BIOM2012 GIT - Lecture 4 (1) PDF

BIOM2012: Systems Physiology Module: Gastrointestinal System (Lecture 4) Ben Weger, PhD ([email protected]) Institute of Molecular Bioscience Physiology of Circadian Rhythms  BIOM2012 GI Module Lecture 1: Overv...

BIOM2012: Systems Physiology Module: Gastrointestinal System (Lecture 4) Ben Weger, PhD ([email protected]) Institute of Molecular Bioscience Physiology of Circadian Rhythms  BIOM2012 GI Module Lecture 1: Overview of digestion and absorption processes in the GIT, phases of gastric secretions, secretions of the Gastrointestinal system and their functions, digestive enzymes Lectures 2 & 3: The remaining GI system secretions and their functions, the intestinal phase of gastric secretion, motility in the GIT, the enteric nervous system Lecture 4: Liver anatomy and structure, functions of the liver, circadian clock and the Gastrointestinal system Organs of the Digestive System Major Organs of the Accessory Organs of Digestive Tract the Digestive System Teeth Oral Cavity (Mouth): Pharynx (throat): Tongue Salivary Glands Esophagus: Liver Stomach: Small Intestine Gallbladder (Duodenum, Jejenum, Ileum ) Pancreas Large Intestine (Colon, Cecum/Appendix, Colon Rectum, Anus) Rectum 3 Key function of the liver Regulates Blood Glucose Fat Metabolism 1. Releases glucose into the 1. Produces and distributes blood bloodstream to maintain normal lipids (lipoproteins). levels. 2. Breaks down fatty acids via β- 2. Stores glucose as glycogen oxidation, producing Acetyl- Detoxification and breaks it down when CoA for energy and xenobiotics (foreign chemicals) needed (glycogenolysis). biosynthesis 3. Synthesizes glucose through gluconeogenesis during Protein Synthesis various plasma fasting or energy demand. proteins essential for blood functions (e.g., albumin, clotting factors) Vitamin Storage (fat-soluble vitamins (A, D, E, K) and vitamin B12) Hormones Bile Production Nitrogen Excretion Converts NH3, a byproduct of protein Waste Management Degrades old or damaged proteins. metabolism, into urea for excretion by the kidneys (urea cycle). Iron Metabolism  Liver Blood Supply The liver receives blood from two sources: Arterial Blood (25%) Delivered via the hepatic artery, supplying O₂-rich blood Venous Blood (75%) 25% Delivered via the hepatic portal vein, carrying blood from the digestive tract (e.g., stomach, small intestine and large intestine). This blood contains: Nutrients 75% Drugs Hormones Pathogens (e.g., bacteria, viruses) Toxins O2 poor Blood leaves the liver through the hepatic vein. he primary role of the hepatic portal vein? ygenated blood to the liver Liver Lobule: Structural and Functional Unit The liver is organised into hexagonal units called liver lobules. The portal vein and hepatic artery both branch Portal extensively within the liver, supplying blood to the portal venules and hepatic arterioles, which triad converge at the corners of the lobule. A portal triad is found at each corner of the lobule, consisting of: A portal vein branch Hepatic A hepatic artery branch A bile duct, which drains bile from hepatocytes vein via bile canaliculi. Both the portal vein and hepatic artery empty blood into a shared capillary network known as liver sinusoids. The blood from sinusoids is collected by central veins, which drain into larger hepatic veins. The hepatic veins then empty filtered blood into the inferior vena cava (IVC), which returns it to the heart via the right atrium. 6  Schematic representation of the structure of the hepatic lobule There are 4 basic cell types that reside in the liver: Hepatocytes: The main functional cells of the liver are responsible for functions such as metabolism, detoxification, protein synthesis, and bile production. Liver Endothelial Cells (LEC) : Hepatocytes Line the blood vessels (sinusoids) in the liver, facilitating the exchange of substances between the blood and hepatocytes. Stellate Cells: LEC Store vitamin A and play a key role in liver fibrosis when activated. Kupffer Cells: Specialised macrophages that reside in the liver and are responsible for phagocytosing pathogens, senescent erythrocytes, dead cells, and debris. Kupffer Stellate cell cell 7 Liver Zonation and Functional Variability Blood flow along the lobule’s radial axis creates gradients of oxygen, nutrients, and hormones This spatial variability results in the non-uniform expression of key liver functions à liver zonation Examples of zonated liver functions: Pericentral (Zone III): Drug detoxification Bile acid production Oxygen, Periportal (Zone I): Nutrients, hormones Cholesterol biosynthesis Protein secretion Zone III Zone II Zone I DOI: 10.1038/s41575-019-0134-x 8 Key function of the liver Regulates Blood Glucose Fat Metabolism 1. Releases glucose into the 1. Produces and distributes blood bloodstream to maintain normal lipids (lipoproteins). levels. 2. Breaks down fatty acids via β- 2. Stores glucose as glycogen oxidation, producing Acetyl- Detoxification xenobiotics (foreign and breaks it down when CoA for energy and chemicals) needed (glycogenolysis). biosynthesis 3. Synthesizes glucose through gluconeogenesis during Protein Synthesis various plasma fasting or energy demand. proteins essential for blood functions (e.g., albumin, clotting factors) Vitamin Storage (fat-soluble vitamins (A, D, E, K) and vitamin B12) Hormones Bile Production Nitrogen Excretion Converts ammonia, a byproduct of Waste Management Degrades old or damaged proteins. protein metabolism, into urea for excretion by the kidneys (urea cycle). Engages in the breakdown of aged Iron Metabolism red blood cells through Kupffer cells (macrophages). Examples of Protein Secretion by the Liver The liver synthesises and secretes a variety of important plasma proteins Some examples: Albumin: 60% of plasma proteins; Function: - maintain osmotic pressure - transports various substances in the blood, including hormones (e.g., thyroid hormones and cortisol), fatty acids, bilirubin, drugs, and calcium Carriage Proteins (Binding Proteins) Transferrin (Fe3+), Ceruloplasmin (Cu2+), Transcortin (Cortisol) Blood coagulation factors: fibrinogen, prothrombin, factor V, VII, IX, X, XI, XII, and protein C and S Anti-clotting proteins: Plasminogen, antithrombin III (Pro-)Hormones: e.g., IGF-1 (Insulin-like Growth Factor 1), Thrombopoietin (platelet rough formation), Angiotensinogen (Precursor to angiotensin, which helps regulate blood pressure and fluid balance. Apolipoproteins Immune proteins: Proteins of the complement proteins, C-reactive peptide (level rises in response to inflammation) not examinable Key function of the liver Regulates Blood Glucose Fat Metabolism (source or sink) 1. Produces and distributes blood 1. Releases glucose into the lipids (lipoproteins). bloodstream to maintain normal 2. Breaks down fatty acids via β- levels. oxidation, producing Acetyl- Detoxification xenobiotics (foreign 2. Stores glucose as glycogen CoA for energy and chemicals) and breaks it down when biosynthesis needed (glycogenolysis). 3. Synthesizes glucose through Protein Synthesis various plasma gluconeogenesis during proteins essential for blood functions fasting or energy demand. (e.g., albumin, clotting factors) Vitamin Storage (fat-soluble vitamins (A, D, E, K) and vitamin B12) Hormones (e.g., IGF-1, thrombopoietin, Bile Production Angiotensinogen) Nitrogen Excretion Converts ammonia, a byproduct of Waste Management Degrades old or damaged proteins. protein metabolism, into urea for excretion by the kidneys (urea cycle). Engages in the breakdown of aged Iron Metabolism red blood cells through Kupffer cells (macrophages). Lipid transportation What are lipoproteins? These complex particles are essential for the transport of lipids in the blood or extracellular fluids (à lipid-carrying vehicles) Two organs can produce them: The small intestine and liver Biochemistry 39: 9763, 2000 Chylomicrons originate and are synthesised in enterocytes. Dietary fats and cholesterol, along with any cholesterol that returns to the intestine from the liver, get packaged into chylomicrons. They then enter the lymphatic system … Influenced by receptors (e.g., Niemann-Pick C Lipid transportation …move into circulation, and provide a Muscle significant source of energy, particularly for muscle cells. Chylomicrons have a very short residence time in circulation (hours). As they offload triglycerides, they become smaller, turning into chylomicron remnants, which then return to the liver for further processing. 16 Causal high ApoB to athereosclorosis: https://www.sciencedirect.com/science/article/pii/S266666772 2000551?via%3Dihub Lipid transportation The liver is the second major site for lipoprotein synthesis. It can produce VLDLs The liver releases these VLDL molecules into circulation, where they deliver triglycerides to other tissues. Muscle As VLDLs offload triglycerides, they become smaller and are reclassified as IDLs. This process continues until they eventually become LDL molecules. The primary role of these LDL molecules is to transport cholesterol back to the liver (via LDL receptor) Additionally, LDLs can transfer cholesterol from HDL particles. Cholesterol is eliminated through its conversion into bile acids, allowing the body to maintain cholesterol homeostasis 17 https://www.sciencedirect.com/science/article/pii/S266666772 2000551?via%3Dihub Key function of the liver Regulates Blood Glucose Fat Metabolism 1. Releases glucose into the 1. Produces and distributes blood bloodstream to maintain normal lipids (lipoproteins). levels. 2. Breaks down fatty acids via β- 2. Stores glucose as glycogen oxidation, producing Acetyl- Detoxification xenobiotics (foreign and breaks it down when CoA for energy and chemicals) needed (glycogenolysis). biosynthesis 3. Synthesizes glucose through gluconeogenesis during Protein Synthesis various plasma fasting or energy demand. proteins essential for blood functions (e.g., albumin, clotting factors) Vitamin Storage (fat-soluble vitamins (A, D, E, K) and vitamin B12) Hormones (e.g., IGF-1, thrombopoietin, Bile Production Angiotensinogen) Nitrogen Excretion Converts ammonia, a byproduct of Waste Management Degrades old or damaged proteins. protein metabolism, into urea for excretion by the kidneys (urea cycle). Engages in the breakdown of aged Iron Metabolism red blood cells through Kupffer cells (macrophages). Systemic and cellular iron uptake Two sources of iron: Uptake of dietary iron Recycling of hemoglobin via Kupffer cells DMT1 transports Fe²⁺ into the duodenal enterocyte. Kupffer cells phagocytose senescent erythrocytes, releasing iron. Iron transport and metabolism: Fe²⁺ leaves the cells (duodenal enterocytes or macrophages) via ferroportin (FPN). In the blood, Fe³⁺ binds to transferrin (Tf) in plasma. Tf-bound iron can be taken up by cells via TfR1 (Transferrin Receptor 1). In the liver, iron is stored in ferritin. The hepatokine Hepcidin is a systemic regulator of iron uptake The hormone hepcidin is a key regulator of iron metabolism An increase in iron levels in the plasma and iron storage stimulates hepcidin production in hepatocytes. Hepcidin secretion is suppressed under iron deficiency. Its main target is ferroportin (FPN). FPN, the only known cellular iron exporter, is Hepcidin present on cells including duodenal enterocytes, macrophages, and hepatocytes. Hepcidin binding to FPN results in its degradation, leading to less iron being released into the blood. à reduced overall iron availability. Key function of the liver Regulates Blood Glucose Fat Metabolism 1. Releases glucose into the 1. Produces and distributes blood bloodstream to maintain normal lipids (lipoproteins). levels. 2. Breaks down fatty acids via β- 2. Stores glucose as glycogen oxidation, producing Acetyl- Detoxification xenobiotics (foreign and breaks it down when CoA for energy and chemicals) needed (glycogenolysis). biosynthesis 3. Synthesizes glucose through gluconeogenesis during Protein Synthesis various plasma fasting or energy demand. proteins essential for blood functions (e.g., albumin, clotting factors) Vitamin Storage (fat-soluble vitamins (A, D, E, K) and vitamin B12) Hormones (e.g., IGF-1, thrombopoietin, Bile Production Angiotensinogen) Nitrogen Excretion Converts ammonia, a byproduct of Waste Management Degrades old or damaged proteins. protein metabolism, into urea for excretion by the kidneys (urea cycle). Engages in the breakdown of aged Iron Metabolism red blood cells through Kupffer cells (macrophages). Liver Detoxification The liver is responsible for metabolising and detoxifying many endogenous (=originating within the body) and exogenous (= originating outside the body) compounds. Xenobiotics are compounds foreign to an organism, such as drugs, toxins, or environmental pollutants. Some compounds taken up by hepatocytes (e.g., proteins) are completely digested within lysosomes. Other compounds undergo biotransformation through three phases: Phase I: Modification Phase II: Conjugation Phase III: Secretion/Excretion Hepatocytes are the primary cells responsible for this biotransformation/detoxification of drugs and other xenobiotics. 26 Three Phases of Detoxification Phase I: Modification Involves the chemical modification of toxins or drugs. Cytochrome P450 enzymes add or expose reactive groups (e.g., hydroxyl or carboxyl groups), making the molecule more hydrophilic (water-soluble) and reactive for Phase II. Key reactions include oxidation, reduction, and hydrolysis. Three Phases of Detoxification Phase II: Conjugation In this phase, the functional groups introduced in Phase I are conjugated with polar molecules (e.g., glutathione, sulfate, or glucuronate). This process makes the metabolites more hydrophilic, facilitating their excretion. Three Phases of Detoxification Phase III: Secretion/Excretion Drug The metabolic products of Phase I may be directly excreted, but often require further metabolism through Phase II to increase water solubility. Phase I In Phase III, conjugated metabolites are Phase II Conjungated introduce or metabolites actively transported out of the hepatocytes, expose a typically using membrane transport proteins polar group (e.g., ATP-binding cassette (ABC) transporters). àexcretion via urine or faeces Excretion Pathways: Bile Serum Most drugs are excreted by the kidneys (urine) Kidney Intestine Some metabolites (larger molecular weights) are excreted into bile and are eliminated via faeces. Urine Faeces Which of those cells plays a major role in detoxification of drugs Hepatocytes: Stellate Cells: Kupffer Cells: Liver Endothelial Cells (LEC) : https://padletuq.padlet.org/bweger/lecture-4- 9ldbl1cvft3t8ob7 32 Timing of tolerability of anticancer drugs THE CIRCADIAN CLOCK! From Levi F, 2010 Not examinable We live to a 24 h beat. Most organisms posses a circadian clock that helps them to adapt to it. à Humans have an intrinsic clock with a period of ~ 24.5 hours The central clock resides in the suprachiasmatic nuclei (SCN) of the hypothalamus 7 days recording SCN Welsh et al., 2010 SCN neuron Light A central clock in the suprachiasmatic nucleus (SCN) synchronises peripheral tissue clocks in most cells and drives rhythmic physiology Rhythmic Physiology Masri & Sassone-Corsi, Nat Med, 2018 The molecular circadian clock regulates the circadian behavior All known circadian oscillators consist of negative feeback loops of gene expression Activator Repressor Molecular feedback loop of the mammalian circadian clock CCGs not examinable A complex network of circadian clocks and feeding cycles controls daily rhythms in mammals Sleep/ Wake cycle Body temperature Feeding Circadian Light Clock 24h Metabolism GIT … Circadian rhythms in the GIT Bile secretion into the gallbladder and bile excretion Liver blood flow into the duodenum Circadian rhythms in the GIT Basal gastric acid secretion Small intestinal motility Circadian rhythms in the GIT DOI: 10.1016/j.cell.2016.11.003 Key Objectives & Expected Learning Outcomes (Lecture 4): You should be able to: Explain the blood supply to the liver and the structure of liver lobules, including the concept of liver zonation. Describe the key functions of the liver, including iron metabolism, lipid transport, and the three phases of detoxification. Understand the concept of the circadian clock as an endogenous oscillator that regulates a wide range of physiological processes, including the functions of the GI tract.  [email protected] COMMONWEALTH OF AUSTRALIA Copyright Regulations 1969 WARNING This material has been reproduced and communicated to you by or on behalf of the University of Queensland pursuant to Part VB of the Copyright Act 1968 (the Act). The material in this communication may be subject to copyright under the Act. Any further reproduction or communication of this material by you may be the subject of copyright protection under the Act. Do not remove this notice.