvate. 3. NAD In Glycolysis NADH: required for 1st ATP production. In aerobic conditions NADH feeds respiratory chain, in anaerobic conditions this is regenerated (NADH NAD+) to form lactate. 4. Glycerol Glycerol = formed from the breakdown of fat. Metabolised in the liver to form Dihydroxyacetone phosphate (converted to glyceraldehyde-3-phosphate to generate an extra ATP) 5. Fructose Common sugar in diet, it tastes x10 sweeter than glucose. Can also be metabolised by hexokinase to form fructose-6-phosphate. Glycogen Synthesis and Mobilisation Learning Objectives Describe the structure of glycogen Describe the role of liver glycogen as a source of blood glucose during normal feeding cycle Discuss the circumstances under which glycogen synthesis and degradation will occur. Discuss how the key enzymes glycogen synthase and glycogen phosphorylase are controlled by reversible phosphorylation Explain the different roles of glycogen storage in muscle and liver in relation to the metabolic fate of glucose-1-phosphate 1. Glycogen Liver (~100g): Glucose absorbed 2-3 hours after a meal. If not eating, liver glycogen is used to maintain glucose levels in the blood. Muscle (~400g): Glycogen to act during bursts of activity. Storage: glycogen is a glucose store. It is less osmotically active then glucose. It is converted in the liver to maintain blood glucose, or to ATP via anaerobic/aerobic mechanisms in the muscle. Structure: Starts with a protein primer: glycogenin (extended with 1-4 links to form a chain). Glycogen has a branched structure: the more branches = the more ends so the faster it can be broken down and build again. Branching enzymes create 1-6C linkages every 12-14 residues. 2. Glycogen Metabolic Pathways For glucose to be converted to glycogen (SYNTHESIS): (1): Glucose-6-phosphate is converted to glucose-1-phosphate. (2): Glucose-1-phosphate is converted to UDP-Glucose. The energy from this reaction comes from uridine triphosphate (UTP) catalysed by UTP—glucose-1-phosphate uridylyltransferase (enzyme). (3): Glycogen is synthesized from monomers of UDP-glucose initially by the protein glycogenin. UDP is removed to form 2.1 Control of Glycogen Synthesis Various phosphorylation sites control glycogen synthase activity. (1) Dephosphorylation by insulin: activation of protein phosphatase-1 (increases GS activity). (2) GS phosphorylated by Protein Kinase A and Phosphorylase Kinase (decreases GS activity controlled by cAMP, glucagon, and adrenalin). 3. Control of Glycogen metabolism Insulin: increases glucose storage (glycogen synthesis) when high glucose levels (beta cells) Glucagon: Breaks down glycogen to release glucose into blood when low glucose levels (alpha cells) 4. Glycogen Breakdown Liver: Breakdown of glycogen catalysed by glycogen phosphorylase (breaks 1-4 links by adding in a phosphoryl group). G6P can then by dephosphorylated and exported as glucose). This maintains blood glucose levels during short term fast (stimulated by glucagon) Muscle: All glycogen breakdowns in muscle feeds into glycolysis and energy production in that cell only. Can be a medium term energy supply for muscle. Cannot be converted to glucose to be exported. Under anaerobic conditions: glycolysis produces lactate (stimulate by adrenalin) Control of Breakdown: Adrenalin and Glucagon activates adenylyl cyclase to convert ATP to cAMP. In turn, cAMP activates Protein Kinase A (PKA) to convert ATP to ADP. This used to convert phosphorylase kinase b into phosphorylase kinase a, which then acts as an enzyme to convert ATP into ADP: this is used to convert glycogen phosphorylase b to glycogen phosphorylase a. Glycogen phosphorylase cleaves glycogen to produce glucose-1-phosphate, which can then be converted to glucose-6-phosphate.. SUMMARY Glucagon/Adrenaline: phosphorylates, glycogen breakdown (phosphorylase), increases cAMP Insulin: dephosphorylates, glycogen synthesis, breakdown cAMP. 5. Disorders of Glycogen Metabolism There are various autosomal recessive diseases. Specifically: looking at Type V: McArdles. McArdles: deficiency in glycogen phosphorylase in muscle tissue. It is autosomal recessive, patients struggle wit exercise at first and need a “2nd wind”. Rapid exercise causes muscle damage due to low ATP, so patients need to avoid fast bursts of exercise. Anterior Abdominal Wall Learning Objectives Describe the arrangement of the muscular layers of the anterior abdominal wall Explain the origin of the layers of the spermatic cord Describe the basic anatomy of the inguinal ligament Explain where hernias commonly form and why 1. Intercostal Muscles (Review) External Intercostal: “hand in the pocket”: running inferiorly and anteriorly. Involved in inspiration. Internal Intercostal: Opposite of external direction (superiorly and posteriorly). Expiration. Innermost Intercostal: Some direction as internal intercostal. 2. Muscles of Abdominal Wall They are found laterally: external and internal oblique, transversus abdominis. External Oblique: most superficial. Runs inferiorly and anteriorly (in the same direction as the pectoralis major). It runs until mid-clavicular line, where it stops at its aponeurosis (sheet of white fibrous tissue which takes the place of a tendon in sheet-like muscles the external oblique aponeurosis). Internal Oblique: The most middle layer of abdominal wall, runs from ribs superiorly to iliac crest inferiorly, runs in anterior-superior direction (opposite of external oblique) Transversus Abdominis: Deep layer of abdominal muscle runs across a transverse plane (reality: hard to differentiate). Rectus Abdominis: Runs from the xiphoid process to pubic synthesis. It contains tendionous intersections along the length of the muscle (these give the definitions of a “six pack”). Linea Alba: fibrous section that runs down along the midline the rectus abdominis. 2.1 Rectus sheath The Rectus Abdominis is enclosed by aponeurotic sheath (rectus sheath), which is derived from aponeurosis of the external oblique, internal oblique and transverse abdominis (sheath has a different structure above and below the arcuate line). The abdominal wall is innervated by the internal thoracic arteries (comes from subclavian arteries). Run either side of the sternum. Don’t end at the thorax change name to become the superior epigastric arteries. Inferior epigastric arteries arise from the internal iliac. 3. The Pelvis (Inguinal Ligament) Consists of the ilium, ischium, and pubis. You should be able to palpate the anterior superior iliac spine and the pubic tubercle: the free border between this inguinal ligament. The external oblique’s aponeurosis (it’s inferior border) rolls under itself to creative the inguinal ligament. Within this ligament is the inguinal canal: complicated structure that contains femoral nerves, arteries and veins. The spermatic chord also passes through this. Men: testes develop in abdomen (posterior wall) and descend through the inguinal canals to reach the scrotum (occurs through development of foetus). The space that is leaves behind: “weak point”. Hernia: (internal part of the body passes through a weakness). Can cause for direct (acquired, rarely enters scrotum) and indirect (congenital: present from birth, commonly enters scrotum). 4. Regions of the Abdomen √ 5. Oesophagus (Review) Contains three constrictions: Cervical constriction (upper oesophageal sphincter) Thoracic constriction (crossed by aortic arch end left main bronchus) Diaphragmatic constriction (piercing of diaphragm). Enters the stomach at the cardinal orifice (7th costal cartilage, left midline). The oesophagus is innervated by the vagus nerve. 6. Stomach Inside the stomach there are loads and loads of folds: rugae. Oesophagogastric Junction: change in mucosa from stratified squamous to simple columnar/glandular mucosa (stomach). 7. Duodenum, Jejunum, Ileum Second part of the duodenum curves around the pancreas (pancreas empties all of it’s digestive enzymes). The jejunum: fond largely in left upper quadrant, whereas the ileum in right lower quadrant. Jejunum Ileum: contains Peyer’s glands. Large Intestine ---------------------------------------------------------------------------------------------------------------------------------- Mouth to Oesophagus Learning Objectives Describe the peripheral branches of the facial nerve and the muscles of facial expression Describe the peripheral branches of the trigeminal nerve, the sensory innervation of the face and the muscles of mastication Outline the peripheral course and distribution of the hypoglossal nerve, glossopharyngeal nerve and the lingual nerve and thus demonstrate an understanding of the motor and sensory innervation of the tongue Describe the anatomy and the nervous innervation of the salivary glands and ducts State the anatomical arrangement and function of the tonsils and adenoids within the walls of the pharynx Define the boundaries and describe the major features of the naso, oro and laryngopharynx Outline the nervous innervation of the pharynx, the control of swallowing and the gag reflex Outline the course and the branches of the external carotid artery Describe the layers and the nervous innervation of the oesophagus Explain how the gastro-oesophageal junction contributes to the prevention of reflux Cranial nerves (12): Will be looking at (5) Trigeminal, (7) Facial, (9) Glossopharyngeal, (10) Vagus and (12) Hypoglossal (innervate mouth to oesophagus). Colour of CN: purple 1. The Mouth Lips: entry/exit to the mouth (Facial nerve) Teeth: moves by muscles of mastication (mechanical digestion of food): Mandibular branch of the trigeminal nerve Salivary glands: chemically digest food (Facial, glossopharyngeal) Tongue: moves food to the back of the mouth (Hypoglossal) Soft palate: elevates to prevent passage of food into nasal cavity (vagus) Tonsils: immunological defence. Mandible and Maxilla: Maxilla superiorly, mandible inferiorly. Mandible consists of two fused bones: 90 degrees to the body ramus. Contains a coronoid process (for temporalis muscle) and a head (condyle: temporomandibular ligament). The internal aspect of the mandible contains the mandibular foramen (entrance of inferior alveolar vessels) Lips: Orbicularis oris (circular muscles around lips that act as a type of sphincter). Innervated by the facial nerve. This is one of the muscles of facial expression (all innervated by the facial nerve). Another type: Buccinator, which makes up the cheek. Underneath facial nerve: carotid gland. Trigeminal nerve (V): provides sensory information for the entire face. Three branches: ophthalmic (V1), maxillary (V2) and mandible (V3). Important for teeth (no motor but sensory supply) Teeth: Lower teeth Innervated by the mandibular part (V3) of the trigeminal nerve. Upper teeth innervated by the maxillary part (V2) of the trigeminal nerve (note superior and inferior alveolar nerves) Muscles of Mastication: group of muscles all innervated by the mandibular branch of the trigeminal nerve. Collectively move the mandible with respect to the facial skeleton. Four different muscles: Temporalis (temporal region): sits on coronary process or ramus, muscles fibres: like a fan Vertical fibres: Pull jaw upwards (elevation) Horizontal fibres: Pull jaw backwards (retraction) Masseter: Mainly involved in elevation, also does some protrusion due to angling. Lateral Pterygoid: Depression and protrusion Medial Pterygoid: Elevation and protrusion 2. Salivary Glands Three major salivary glands in head and neck, each receiving parasympathetic nerve supply Parotid: Main gland, supplied by the glossopharyngeal nerve, facial nerve runs through it. Drains to the mouth via the parotid duct (level of upper 2nd molar) 2. Sublingual and Submandibular: Supplied by the facial nerve. 3. Tongue Composed of two groups of skeletal muscle: intrinsic and extrinsic muscles. Covered by a mucous membrane, receive motor output from the hypoglossal nerve. Made up of a 1/3 posterior part and 2/3 anterior parts. The posterior part has a different type of tissue than anterior part: lingual tonsils. Vallate papillae: landmark that separates the two (V shaped line of specialised taste buds). The foramen cecum is located at the apex between the anterior and posterior parts. Important to know the difference, have difference nerve supplies for two different senses: general (sense of touch, pressure, pain temperature) and special (taste) Chordae tympani (from the facial) run along the lingual nerve (from the mandibular of the trigeminal nerve): looks like they fuse. 4. Soft Palate Hard Palate: composed of the maxilla and palatine bones. The soft palate is composed of muscles covered by a mucous membrane (elevates when food is being swallowed to prevent entrance into the nasal cavity). Soft palate: innervated by vagus. Uvula is part of the soft palate. Other parts of the soft palate: arches. Palatine Tonsils: collection of lymphoid tissue on each side of the oropharynx, palatine arches. Swallowing: Tongue pushes bolus of food to the back of the mouth. The larynx pushes up/pulled upwards: epiglottis on of the larynx closes, food goes posteriorly to oesophagus. 5. Pharynx and Oesophagus Sensory information from the pharynx is from the glossopharyngeal nerve. Constrictor Muscles: innervated by the vagus nerve, constrict to push bolus to oesophagus (superior, middle, inferior). Stylopharyngeus: elevates pharynx during swallowing, innervated by the glossopharyngeal nerve Gag Reflex: response to touching the posterior pharyngeal wall (activates glossopharyngeal nerve) and involves a brisk/brief elevation of soft palate, contraction of pharyngeal muscles (vagus nerve). Abdominal Clinical Skills (No notes required) Gut as an Immune Organ Learning Objectives Appreciate that the gut is a highly vulnerable tissue, susceptible to infections. Realise that only a single layer of epithelium separates the gut lumen from the tissues. Appreciate that the gut contains the majority of the immune system in the body IgA is the secretory immunoglobulin While the gut epithelium is absorbing nutrients, it is also transporting large amounts of IgA into the gut lumen Absence of T cells in the gut leads to chronic low grade infections That mucosal protective immune responses are generated in Peyer's patches and expressed in lamina propria 1. Introduction Large structure on the right of an image: lymph node. Blue stained dots: lymphocytes, present in all villi. Within the lymph node B cells and T cells can be found, as well as IgA plasma cells. Core of villi: CD4+ helper cells Epithelium: CD8+ toxic cells HIV: Kills T cells in the gut: so, the gut is not able to protect itself from low grade pathogens. Treatment lies in HAART therapy, which has shown to restore levels of CD4 cells (completely depleted during HIV). Harmless Antigens: Gut is exposed to 10^13 that sit mainly in the colon. The immune systems job is to recognise self from non-self, and harmless from non-harmless. Non-responsiveness to harmless antigens is maintained by T reg cells: a class of CD4+ helper cells. Oral Tolerance: a type of peripheral tolerance (one that stops lymphocytes from attacking bodies own tissues and harmless) that is induced by antigens (such as food proteins) given orally. The mechanisms that make this occur are complex: T cell deletion, T cell anergy etc… 2. Pathogens in the Lumen Peyer’s patch (PP): organised lymphoid follicles (elongated patches of interstitial epithelium. These monitor intestinal bacteria and preventing growth of pathogenic bacteria. They exhibit prominent B cell zones with germinal centres. They are highly active and divide all the time (mutations). M (Microfold) Cells: Specialized epithelial cells: MALT. Involved in phagocytes that engulf antigens and transport them from the lumen to lymphocytes nearby (initiating a response/tolerance). Basically, everything antigen put into the gut is taken up by M cells. The T and B cells activated by gut antigens in the Peyer’s patch leave and migrate to the lamina propria through the lymphatic system. The activation of peyer’s patches and mucosal lymphocytes depends on bacterial flora. 3. Gut Homing Gut homing is the process by which activated T cells are targeted to the gut to produce an effective immune response when necessary. Mechanism: Gut dendritic cells present to T cells in the presence of retinoic acid (which comes from vitamin A and is converted through the Gut DC. The Gut DC induces lymphocytes to express alpha 4 beta 7 and CCR9 (integrin). Homing is caused by the interaction of the gut cell with these integrins: Epithelial cells make CCL25: the ligand for CCR9 Endothelial cells in the gut express MadCAM (gut addressin), ligand for alpha 4 beta 7. 4. IgA (secretory antibody) In the gut, there are three times as many plasma cells making secretory IgA than in the rest of the body (makes up 80% of the immunoglobin producing cells). IgA is a dimer in mucous secretion (not in plasma). IgM is a pentamer in plasma. These two types of antibodies are bound by a J chain (joining chain). IgA is actively transported across the epithelium by the polymeric Ig receptor (cell is taken in by cell and through transcytosis released into the lumen). IgM also has a secretory component and is also taken into the lumen to sit on the endothelium and protect the gut (increased production in IgA deficiency). IgA is not a good mediator of inflammatory reactions, and you can live without IgA. Their mechanism of action involves agglutination (clumping of particles) so that the pathogen cannot enter the endothelium. This gives effective immunity: the virus cannot survive in the lumen and dies. Lactation: breast endothelial cells express MadCAM and B cells travel to the breast through the thoracic duct from peyer’s patches in the gut to produce antibody IgA. This passing of IgA through the breast milk gives immunity to various pathogens in the baby (newborns have no IgA). Liver Metabolism Learning Objectives Give an overview of the role of the liver in carbohydrate, lipid and protein metabolism Describe the role of the liver in glucose homeostasis Describe how the liver acts as an organ of detoxification Discuss the role of the liver in protein synthesis Describe the storage functions of the liver Describe the components of the biliary tree (including the sphincter of Oddi) Outline the formation and functions of bile Describe the function of the gallbladder and its control Describe the enterhepatic circulation of bile Describe the origin, metabolism and excretion of bilirubin 1. Blood supply to the liver Portal circulation drains the gut, and 75% of blood supply of the liver is therefore portal. This is unusual: most organs have a blood supply of arterial blood. Remaining 25%: arterial. 2. Hepatic Lobule Structural unit of the liver (hard to see in microanatomy). Blood enters through the portal venule (hepatic portal vein: deoxygenated blood from gut) and the hepatic arteriole (oxygenated blood). These two blood supplies mix as the enter the sinusoid and travel to the central vein (to hepatic veins, which drain into the inferior vena cava). The bile duct runs very closely to these, but in the opposite direction (towards the portal field). 3. Carbohydrate Metabolism Most carbohydrate ends up in the liver as glucose (sucrose, lactose, starches are all turned into glucose by being broken down). Glucose is taken in by hepatocytes. In the presence of oxygen, it will feed into the Krebs cycle. Hepatocytes also store glucose in the form of glycogen (through the process of glycogenesis) and can break it back down through glycogenolysis. Hepatocytes can generate glucose through gluconeogenesis (see next lecture) from materials such as lactate, pyruvate, amino acids and glycerol. Insulin: Counteracted by glucagon. Promotes glycogen synthesis Suppresses gluconeogenesis Accelerates glycolysis (increase FA synthesis) 4. Protein Metabolism There are essential and non-essential amino acids (essential need to be taken up through diet). Transamination: transfer of amino group to keto-acid. This is catalysed by transaminase. Alanine and asparate aminotransferases (ALT and AST): are indicators of hepatic injury: hepatocyte dies it releases these enzymes. High concentration ~ hepatic injury. Deanimation: removing an amino group (often forms a keto acid and an ammonium ion). Dangerous: excess ammonia depletes ketoglutarate which is used in the Krebs cycle. Also, NH3 in astrocytes (CNS) excess glutamine. Increased osmotic pressure (water drawn in) which causes swelling (life-threatening). Removal of Ammonia: (also produced by gut bacteria) NH3 is reduced to NH4, NH4+ is converted to urea through the urea cycle. Ammonia is toxic, urea is not and can be excreted. Raised serum urea: could indicate renal failure, as urea is secreted in the kidney. Could also show that there is too much ammonia, a significant increase in the consumption of protein or bleeding in the stomach/stomach ulcers. Plasma Proteins: Plasma: liquid component of the blood: “cell-free”. Contains albumin, globulins, clotting factors, water, glucose and electrolytes. Albumin + clotting factors liver. 90% of plasma proteins are made in the liver. Serum: plasma without the clotting factors. 5. Lipids Lipids are not water soluble and are therefore transported in lipoproteins (arrangement of phospholipid layer with non-soluble material on the inside). Triglycerides can be broken down into fatty acids and glycerol. Fatty acids: acetyl CoA (acetyl group - Coenzyme A) used in respiration, cholesterol synthesis Glycerol: can be converted to glucose in gluconeogenesis. The liver converts excess glucose to fatty acids, synthesizes phospholipids and ketone bodies. Ketogenesis: occurs in the absence of glucose (switched off by insulin). Breaks down lipids and proteins. Fatty acids can then be converted to acetyl CoA to produce ketone bodies (energy). In the opposite scenario (excess), liver produces very low density lipoproteins. 6. Bile Bile is an emulsifier that dissolves fat. It is made in the liver and stored in the gallbladder. Up to 800ml of bile is produced daily. It is secreted by hepatocytes in canaliculi (small bile ducts). It is composed mainly of water (>90%), bile salts, bilirubin, cholesterol, fatty acids, lecithin, Na+/K+/Ca2+/Cl- etc… Cholangiocytes: epithelial cells of the bile ducts, can modify bile (production) by the addition of HCO3-. The bile duct is stimulated by Cholecystokinin (CCK). This hormone is secreted in response to fatty acids being in the lumen of the duodenum. This causes the gall bladder to contract (bile is secreted) and the sphincter of Oddi is relaxed. Secretion of secretin is stimulated by the presence of an acidic chime in the duodenum: stimulates biliary ductal cells. Cholesterol is oxidised to form cholic acid and chenodeoxylic acid, which are conjugated to glycine or taurine. They are secreted as sodium salts, and are involved in the absorption of lipophilic substances (fatty acids, monoglycerides, cholesterol). Bile salts are usually absorbed in the ileum. If not reabsorbed: move through to the colon. This can cause diarrhea due to the increased oncotic pressure of bile salts in the lumen. 7. Cholesterol Exogenous (from diet) or endogenous (synthesized in the liver). Cholesterol is synthesized from acetyl-CoA. Statins inhibit the endogenous production of cholesterol (inhibit HMG-CoA reductase) Bilirubin: RBC breakdown occurs in the spleen (haemoglobin is broken down into heme and globin. The heme element contains iron, and the non-heme part is turned into bilirubin bound to albumin). It is conjugated to glucoronate. Send through the bile duct into the intestine for excretion If flow of bile is obstructed: bilirubin will build up. This can cause jaundice: yellowing of skin. 8. Drug Metabolism Consist of various phases. Example: paracetamol. Excess paracetamol: causes the build-up of NAPQI (toxic intermediate). This toxic intermediate can be interfered by gluthoine, but only if the person is healthy. Cysteine: treatment of overdose. Gluconeogenesis Learning Objectives Define gluconeogenesis and state the tissues in which gluconeogenesis is active. State the circumstances under which gluconeogenesis will occur. Understand that gluconeogenesis is the reverse of glycolysis, paying attention to the by-pass steps (glucose 6-phosphatase, fructose 1,6-bisphosphatase, phosphoenolpyruvate (PEP) carboxykinase, pyruvate carboxylase). List the major precursors used for gluconeogenesis, and identify their tissues of origin. Describe how fatty acid oxidation facilitates gluconeogenesis. Outline the hormonal regulation of gluconeogenesis 1. Gluconeogenesis Done by the liver, becomes important during times of prolonged starvation. Initially, blood glucose comes from the liver glycogen stores. However once depleted: glucose synthesis is dependent on gluconeogenesis. Reverse of glycolysis with a few steps changed (thermodynamics): three steps in glycolysis are not reversible. Requires both energy and carbon (lactate, amino acids, glycerol). We cannot use fatty acids to make glucose, fatty acids only provide the energy (they are the ‘fuel’). Mechanism: Glucokinase and phosphofructokinase are bypassed by phosphate enzymes glucose-6-phosphatase and fructose 1,6-biphosphatase (removes phosphate from the sugar and ‘dumps’ it into water/cytoplasm). F1,6BP is also required to produce glucose from glycerol. In glycolysis: conversion of PEP (phosphoenolpyruvate) to pyruvate is one step. However, in gluconeogenesis this is not the case. Pyruvate to PEP conversion requires energy (4 ATPs) and carboxylation. 1. Pyruvate Carobxylase (PC) produces oxaloacetate from pyruvate (CO2 produced, 1 x ATP used) 2. There is no oxaloacetate transporter to carry this molecule back into the cytoplasm, so we use a second enzyme called malate dehydrogenase: there is a malate transporter in the mitochondria so it is transported to the cytoplasm. Previous reaction is reversible it converts back to oxaloacetate. 4. Oxaloacetate in the cytoplasm can then be acted on by phosphoenolpyruvate carboxykinase (PEPCK) drives the reaction to PEP using GTP. CO2 is produces. 2. Fatty Acid Metabolism Fatty acids undergo beta-oxidation to form acetyl-coA and NADH (by fatty acid oxidase) to produce ATP. These products can inhibit pyruvate dehydrogenase (oxaloacetate will not produce acetyl-CoA and instead can be used for glucose formation using ATP from fatty acid oxidation). This ATP is then used to activate pyruvate carboxylase (levels of acetyl CoA regulate activating pyruvate carboxylase). Reason why fatty acids can’t be used to make glucose: oxidation of fatty acids yields enormous amounts of energy on a molar basis, however, the carbons of the fatty acids cannot be utilized for net synthesis of glucose. The two-carbon unit of acetyl-CoA derived from β-oxidation of fatty acids can be incorporated into the TCA cycle, however, during the TCA cycle two carbons are lost as CO2. Thus, explaining why fatty acids do not undergo net conversion to carbohydrate. 3. Gluconeogenesis in fasting and exercise The Cori Cycle: allows for anaerobic metabolism in muscle to occur. Lactate produced form anaerobic metabolism is converted to glucose in the liver. This acts as an energy transport cycle (glucose converted in the liver is send directly back to the liver) and there is no net synthesis. Essentially, the liver puts energy in to form the glucose which is then used. Does not occur in oxygen (the conversion of pyruvate to acetyl CoA must be blocked, done by the oxidation of fatty acids creating more acetyl CoA). If this does not occur, pyruvate feeds into the TCA cycle instead of being made to lactate. Glucose from glycerol and amino acids Glycerol is produced from Triglyceride (TAG) breakdown. It enters as Dihydroxyacetone-phosphate converted Glyceraldehyde-3-Phosphate (and then continues glycolysis/gluconeogenesis). Glycogenic amino acids: amino acids are broken down to produce alanine (hepatic gluconeogenesis) and glutamine (renal gluconeogenesis) through proteolysis in the muscle. Both these processes then produce glucose (as seen in diagram). Analine produces pyruvate which feeds into oxaloacetate in the TCA cycle, while glutamine/glutamate produces alpha-ketoglutarate which is also in the TCA cycle. Control of Gluconeogenesis Gluconeogenesis: controlled by glucagon, adrenalin and insulin. Glucagon: increases cAMP levels and increases activity of protein kinase A (and therefore pyruvate dehydrogenase: converts pyruvate into acetyl-CoA). NOTE: Gluconeogenesis: excessive in diabetes because of increased supply of precursors along with increased fatty acids. Also, increases in glucagon to insulin ratio. Tricarboxylic Acid (TCA) Cycle & ETC LEARNING OBJECTIVES Describe the role of the TCA cycle as a common end-point for energy production from glucose, fatty acids and amino acids. Explain the biosynthetic roles of the TCA cycle. List the regulatory dehydrogenases of the TCA cycle and describe how they are regulated. Understand that glucose and lipid utilisation is reciprocal. Define metabolic inflexibility. Outline the metabolic responses to hypoxia, including the role of HIF, and the mechanisms of hypoxia tolerance. Explain the role of reactive oxygen species (ROS) and antioxidants 1. TCA Cycle Overview Centre of metabolism taking part in glucose, fatty acids, amino acids as well as biosynthesis. PDC = Pyruvate Dehydrogenase Complex Pyruvate Dehydrogenase Complex (PDC): Essentially unidirectional (loss of CO2). Called a complex because it is a three-stage process involving three different enzymes (E1, E2, E3). Important: TPP, Lipoate, FAD are prosthetic groups E1: Thiamine pyrophosphate (TPP) is converted to Acyl-TPP through the decarboxylation (pyruvate to CO2) and acetyl transfer reaction, reaction catalysed by pyruvate dehydrogenase. E2: Dihyrolipoamide acyltransferase: acyl to CoA to form acetyl-coA. E3: Regenerate lipoamide arm through the reduction of FAD to FADH (enzyme: Dihydrolipoyl dehydrogenase). Side reaction NAD is reduced to form NADH + H+ (can be used in ETC). NOTE: TPP from vitamin B1. Heavily Controlled: This step is controlled by feedback inhibition. Also, subject to covalent modification by phosphorylation (done by PDH kinase and protein kinase A responds to cyclic cAMP). If glucose is high, are stimulating pyruvate dehydrogenase, if levels are low are inhibiting it (shifts towards fat metabolism). 3. Products of the TCA: Four oxidation reactions occur (two of which loss of CO2). Because of this loss: reactions are essentially irreversible under cellular conditions. TCA reduces cofactors/coenzymes NADH and FADH. Reduced cofactors feed into the electron transport chain. Electron transfer down electrode potential gradient pumps protons from mitochondrial matrix to inner membrane space. ATP is then produced using the energy stored in this proton gradient as protons flow through it. Components of the ETC: Made up of four complexes: Complex I: Two electrons removed from NADH, transferred to UQ (protons moved) Complex II: (No protons transported across): FADH2: electrons transferred to UQ Complex III: Electrons removed from UQ and transported to Cytochrome C Complex IV: Electrons removed from cytochrome C to combine with O2 H2O. Many of the reactions found here involve metals (copper, iron etc…). 5. Uncoupling Coupling: “electron transport chain and oxidative phosphorylation are coupled by a proton gradient across the inner mitochondrial membrane.” Uncoupling: can use the energy from ETC for other processes such as: 1. Non-shivering thermogenesis: Provides for an alternative flow of protons back to the inner mitochondrial matrix. This alternative flow results in thermogenesis rather than ATP production. Involves an uncoupling protein 1 (thermogenin) in brown adipose tissue. 2. Natural Antibiotics: Gramicidin: forms two half channel: neutralises the charge gradient and kills the bacteria (same in Nigericin, where protein can permeate membrane). Valinomycin: enables dissipation of charge through movement of K+. 3. Dinitro-phenol: can cross the membrane of the mitochondria (carrying a proton or not). It acts as a carrier for proton and neutralizes the charge. This also releases the energy as heat (it’s presence makes you feel hot overheating). Has a very close therapeutic window and lethal dose. 6. Control of TCA and Biosynthesis TCA cycle rate depends on NAD+ availability and is substrate controlled. NAD+ availability depends on ETC rate (linked to ATP to ADP ratio). In muscles, dehydrogenases in TCA cycle (a-ketoglutarate dehydrogenase and isocitrate dehydrogenase) are stimulated by calcium. Also substrate regulation via oxaloacetate needs to be “topped up”. Enzyme that’s involved with this: pyruvate carboxylase. 7. Changes in oxidative metabolism in hypoxia Hypoxia: reduce the amount of oxygen results in reactive oxygen species/radicals as electrons build up in ETC (especially complex I). Changes that occur: Limit ATP use by switching off non-essential cell functions Improve anaerobic ATP production efficiency. Limit oxidative stress, providing protection against ischaemia. Metabolic adaptions to hypoxia: can be mediated via changes in gene expression, predominantly involving transcription factor HIF1. Normal conditions, HIF1 is degraded. In oxygen limiting situations, HIF is stabilised and binds to upstream elements of promotors. HIF1 present: inhibits biogenesis of mitochondria and promotes their death, suppresses biogenesis. Loss of mitochondrial density: prevent oxidative stress by restricting production of reactive O2 species. Become more dependent on anaerobic metabolism for source of energy. Fatty Acid Production and Oxidation LEARNING OBJECTIVES Describe the control of fatty acid synthesis via regulation of acetyl-CoA carboxylase. Understand the purpose of triglyceride mobilisation (lipolysis). State the products of lipolysis and contrast the metabolic fates of the glycerol and fatty acid moieties in triglyceride. Understand how the activity of hormone-sensitive (triglyceride) lipase is regulated. Outline the overall pathway of fatty acid activation and transport into the mitochondrial matrix via the carnitine shuttle. Regulatory importance of malonyl-CoA for regulation of mitochondrial long-chain fatty acid oxidation at the level of carnitine palmitoyl transferase I. Outline the general features of the beta-oxidation spiral and understand the role of beta-oxidation in ATP production. State the site and mechanism of ketone body production (ketogenesis). Specify the fate of ketone bodies in tissues such as the muscle and brain. Describe the effects of excessive ketone body production. 1. Lipid as an energy store Carbohydrate stores only provide short term energy buffering: lipids (triglycerides) are the ultimate store: contains a high-energy density, body have almost a limitless capacity to store fat (stored in white adipose tissues). NOTE: Ketone bodies are another source used in more long term starvation. 2. Lipid breakdown Lipolysis: releases fatty acids and glycerol. Fatty acids can be oxidized for energy (in oxidative tissues: not in the brain and RBCs) or converted to ketone bodies in the liver for use in non-oxidative tissues. Glycerol can be used for glucose synthesis in the liver. Control: Triglycerides released from adipose stores by HSL (hormone sensitive lipase). Responds to glucagon (increased activity) and insulin (decreased activity). However not completely controlled by HSL, also involves ATGL (adipose triglyceride lipase), which is not controlled in the same way as HSL. Triacylglycerol ATGL diacylglycerol HSL fatty acids and glycerol. 3. Oxidation of Fatty Acids Three step process. First step: activation of fatty acid by acetyl-CoA. Step two: transport into mitochondria via carnitine shuttle. Step: 3 is beta oxidation in the mitochondria. Carnitine Shuttle: Various steps to move fatty from cytosol to mitochondrial matrix. Fatty acid converted to fatty acyl-CoA by acyl-CoA synthase, uses ATP. Fatty acyl-CoA moved through outer mitochondrial membrane to form fatty acyl-carnitine by CPT-I (Carnitine palmitoyltransferase I). Fatty acyl-carnitine is moved through inner mitochondrial membrane by translocase. Converted back to fatty acyl-CoA in mitochondrial matrix by CPT-II Control of shuttle: transport inhibited by malonyl-CoA: involved in fatty acid synthesis. Transport is stimulated by glucagon via cAMP. Also, regulated transcriptionally. Beta oxidation: Fatty acids are oxidized by acetyl-CoA dehydrogenases in mitochondrial matrix. Cyclic set of reactions, remove 2C units. For each fat, going around the cycle various times (there are different isoforms with different chain length preferences). Not in brain, RBCS. Produces NAD and acetyl-coA which feed into TCA and ETC to produce ATP. NOTE: Unsaturated fats required extra enzymes. 5. Lipogenesis A two-stage process (occurs in the liver, white adipose tissue and lactating mammary glands). Stimulated in response to high blood sugar. Done through pyruvate dehydrogenase (PDH) (previously covered) dephosphorylation and acetyl-CoA carboxylase (ACC) conversion. Stage 1: formation of malonyl CoA (from citrate acetyl-coA malonyl-CoA) Stage 2: fatty acids synthetase (elongates chain by 2 carbon units). Control: By acetyl-CoA carboxylase: produces malonyl CoA and inhibits the carnitine shuttle and hence fatty acid oxidation (so fatty acids can be produced It is stimulated by insulin. The enzyme is further controlled in three ways: Polymerization: promoted by citrate Phosphorylation: by AMP dependent kinase and PKA. Genetic Control (longer term). 4. Ketone Bodies Soluble fuels, can be used in place of glucose by several tissues (including the brain). Example: acetoacetate. Ketone bodies are produced in the liver by mitochondria. Ketogenesis: starts with 2X acetyl-CoA, which combine to form acetoacetyl-CoA (CoA group removed). This is then converted to 3-hydroxy-3methylglutaryl-CoA by HMG-CoA synthase. This is then converted to ACETOACETATE (ketone) by HMG-CoA lyase. Acetoacetate can be split into further ketone bodies (D-beta-hydroxybutyrate and acetone). Control: Accumulation of acetyl-CoA in the liver due to TCA cycle being broken down (depletion of oxaloacetate to feed the gluconeogenesis pathway). Utilisation: Utilized by extrahepatic tissues, converted back to acetyl-CoA and used for TCA cycle. In starvation brain switches from 100% glucose to using 50% ketone bodies. Ketone Bodies: Ketoacidosis can result if there is no insulin to inhibit ketone production. 5. Oxidation of glucose and lipid Reciprocal control: high glucose conditions levels of citrate rise exported. This is then converted to malonyl-CoA (which can be produced in fatty acid synthesis). This in turn inhibits the uptake of fatty acids by mitochondrion, preventing fat oxidation when glucose is plentiful. Extremes of Metabolism LEARNING OBJECTIVES Outline the characteristics of muscle slow twitch (type 1) and fast twitch (type 2) fibers. Compare the metabolic pathways employed during sprinting, middle-distance running and marathons. Describe the regulatory role of AMP-activated protein kinase (AMPK) in exercise. Describe how AMP affects glucose handling by skeletal muscle. Understand the mechanism whereby AMPK lowers malonyl-CoA concentrations and allows increased fat oxidation. Outline the metabolic adaptations occurring during fatigue. Explain the contributions of different metabolic pathways to the maintenance of the starved state. Describe the mechanisms by which the body metabolizes alcohol Understand the effects of the metabolism of ethanol on carbohydrate and fat metabolism. 1. Muscle Fibres Type 1 Slow Twitch: develop tension slowly, to do this use oxidative metabolism from glucose and in the longer term fatty acids. They therefore contain a lot of mitochondria. Type 2 Fast Twitch: anaerobic metabolism, create energy via glycolysis to lactate. Main fuel of this muscle fibre is glycogen. This breaks down to glucose during longer period of exercise. Subtypes: A: Contain myoglobin thus also aerobic and B: Anaerobic The balance between these two types of muscle can change depending on what type of exercise. ATP in exercise: demand for ATP in skeletal muscle in exercise can increase x 100 (fast burst ~ quick loss of ATP). The ATP can be replenished from various sources (phosphocreatine, glycogen, triacylglycerol). Use of energy: phosphocreatine muscle glycogen blood glucose/FAs. Intensity of exercise: decrease in level of ATP, ADP and AMP increase. AMP: Metabolic signal, increasing glucose uptake in the short term and FA oxidation in the long term 2. Metabolic Changes during exercise Muscle glycogen sufficient capacity to provide ATP during sprinting. Contraction of muscle occurs due to the influx of calcium. Calcium binding subunit calmodulin activates phosphorylase kinase phosphorylates glycogen phosphorylase and results in the breakdown of glycogen. Pyruvate dehydrogenase complex: controls entry to TCA and therefore it’s activity is regulated by phosphorylation via PDH phosphatase: activity increased by calcium (more energy). Also by low NADH and ATP conc. Allosteric Control (binding of non-substrate molecule) by Calcium: Enzymes controlled are alpha-ketoglutarate dehydrogenase and isocitrate dehydrogenase (increased activity for increased energy production). Also, responds to low NAD levels. 2.1 AMP: allosterically activates enzymes at start of glycolysis and glycogenolysis, specifically glycogen phosphorylase (only when it’s not phosphorylated) and phosphofructokinase-1, Also acts increase transport through increasing number of GLUT4 channels. PFK-1: inhibited by high levels of ATP. In the heart: second mechanism (using PKF2) is used. This produces F-2,6-BP: allosteric activator of PK1. 2.2 AMPK (Kinase): dependant protein: heterotrimeric of 3 subunits. Two regulatory, one catalytic. Used as a sensor for energy status as well as a stimulator of GLUT4 glucose transporters to the membrane (independent of insulin). AMPK is controlled by phosphorylation on Thr172 of the alpha subunit: not dependant on AMP. Prolonged exercise shift from glucose to fatty acid metabolism. AMPK mediates this: phosphorylates acetyl-CoA carboxylase to prevent acetyl-CoA build up in cytoplasm and build-up of malonyl-CoA (MC inhibits CPTI). This in turn activates the carnitine shuttle. 3. Muscle fatigue in exercise 1) Running out of glycogen. Hard to rebuild glycogen in sports with short bursts of energy. Longer fatty acid oxidation: power output of only 60% maximum. 2) Depletion of phosphocreatine: harder to regenerate ATP 3) Excessive rates of conversion of glycogen and glucose lactic acid. This decreases pH and inhibits glycolysis and oxidative phosphorylation (causes stitches). 4) Insufficient (aging), inflexible (obesity) or inefficient mitochondria. Density of mitochondria increases with exercise: inability to switch to oxidative metabolism or insufficient to meet needs. 4. Alcohol Metabolism Ethanol Acetaldehyde If acetaldehyde is converted to NADH and acetyl-CoA: has little effect. The problem is there is only limited acetylaldehyde dehydrogenase to do this. Leads to build-up of acetaldehyde (toxic). Alcohol Dehydrogenase (NADH) + NAD Acetate + NADH (via acetylaldehyde dehydrogenase) ATP + Acetate + CoA AMP + PPi + Acetyl-CoA Antabuse: inhibits acetaldehyde dehydrogenase, so makes the awful effects set on more quickly. Alcohol blocks gluconeogenesis (don’t need to know mechanism). Biochemical effects of alcohol: High levels of NADH causes inhibition of the TCA cycle (malate dehydrogenase which is involved in the production of NADH, depletion of NAD+). Lactate dehydrogenase and pyruvate dehydrogenase: conversion of pyruvate to lactate is increased as NAD+ needs to be regenerated lactic acidosis. (NOTE: NAD+ is regenerated in anaerobic conditions from NADH produced in glycolysis). High levels of Acetyl-CoA: Causes the production of fatty acid and ketones (excess). 5. The Immune System Variable energy demand: Need to produce reactive oxygen species (to kill microbes) Energy to make antibodies (“anabolism of immune mediators) Energy is required in phagocytosis. Require lots of NADPH (anabolic NADP). This comes from the pentose phosphate pathway. In immune cells, parts of the TCA have been taken out (such as malate, glutamine) to produce reactive oxidative species that can kill microbes. 6. Cancer Metabolism Warburg effect: regardless of how much O2, cancer cells have major up regulation of glycolysis (due to mutations of Hif protein). This is partially so they can get fast energy. Like immune cells, increased use of amino acid skeletons, feeding into TCA cycle to increase energy production. Blood Supply to the Gut Learning Objectives Explain the anatomy and the distribution of the 3 unpaired arteries of the abdominal aorta Describe the blood supply to the liver. Explain the formation of the hepatic portal vein Identify the structures entering the porta hepatis Describe the relations of the principal organs in the abdomen Identify abdominal organs and vessels on suitable radiographs, CTs and MRI scans 1. General Structure of Blood Supply to the gut Foregut is supplied by the coeliac trunk (T12) Midgut is supplied by the superior mesenteric artery (L1) Hindgut is supplied by the inferior mesenteric artery (L3) NOTE (See the pattern): Bifurcation of Carotids C4 Arch of Aorta T4 Aortic Bifurcation L4. 2. The Coeliac Trunk Supplies the abdominal oesophagus, stomach, liver, gall bladder, pancreas, proximal duodenum. Arteries that come of the coeliac trunk are retroperitoneal. Stomach: supplied by two gastric arteries. Lesser Curvature: supplied by the left gastric artery. Right gastric artery arises from the hepatic proper. Both these arteries: located in the lesser omentum. Greater Curvature: supplied by the right gastroepiploic (from gastroduodenal artery) and the left gastroepiploic (from the splenic). These vessels anastomose. Gastroepiploic are in the greater omentum 3. Superior Mesenteric Artery (Midgut) Majority of the SMA is in the mesentery. It starts of behind the head of the pancreas, comes over the duodenojejunal junction and descends into the mesentery. It supplies the jejunum and the ileum via jejunal and ileal arteries, as well as supplying the ascending and transverse colon via the ileocolic, the right and the middle colic arteries. It arises from L1 between the mesentery layers. Blood supply to Jejunum vs Ileum The jejunum has a much richer blood supply (more absorption occurs here). Arteries are therefore larger. The vasa recta are much more less numerous but much larger compared to the ileum. In both areas, there is significant anastomoses of vessels arterial arcades (windows between vessels anastomosing. 4. Inferior Mesentery Artery Much smaller compared to IMA (located in the ‘watershed area’ between midgut and hindgut). 5. Hepatic Portal System Branches of the SMV and IMV follow that of the areas. E.g. the Splenic and superior mesenteric veins meet posterior to head of pancreas to form the portal vein. Retroperitoneal: Splenic and IMV Mesentery: SMV (same as arteries). 6.1 Nerve Supply: The Parasympathetic Division Vagus Nerves Clockwise rotation of the gut results in the following: Left vagus anterior vagal trunk (gastric branches, hepatic branches) Right vagus posterior vagal trunk (gastric branches, coeliac branch). Peritoneum Learning Objectives Describe the location and the function of the visceral and parietal peritoneum. Outline the embryology of the foregut, the midgut and the hindgut and the formation of the peritoneal cavity. Describe the rotation of the gut, understanding the derivatives of the dorsal and ventral mesentries. Outline the extent and the subdivisions of the peritoneal cavity. Describe the difference between retroperitoneal organs and intraperitoneal organs. Describe the general arrangements of the gastrointestinal tract and associated viscera. Peritoneum: Serous membrane (mesothelium) lining abdominal cavity. Parietal: abdominal cavity, covering some organs on posterior abdominal wall. Visceral: covers the abdominal viscera. Cavity in between: serous fluid allows movement. These two layers are continuous with each other. 1. Intraperitoneal Intraperitoneal: surrounded by peritoneal cavity. Include. Can move within the abdomen (aids gut distention). Liver Stomach Ileum Jejunum Double folds of peritoneum surrounding organs: Mesentry: small intestine (posterior abdominal wall) Lesser and greater omentum: stomach (to other organs). Mesocolon (connects colon to posterior abdominal wall). Ligaments (connect viscera to abdominal wall) used for other organs) 2. Division of the Gut Tube Foregut: The stomach, 1st part of the duodenum, liver, pancreas and spleen (coeliac trunk) Midgut: Caudal duodenum, small and large intestine up to splenic flexure (ascending colon, 2/3 transverse) (SMA) Hindgut: Splenic flexure, descending, sigmoid colon, rectum, upper anal canal (Inferior Mesenteric Artery) 3. Development of the Foregut Begins as a straight gut tube with connections to the anterior and posterior abdominal wall via the dorsal and ventral mesogastrium (in the embryo) As the foregut rotates, the dorsal and ventral mesogastrium rotate with it. Line of attachment of ventral mesogastrium: swings to the right and ends up running along the lesser curve of the stomach. At the back: attachment of dorsal mesogastrium: swings to the right and ends up running along the greater curve of the stomach 4. Peritoneal Folds (Purple) Liver: develops in the ventral mesogastrium Grows rapidly and presses against the body wall. Is only organ attached to anterior wall (faliciform ligament). Free border of lesser omentum: bile duct, hepatic artery, hepatic portal vein Contains ligamentum teres (remains of left umbilical vein). The spleen and pancreas: develops in the dorsal mesogastrium (see 3). Lesser Sac (omental bursa): Spleen and liver create a space behind stomach (small because of the growth of the liver). The lesser sac is formed by: Lesser omentum (inferior liver to lesser curvature of stomach) Hepatoduodenal ligament (porta of liver, superior duodenum) Hepatogastric ligament (liver to lesser curvature of stomach). Greater omentum (from the greater curvature to the transverse colon: loops down). Large flap of loose connective tissue and fat. Travels down from stomach and up again to transverse colon. Very vascular, contains many immune cells. The lesser sac and greater sac are continuous with each other through the epiploic foramen. The transverse colon is held by the transverse mesocolon (transverse colon posterior wall). As the greater omentum grows: comes together with the transverse mesocolon. Mesentery from small intestine to posterior body wall. Anchors small intestine and provides pathway for blood supply (superior mesenteric artery. 5. Development of Mid Gut The midgut consists of caudal duodenum, caecum, vermiform appendix, ascending colon, right 2/3 transverse colon. These are supplied by the superior mesenteric artery. Development, the midgut is continuous with vitelline duct (into the umbilicus). As the midgut develops: protrudes into vitelline duct forming a loop It makes a turn counter clockwise (distal part to the left, proximal part to the right). Distal lobe develops a bulge cecum. The proximal tube becomes convoluted The body continues to grow until there is enough space for the mid gut to return. The proximal part of the loop returns first. Under the distal part, moves to the left. Distal part returns last, passes in front of the proximal part (on the right) Clinical Applications Omphalocele: Among the most congenital abnormalities; failure of central fusion at umbilical ring causing incomplete closure of the abdominal wall and persistent herniation of the midgut (doesn’t retract back into space). Ascities: large amount of inflammation (e.g. result of serosis of liver) fluid in cavity. 6. Subdivision of the peritoneal cavity (apart from lesser sac) 7. Subdivision of Peritoneal Cavity 8. Retroperitoneal Static structures organs behind the peritoneum. Imaging the Bowel with Endoscopy LEARNING OBJECTIVES 1. Problem with imaging the GI Tract Only two orifices, long tube, not much light and has many bends. 2. Types of Endoscopy Upper GI endoscopy Enteroscopy Capsule endoscopy Double balloon endoscopy Colonoscopy 3. Goals of the endoscopy Diagnosis Macroscopic Histology Manometry Endomicroscopy Therapy Surveillance Screening 3. Endoscopy vs radiology Advantages: Macroscopic real time view Obtain histology Visualise entire bowel Therapeutics Disadvantages: Sedation (put to sleep) Technically demanding Complications Limited to luminal views (except US). The light properties to enhance detection/diagnostic Narrow Band Imaging: Optical image; light of specific blue and green wavelengths is used to enhance the detail of certain aspects of the surface of the mucosa Autofluorescence: ability to rapidly examine a large surface area of gastrointestinal mucosa to detect small areas of dysplasia or cancer. Chromo-Endomicroscopy: intra vital contrast, detect lesion with conventional endoscopy. 4. Upper GI Diagnostic Investigation Dysphagia (difficulty swallowing) Odynophagia (painful swallowing) Epigastric pain Haemetemesis/meleana (vomiting of blood) Weight loss, Anaemia Diarrhoea/malabsorption Surveillance 5. Upper GI Therapeutic investigation Dilatation (enlargement) Haemostasis (presence of blood) Stent (holding open channels/preventing collapse) Variceal management (management of viscera) Gastrostomy insertion (tube from nose into stomach) Botox injection (steroid injection LOS) Polypectomy (removal of colorectal polyps to prevent them from turning cancerous) 6. Reasons for Enteroscopy/Capsule Endoscopy Anaemia/bleeding Diarrhoea Abnormal x-ray Small bowel samples (taking a tissue). Therapy (to see effect of treatment) 7. Type: Ideal Small Bowel Investigation Ideally a safe/minimally invasive. Examines the entire SB. Picks up flat lesions, does not require active bleeding However it cannot take up biopsies. 8. Double Balloon Endoscopy Pan GI endoscopy with oral/rectal intubation. Sedation (to put to sleep)/GA: long procedure. Full therapeutics available. Image shows the mechanism: a tube is inserted in the mouth or rectum (under complete or partial sedation) and passed through the GI tract to the small bowel. Here, a balloon is inflated to decrease friction of the tube. It is deflated/reinflated until the whole bowel is captured. 8. ERCP (Endoscopic retrograde cholangiopancreatography) Endoscopic retrograde cholangiopancreatography (ERCP) is a technique that combines the use of endoscopy and fluoroscopy to diagnose and treat certain problems of the biliary or pancreatic ductal system (involves stone removal, tumour stenting, manometry measures function of LOS). 9. Colonoscopy Carried out in case of rectal bleeding, altered bowel habit, abdominal pain. Surveillance, therapy Polypectomy. EMR: endoscopic mucosal resection (EMR) is a procedure to remove cancerous or other abnormal tissues (lesions) from the digestive tract. Dilatation Stent insertion. 23. Nausea and Vomiting Learning Objectives Emesis (nausea + vomiting) is a normal defensive reflex which becomes a medical issue if induced by drugs or disease (Pregnancy, motion, drugs, gastrointestinal/ painful conditions, surgery). Can be especially severe during cancer chemotherapy and palliative medicine There are different classes of anti-emetic drugs with different actions; no drug is effective against all types of emesis Old, 'established' anti-emetic drugs are commonly used, often with a 'mixed pharmacology' (antagonise at M1, H1 and/ or D2 receptors) and side-effects Antagonists at 5-HT3 and NK1 receptors are used to inhibit severe emesis often in combination with the steroid, dexamethasone Nausea is not the same as vomiting and is more difficult to treat 1. Defensive Responses Vomiting may be induced by pregnancy, bulimia, chemotherapy, abnormal motion, drug side-effects (NSAIDs, oral contraceptives), end of life, illness, norovirus, post-operative/opioid, gastroparesis Vomiting: forceful expulsion of gastric contents from the mouth. This is caused directly by powerful contractions of the abdominal muscles, opening of the gastric cardia (connection between oesophagus and stomach) and contraction and descent of the diaphragm. Coordination: The area posterma (aka the vomiting centre): medullary centre. It connects to the nucleus of the solitary tract and other autonomic control centres in the brainstem. It is excited by visceral afferent impulses coming from the GI tract. It makes up part of the dorsal motor nucleus of the vagus (DMV), the reticular formation and ventrolateral medulla. Sensory Inputs: Has various inputs Motion/space (e.g. migraine) feed into the brainstem to initiate a response in the AP. Compression: also, feeds into brainstem. Pain: also, feeds into brainstem. Vagus Nerve: links various inputs together: pregnancy, ischaemia, obstruction, poisons, cytotoxins etc… feeds into NTS. Blood circulation: can directly activate AP Receptors: each of these inputs acts on variable receptors in the brainstem/NTS/AP Motion: Acetylcholine (M1) Blood circulation: Dopamine (D2) Steroids: Histamine (H1), Cannabinoid (CB1) Ischaemia, GI: 5-HT receptors, NK1. 2. Old Drugs used to prevent vomiting Motion Sickness: Hyoscine (scopolamine): blocks the effects of Ach in brainstem and/or vestibular nuclei (and is therefore a muscarinic receptor antagonist) NOTE: many anti-emetic (prevent vomiting) were developed before ‘genomic revolution’ consisting mainly of dopamine D2 receptor antagonists. Often given in combination with H1, M1 antagonists. M1 dry mouth. Works to inhibit receptors on NTS/brainstem innervated by vagus nerve. H1 drowsiness (e.g. Cyclizine). Same mechanism as M1 (NTS/brainstem). D2 extrapyramidal (slow movement, muscle spasm etc…). Worked to antagonise D2 receptors directly on the area posterma. Cannabinoid Derivatives: Delta-9terahydrocannabinoids (e.g. nabilone) that work on receptors of the NTS, brainstem. These may treat mild/moderate emesis but poorly effective against severe emesis. They are appetite promoting but are limited by their side effects. 3. New drugs for chemo-/radio-therapy Cisplatin: type of chemotherapy. Initially: will cause negative damage vomiting. Serotonin (5-HT) is released by the enterochromaffin cells of the small intestine in response to chemotherapeutic agents, may stimulate vagal afferents (via 5-HT3 receptors) to initiate the vomiting reflex. 5-HT3 Receptor Antagonists: The 5-HT3 antagonists, informally known as "setrons", are a class of drugs that act as receptor antagonists at the 5-HT3 receptor, a subtype of serotonin receptor found in terminals of the vagus nerve and in certain areas of the brain. 4. Anti-Emetic Activity of Corticosteroids (e.g. dexamethasone) Anti-inflammatory, enhances ant-emetic efficacy of several other anti-vomiting drug but can also act alone for anti-nausea effects. For moderately/severe forms of emesis: 5-HT3 receptor antagonist and dexamethasone. 5. Selective NK1 Receptor Antagonists (e.g. aprepitant). Achieves further control if given in combination with other anti-emetics. NK1 is a neurotransmitter used by the vagus and some brainstem nerves, and its inhibition gives an anti-emetic effect. It blocks actions of substance P (neurotransmitter/neuropeptide). Severe forms of emesis: 5-HT3 receptor antagonist + NK1 receptor antagonist + dexamethasone. 6. Palliative Care Often causes nausea because of opiate medication, reflux, gastric stasis and intestinal obstruction. Partial Bowel obstruction: given metoclopramide (D2 antagonist, 5-HT4 agonist) and prucalopride (5-HT4 agonist). These stimulate gastrointestinal propulsion. Reduces inflammation: Dexamethasone: Reduced build-up of fluid in lumen: Octreotide (somatostatin antagonist), Nasogastric tube, venting, gastrostomy tube to remove fluid. 7. Nausea Unpleasant sensation at the back of the throat, gives the sense/urge of vomiting. Can be accompanied by other symptoms: cold seat, salivation, loss of gastric tone, duodenal contractions. Mechanism is not fully understood, but does involve ghrelin: Ghrelin receptor agonists: increase appetite, reduce vomiting, increase gastric emptying. Cancer patient with impaired appetite can receive ghrelin to reduce nausea. Dysregulation of gastric rhythms: There is increased activity of ICCs in nausea. 24. Lipoproteins Learning Objectives State the major tissues in which triglyceride is stored and understand the purpose of triacylglycerol storage. State the major tissues in which fatty acid synthesis (lipogenesis) occurs and understand its purpose. Draw the coat/core structure of plasma lipoproteins. State the four major classes of lipoproteins, their prominent core lipids and their functions. Outline the role of lipoprotein lipase in the hydrolysis of lipoprotein triglyceride. Outline the role of lipoproteins and the transport of cholesterol and cholesterol esters. Understand the consequences of a failure to remove low-density lipoprotein (LDL) from the circulation. Understand that elevated plasma cholesterol is a cardiovascular risk factor, but that elevated high-density lipoprotein (HDL) is cardioprotective. List several aspects of lifestyle which elevate HDL. Outline the function of bile acid binding resins. Describe the role of HMG-CoA reductase inhibitors. 1. Lipoproteins Most fatty acids are taken up by the diet (about 90% is triacylglycerol or TAG) and the rest comes in the form of cholesterol, cholesterol esters, phospholipids and free fatty acids. Fatty acids are formed spontaneously in case of excess energy + glycerol-3-phosphate TAG. TAG are packaged into lipoproteins as they are not easily transported due to being hydrophobic. These lipoproteins consist of cholesterol and proteins (called apoproteins). Chylomicrons: dietary TAG lipoproteins. Liver derived TAG: released as VLDL. Lipoprotein Structure: TAG/cholesterol esters are packaged on the inside, surrounded by a phospholipid layer, free cholesterol and apoproteins (these depends on the lipoprotein type). Apoproteins can be embedded (apoB) or loosely bound (apoC). The type of apoproteins is characteristic the lipoprotein (with their main components) Chylomicron: lowest density (<0.95 kg/l), contains TAG, B48 (and A, C, E) VLDL: (density: 0.95-1.006), contains TAG, B100 (and A, C, E). VLDL shrink into a remnant particle (IDL) and are converted to LDL by the liver. IDL: (density: 1.006-1.019) contains TAG and cholesterol, B100 (E) LDL: (density: 1.019-1.063) contains cholesterol (as esters), B100. Delivers cholesterol esters to peripheral tissues (considered bad lipoproteins). HDL: (density: 1.063-1.210) contains protein, AI, AIII (C, E). Scavenges cholesterol from peripheral tissues and converts this to cholesterol esters, distributed to other lipoproteins. HDL considered good lipoproteins. ApoB100: controls the metabolism of LDL, shorter version (apoB48) controls chylomicrons. ApoE: controls receptor binding/removal of remnant particles, catabolism of TAG ApoC: acts as enzyme inhibitor (inhibits LPL). Lipoprotein Lipase: “Gatekeeper of lipoprotein metabolism” endothelium adjacent to target cells of LPs. When active it degrades TAG in in chylomicrons/VLDL and unloads fatty acids and glycerol for uptake. ApoC2 is involved in the activation of LPL. After a meal: activity is high in adipose tissue. Most FA derived from TAG in chylomicrons are targeted to adipose tissue for storage. Chylomicrons therefore have a short lifetime. Starvation: High is muscle. FA derived from TAG in VLDL is mainly fed into oxidation. Life of a Chylomicron: Formed in the lumen of the gut (made up of TAG, esterified cholesterol, phospholipids, B48). Released by exocytosis into lacteals (by enterocytes) bloodstream. In the blood: exchange components with high density lipoproteins. HDL donates ApoC-II and ApoE to chylomicron. ApoC-II activates LPL, which breaks down TAG and unloads FAs. Gives ApoC-II back to HDL and becomes a remnant. Due to presence of ApoE it is taken up by liver. 2. Lipoprotein metabolism Endogenous Pathway: TAGs and cholesterol is assembled with B100 to form VLDL in hepatocytes in the liver bloodstream. VLDL particles bump with HDL: which donates ApoC-II and ApoE. Their hydrolyses by LPL allows for the following step (conversion to IDL). These then interact with LDL (expressed on endothelial cells). ApoC-II activates LPL and TAGs are broken down and FAs, glycerol unloaded (VLDL IDL). Still contain ApoE and are picked up by ApoE receptor and taken up by liver and hydrolysed to form LDL (contain high amounts of cholesterol) by hepatic TAG lipase (transforms IDL into cholesterol: rich IDL. Delivered to tissue by receptor mediated (help of B100) on LDL particle. LDL lacks ApoE, and remain in circulation longer (taken up by liver. NOTE: VDLDs cannot bind to LDL receptors because of the conformation of B100 and ApoE proteins. 3. Cholesterol Uptake and Synthesis HMG-CoA regulates the cholesterol uptake into cells. HMG-CoA reductase is involved in the synthesis and is also regulatory. Cells can take up LDL if their cholesterol level is low (through the LDL receptor or the apoB/E). Transcription factor SREBP regulates expression of HMG-CoA reductase and the LDL receptor and therefore decides how much cholesterol is taken in. 4. High-Density Lipoproteins HDL can exchange components (called apoproteins trafficking) with other LPs. They don’t contain many lipids and are made up mainly of apoAI. They are made in the liver and intestine. Disposal of Cholesterol: HDL transports cholesterol from peripheral tissues to the liver for disposal via Bile. HDL binds to “scavenger receptors” and transfers cholesterol to cell membrane. Then redundant parts of HDL then participate in the next cycle. HDL scavenges free cholesterol from cell membranes via the ABCA1 transporter (membrane protein) and esterifies it to cholesterol esters. 25. Nitrogen Metabolism Learning Objectives Understand that the body balances nitrogen intake and output and define the term nitrogen balance. Understand why some amino acids are essential in the diet. Outline the potential uses of amino acids, including their role as signalling molecules. Understand the difference between glucogenic and ketogenic amino acids. General metabolism of the carbon skeletons and amino groups from amino acids and how this interfaces with carbohydrate and lipid metabolism. Understand the function of alanine and glutamine in interorgan carbon and nitrogen flow. Understand that surplus amino acids contribute nitrogen to urea for excretion. Outline how amino groups are funnelled into the urea cycle. Understand why urea is a better excretion product than ammonia. 1. Nitrogen Balance There is nog significant store of nitrogen under normal conditions. Amino acids are used in protein synthesis. Proteins are broken down and nitrogen is excreted in the form of urea. Variants: Positive Balance: during growing/pregnancy, more nitrogen is taken in then excreted. Negative Balance: more nitrogen excreted than ingested in times of fasting, trauma, malnutrition. 2. Amino Acids Essential AAs: must be taken in via diet as the body cannot synthesize their carbon structure. If insufficient the body will break down existing proteins to replenish these. E.g.: Valine, Methionine, Isoleucine, Phenylalanine etc… Conditional Essential AAs: The body can make some amino acids only in a certain amount. These are essential in the diet only in times of insignificant amounts (e.g. glutamine during infection). Amino acids are not just used to make proteins. Are involved in the synthesis/direct use of neurotransmitters, energy metabolism and making of new nucleotides (purines, pyrimidines). E.g.: Tyrosine (Phenylalanine): Tyrosine can be metabolised to form melanin, dopamine, adrenaline, noradrenaline and thyroxine (neurotransmitters). Tryptophan: can used to make serotonin and melatonin (involved in sleep/wakefulness). Arginine: synthesizes nitric oxide (neurotransmitter relaxation of blood vessels). Histidine: metabolised to make histamine (neurotransmitter, immune responses). Glycine, glutamate, aspartate: used directly as neurotransmitters. Transamination: amino transfer between an amino acid and keto acid to form another amino acid and keto acid (highlights the use of the carbon skeleton of amino acids). Amino acid vs keto acid Pyruvate is converted to alanine by the addition of an amino group. Glutamate is converted to alpha ketoglutarate by the removal of amino group. Oxaloacetate is converted to asparate by the addition of an amino group 3. Glucogenic and Ketogenic Amino Acids Glucogenic: amino acid that can be converted into glucose through gluconeogenesis (feed into TCA) (e.g. alanine, aspartate, glutamine/glutamate). Ketogenic: A ketogenic amino acid is an amino acid that can be degraded directly into acetyl-CoA, which is the precursor of ketone bodies. Some AAs can be both glucogenic and ketogenic. 4. Transport of Excess Ammonia NH3 is toxic as it is basic and interrupts pH systems within the body, as well as being very reactive (contains a lone pair of electrons). NH3 is not very soluble and therefore it cannot have a high concentration in water. If we were to excrete NH3 in it’s pure form, we would need to constantly urinate and drink water (mechanism of fish that through constant water supply excrete it in gills). Humans: we produce urea: compound containing two ammonia molecules. More soluble than NH3 and therefore needs less water to excrete. Also, it’s less reactive (and more easily stored). Birds have a similar problem: also, need water but this is very heavy to carry. Therefore, they synthesize uric acid from ammonia (more concentrated, higher solubility in water than urea). Mechanism of Excess Nitrogen Excretion Muscle: Involves transamination reactions: Pyruvate (keto acid) Alanine (aa). This transamination removes an amino group from glutamate (aa) and adds it to pyruvate to form alanine (aa). Glutamate is converted ketoglutarate (keto acid) by the addition of NAD+ and through GDH. By products are NADH and NH3 (to urea cycle/kidneys) Glutamate Glutamine (done by addition of NH3 and GM, uses ATP) NH4+ (a small amount of glutamine can be excreted directly) Alpha ketoglutarate NH4+. Alanine is transported in the blood to the liver, where it is converted to pyruvate. The reverse of the first transamination takes place: alanine is converted to pyruvate by the removal of an amino group, which is added to alpha ketoglutarate for form glutamate feeds into the urea cycle. Pyruvate is used in gluconeogenesis. Glucose then send back to muscle. Enzymes in Glutamate Metabolism: Glutamine can be converted back to glutamate by the addition of water and enzyme GMase. NH3: byproduct. Glutamate: neurotransmitter. Glutamate and related metabolites: Glutamine is an important fuel, other roles: Skeletal Muscle: synthesized, stored and released in fasting (so it can be used as fuel) Kidney: a substrate for gluconeogenesis: formation of ammonia for buffering protons. CNS: used to maintain levels of glutamate (neurotransmitter) Immune cells: Supports phagocytosis by macrophages and neutrophils, provides energy and enhances T-lymphocyte responses to i

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