EHR522 Exercise for Metabolic & Renal Conditions Week 1 Lecture Slides - PDF

EHR522 EXERCISE FOR METABOLIC & RENAL CONDITIONS WEEK 1 – METABOLIC PHYSIOLOGY TEACHING STAFF Karina Liles Subject Coordinator & AEP [email protected] (02) 6338 4102 Consultation: By appointment 2 ORGANISATION OF THE GASTROINTESTINAL SYSTEM Gastrointestinal Tract • A tube that is specialise...

EHR522 EXERCISE FOR METABOLIC & RENAL CONDITIONS WEEK 1 – METABOLIC PHYSIOLOGY TEACHING STAFF Karina Liles Subject Coordinator & AEP [email protected] (02) 6338 4102 Consultation: By appointment 2 ORGANISATION OF THE GASTROINTESTINAL SYSTEM Gastrointestinal Tract • A tube that is specialised along its length for sequential processing of food • A series of hollow organs (mouth to anus) and accessory glands and organs that add secretions to the hollow organs • Each hollow organ serves a specialised function. They are separated at key locations by sphincters 3 ORGANISATION OF THE GASTROINTESTINAL SYSTEM Mouth and Oropharynx • Mechanical breakdown and lubrication of food • Propels food into the oesophagus • Initiates fat and carbohydrate metabolism Oesophagus • Conduit to the stomach Stomach • Temporary food storage • Churns and secretes proteases and acid that facilitate digestion 4 ORGANISATION OF THE GASTROINTESTINAL SYSTEM Small intestine • Continues digestion • Primary site for nutrient absorption Large intestine • Reabsorbs fluids and electrolytes (but no nutrient absorption) • Storage of faecal matter before expulsion Accessory glands include • Salivary glands • Pancreas • Liver 5 ORGANISATION OF THE GASTROINTESTINAL SYSTEM Pancreas • Digestive enzymes secretion • Secretion of bicarbonate to neutralise gastric acid • Secretion into the duodenum via the major and minor duodenal papilla 6 ORGANISATION OF THE GASTROINTESTINAL SYSTEM Liver • Bile secretion (stored in the gallbladder between meals). • Bile acids within bile, secreted at meal times, play a key role in fat digestion 7 NUTRIENT DIGESTION AND ABSORPTION • Digestion – The enzymatic conversion of complex dietary substances to a form that can be absorbed • Most, but not all, digestive processes occur in the small intestine • Absorption – The process of up taking nutrients into cells or across tissues and organs through diffusion or osmosis 8 CARBOHYDRATE DIGESTION • Carbohydrates are classified into three major groups – Monosaccharides (monomers) – Disaccharides (short polymers) – Polysaccharides (long polymers) • The small intestine can directly absorb monomers, but not polymers. In other words, carbohydrates require hydrolysis to monosaccharides before absorption • Some polymers are digestible, others are not • Non-digestible polymers = fibre 9 CARBOHYDRATE DIGESTION • Dietary fibre – non-digestible polymers found in fruits, vegetables and cereals. Can be either soluble or non-soluble • Glycogen – the storage form of carbohydrate in animals. It is the starch equivalent for plants. 10 CARBOHYDRATE DIGESTION • Digestion of carbohydrates involves two steps 1) Intraluminal Hydrolysis – Starch to oligosaccharides by salivary and pancreatic enzymes 2) Membrane Digestion – Oligosaccharides to monosaccharides by brush border disaccharidases 11 INTRALUMINAL HYDROLYSIS • Both salivary and pancreatic acinar cells synthesise and secrete alpha-amylases • Salivary amylase in the mouth initiates starch digestion. It is inactivated by gastric acid • Pancreatic alpha-amylase completes starch digestion in the lumen of the small intestine • The products of starch hydrolysis are disaccharides, which cannot be absorbed by the small intestine – further digestion is required to produce absorbable monosaccharides 12 MEMBRANE DIGESTION • Membrane digestion involves hydrolysis of oligosaccharides to monosaccharides by brush border disaccharidases • The small intestine has three brush border oligosaccharidases, each with a different hydrolytic function – Lactase – Maltase – Sucrase - isomaltase 13 CARBOHYDRATE ABSORPTION • The three monosaccharide products of carbohydrate digestion (glucose, galactose and fructose) are absorbed by the small intestine in a two-step process – 1) Uptake across the apical membrane into the epithelial cell – 2) Coordinated exit across the basolateral membrane 14 CARBOHYDRATE ABSORPTION • The sodium/glucose transporter 1 (SGLT1) is the membrane protein responsible for glucose and galactose uptake at the apical membrane. This is an active transport process, with glucose moving against its concentration gradient • SGLT1 cannot carry fructose, so the apical step of fructose absorption occurs by the facilitated diffusion of fructose through GLUT5 transporter • The exit of all three monosaccharides across the basolateral membrane uses the facilitated sugar transporter, GLUT2. 15 PROTEIN DIGESTION • Proteins must first be digested into their constituent oligopeptides and amino acids before being taken up by the enterocytes • Digestion-absorption of proteins occurs through four major pathways – 1) Several luminal enzymes (proteases) from the stomach and pancreas may hydrolyse proteins to peptides and then to amino acids, which are then absorbed – 2) Luminal enzymes may digest proteins to peptides, but enzymes present at the brush border digest the peptides to amino acids, which are then absorbed 16 PROTEIN DIGESTION – 3) Luminal enzymes may digest proteins to peptides, which are themselves taken up as oligopeptides by the enterocytes. Further digestion of the oligopeptides by cytosolic enzymes yields intracellular amino acids, which are moved by transporters across the basolateral membrane into the blood – 4) Luminal enzymes digest dietary proteins to oligopeptides, which are taken up by enterocytes and moved directly into the blood • Brush border peptidases fully digest some oligopeptides to amino acids, whereas cytosolic peptidases digest oligopeptides that directly enter the enterocyte. 17 PROTEIN DIGESTION • Both gastric and pancreatic proteases, unlike the digestive enzymes for carbohydrates and lipids, are secreted as proenzymes that require conversion to their active form for protein hydrolysis to occur • The protein that is digested and absorbed in the small intestine comes from both dietary and endogenous sources • Of the 20 amino acids, nine are essential. That is, they are not synthesised in adequate amounts by the body and thus must be derived from either animal or plant sources 18 PROTEIN, PEPTIDE AND AMINO ACID ABSORPTION • In adults, proteins are almost exclusively digested to their constituent amino acids and dipeptides, tripeptides or tetrapeptides before absorption. • In contrast, during the neonatal period, the absorption of whole protein by apical pinocytosis occurs. This largely ceases six months of age, however even adults absorb small amounts of intact proteins. • In adults, uncertainty exists regarding the cellular route by which these substances are absorbed, as well as the relationship of the mechanism of protein uptake in adults to that in neonates. 19 PROTEIN, PEPTIDE AND AMINO ACID ABSORPTION • Although whole protein uptake in adults may not have nutritional value, such uptake is clearly important in mucosal immunity and probably is involved in one or more disease processes 20 PROTEIN, PEPTIDE AND AMINO ACID ABSORPTION • Virtually all absorbed protein products exit the villous epithelial cell and enter the blood as individual amino acids • Substantial amounts of protein are absorbed from the intestinal lumen, via a H+-driven cotransporter, as dipeptides, tripeptides or tetrapeptides and are then hydrolysed to amino acids by intracellular peptidases • Additionally, substantial portions of amino acids are released in the lumen of the small intestine by luminal proteases and brush border peptidases and move across the apical membrane of enterocytes through one or more group-specific apical membrane transporters 21 PROTEIN, PEPTIDE AND AMINO ACID ABSORPTION • The absorption of amino acids across the small intestine requires sequential movement across both the apical and basolateral membranes of the villous epithelial cell • Although the amino acid transport systems have overlapping affinities for various amino acids, the general consensus is that at least seven distinct transport systems are present at the apical membrane 22 PROTEIN, PEPTIDE AND AMINO ACID ABSORPTION • Amino acids appear in the cytosol of intestinal villous cells as the result of either their uptake across the apical membrane or of the hydrolysis of oligopeptides that had entered the apical membrane • Movement of amino acids across the basolateral membrane is bi-directional; the movement of any one amino acid can occur through one or more amino acid transporters 23 PROTEIN, PEPTIDE AND AMINO ACID ABSORPTION • At least five amino acid transporters are present in the basolateral membrane • Three amino acid transport processes on the basolateral membrane mediate amino acid exit from the cell into the blood and thus complete the process of protein assimilation • Two other amino acid transporters mediate uptake from the blood for the purposes of cell nutrition • Amino acids exit enterocytes through Na+independent transporters and enter through Na+dependent transporters 24 LIPID DIGESTION • Lipids are typified by their preferential solubility in organic solvents, compared with water • The biological fate of lipids depends critically on their chemical structure, as well as on their interactions with water and other lipids in aqueous body fluids (eg. intestinal contents and bile) • Lipids may be either − Non-polar and completely insoluble in water − Polar and amphiphilic. That is, having both polar (hydrophilic) and non-polar (hydrophobic) groups 25 LIPID DIGESTION • Typical adult Western diets contain approximately 140g of fat (providing approximately 55% of the energy requirements) • This is more than the recommended intake of less than 30% of total dietary calories (<70g of fat) • Of this, more than 90% is triacylglycerols (TAGs) 26 LIPID DIGESTION • Dietary fat is the body’s only source of essential fatty acids, and it acts as a vehicle for the absorption of fat-soluble vitamins • Fat is also the major nutrient responsible for postprandial satiety • The ratio of saturated to unsaturated fatty acids in TAGs is high in animal fats and low in plant fats 27 LIPID DIGESTION • Lipid hydrolysis is catalysed by lipases secreted by the glands and cells of the upper gastrointestinal tract • The products of lipolysis diffuse through the aqueous content of the intestinal lumen, traverse the so-called unstirred water layer and mucus barrier that line the intestinal epithelial surface, and enter the enterocyte for further processing 28 LIPID DIGESTION • A key step preliminary to lipid digestion is the transformation of ingested solid fat and oil masses into an emulsion of fine oil droplets in water • The emulsification of dietary fat begins with food preparation (grinding, marinating, blending and cooking), followed by chewing and gastric churning caused by antral peristalsis against a closed pylorus • Emulsification of ingested lipids is enhanced when muscular movements of the stomach intermittently squirt the gastric contents into the duodenum and, conversely, when peristalsis of the duodenum propels the duodenal contents in a retrograde fashion into the stomach through the narrow orifice of a contracted pylorus 29 LIPID DIGESTION • The grinding action of the antrum also mixes food with the various digestive enzymes derived from the mouth and stomach • Intestinal peristalsis mixes luminal contents with pancreatic and biliary secretions 30 LIPID DIGESTION • Lingual and gastric (acid) lipase initiate lipid digestion - In the stomach, both lingual lipase that is swallowed and a gastric lipase secreted by gastric chief cells digest substantial amounts of lipid • Lingual and gastric lipases are inactive at neutral pH and are also readily inactivated by pancreatic proteases (especially in the presence of bile salts) once they reach the small intestine • In healthy adults, approximately 15% of fat digestion occurs in the stomach 31 LIPID DIGESTION • Pancreatic (alkaline) lipase, colipase, milk lipase, and other esterases – aided by bile salts – complete lipid hydrolysis in the duodenum and jejunum • Once the fatty acids generated in the stomach reach the duodenum, they trigger the release of cholecystokinin (CCK) and gastric inhibitory peptide (GIP) from the duodenal mucosa • CCK stimulates the flow of bile into the duodenum by causing the gallbladder to contract and the sphincter of Oddi to relax • CCK also stimulates the secretion of pancreatic enzymes, including lipases and esterases 32 LIPID ABSORPTION • Products of lipolysis enter the bulk water phase of the intestinal lumen as vesicles, mixed micelles and monomers • Lipids, as mixed micelles and monomers, diffuse across the unstirred water layer on the surface of the jejunal mucosa and cross the enterocyte brush border • For short- and medium-chain fatty acids, which are readily soluble in water, diffusion of these monomers through the unstirred water layer of the enterocyte is efficient • As fatty acid chain length increases, the monomer’s solubility in water decreases, whereas its partitioning into micelles increases 33 LIPID ABSORPTION • When the fatty acid/bile salt mixed micelles reach the enterocyte surface, they encounter an acidic microclimate generated by Na-H exchange at the brush border membrane • It is postulated that fatty acids now become protonated and leave the mixed micelle to enter the enterocyte, either by nonionic diffusion of the uncharged fatty acid, or by collision and incorporation of the fatty acid into the cell membrane, or by carrier-mediated transport through fatty acid translocase 34 LIPID ABSORPTION • After the entry of lipids into enterocytes, the remaining bile salts return to the lumen and are then absorbed passively throughout the small intestine and through active transport in the distal ileum • Membrane proteins have been identified in both enterocytes and hepatocytes that may be responsible for the transfer of fatty acids, phospholipids and cholesterol across their respective cell membranes • As well as providing a mechanism for facilitated or active absorption of the various products of lipid digestion, such carriers may yet be therapeutic targets for inhibiting lipid absorption 35 LIPID ABSORPTION • The enterocyte re-esterifies lipid components and assembles them into chylomicrons • The enterocyte then exports the chylomicrons to the lymph for ultimate delivery to other organs through the bloodstream 36 LIPID ABSORPTION • Chylomicrons are the largest of the five lipoprotein particles in the bloodstream. The other lipoproteins are: − − − − Very-low-density lipoproteins (VLDL) Low-density lipoproteins (LDL) Intermediate-density lipoproteins (IDL) High-density lipoproteins (HDL) 37 LIPID ABSORPTION • The handling of triacylglycerols (TAGs) with mediumlength fatty acid chains is very different - The uptake into the enterocyte of fatty acids derived from medium-chain TAGs does not depend on the presence of either mixed micelles or bile salts - The enterocyte does not re-esterify the medium chain fatty acids, but instead transfers them directly into the portal blood 38 LIPID ABSORPTION • The enterocyte secretes chylomicrons into the lymphatic circulation during feeding and secretes very-low-density lipoproteins during fasting • Chylomicrons are too large to pass through the fenestrae of blood capillaries, and thus they enter lymph through the larger interendothelial channels of the lymphatic capillaries • Lymph flows from the cisterna chyli to the thoracic duct, to enter the blood circulation through the left subclavian vein • The protein and lipid composition of both chylomicrons and VLDLs are modified during their passage through lymph and on entry into the blood 39 DIGESTION AND ABSORPTION OF VITAMINS AND MINERALS • Intestinal absorption of fat-soluble vitamins follows the pathways of lipid absorption and transport • Fat-soluble vitamins include − A (Retinol) − D − E − K • In contrast to their water-soluble counterparts, fatsoluble vitamins do not form classical co-enzyme structures or prosthetic groups with soluble apoproteins. Fat-soluble vitamins can also be stored in fat depots in the body 40 DIGESTION AND ABSORPTION OF VITAMINS AND MINERALS • After ingestion, fat-soluble vitamins are released from their association with proteins by the acidity of gastric juice or by proteolysis • In the proximal small intestine, fat-soluble vitamins incorporate with other lipid products into emulsion droplets, vesicles and mixed micelles, which ferry them to the enterocyte surface for uptake • The absorption efficiency of fat-soluble vitamins varies from 50% to 80% for A, D and K to only 20% to 30% for vitamin E 41 DIGESTION AND ABSORPTION OF VITAMINS AND MINERALS • Enterocytes take up fat-soluble vitamins by simple diffusion or through transporters • In the smooth endoplasmic reticulum of enterocytes, the vitamins associate with lipid droplets that form nascent chylomicrons and VLDLs, which then translocate through the golgi and secretory vesicles for exocytosis into lymph 42 DIGESTION AND ABSORPTION OF VITAMINS AND MINERALS • Fat-soluble vitamin deficiency occurs in various fat mal-absorption states, including those induced by − Malabsorptive bariatric surgery − Drugs that impair triacylglycerol hydrolysis − Drugs that bind bile acids − A reduction of bile acids by impaired hepatobiliary function or by unabsorbable dietary fat substitutes • Fat-soluble vitamin deficiency can also result from impaired hepatic function 43 DIGESTION AND ABSORPTION OF VITAMINS AND MINERALS • Dietary folate (B9) must be deconjugated by a brush border enzyme before absorption by an anion exchanger at the apical membrane • Folate deficiency compromises DNA synthesis and cell division, with folate supplementation during pregnancy reducing the risk of neural tube defects • Cobalamin (B12) binds to haptocorrin in the stomach, and then bound to intrinsic factor in the small intestine, before endocytosis by enterocytes in the ileum 44 DIGESTION AND ABSORPTION OF VITAMINS AND MINERALS • Calcium absorption, regulated primarily by vitamin D, occurs by active transport in the duodenum and by diffusion throughout the small intestine • Magnesium absorption occurs by an active process in the ileum • Magnesium deficiency can affect neuromuscular, cardiovascular and gastrointestinal function 45 DIGESTION AND ABSORPTION OF VITAMINS AND MINERALS • Heme and non-heme iron are absorbed in the duodenum by distinct cellular mechanisms • The most important complication of iron depletion is anaemia • Iron overload produces haemochromatosis, a not uncommon genetic disorder • Ascorbic acid (vitamin C) forms soluble complexes with iron and reduces iron from the ferric to the ferrous state, thereby enhancing iron absorption 46 NUTRITIONAL REQUIREMENTS • Of the total caloric intake in a Western diet - 55 – 60% is carbohydrate - 25 – 30% is fat - 10 – 15% is protein • The daily protein requirement for adult humans is typically 0.8 g/kg body weight, but is higher in pregnant women, post-surgical patients and athletes. • No absolute daily requirement for carbohydrates or fat intake exist 47 NUTRITIONAL REQUIREMENTS • The diet must contain the nine essential amino acids because the body cannot synthesise them • Eleven other amino acids are necessary for protein synthesis, but the body can synthesise their carbon skeletons from intermediates or carbohydrate metabolism • Protein intake is most important to meet the needs for tissue maintenance and repair, for muscle and neural function, and to maintain host defence mechanisms 48 NUTRITIONAL REQUIREMENTS • Burn victims, patients recovering from surgery and patients with disorders of protein absorption all require increased daily protein intake • Vitamins and minerals are not energy sources, but are necessary for certain enzymatic reactions, for protein complexes or as precursors for biomolecules • Vitamins and minerals are essential for such functions as metabolism, immune competence, muscle force production and blood clotting 49 WEEKLY READINGS & ACTIVITIES 50