Lipid Transport and Distribution PDF

Lipid transport and distribution PRESENTED BY SULE GUNTER MEDI11-102 Week 3 Title Lipid transport and distribution Presenter Assistant Professor Sulè Gunter This session will introduce th...

Lipid transport and distribution PRESENTED BY SULE GUNTER MEDI11-102 Week 3 Title Lipid transport and distribution Presenter Assistant Professor Sulè Gunter This session will introduce the concept of lipid transport and distribution in the body, covering triglycerides and cholesterol. We will briefly review lipid absorption from the Why you should attend this session gastrointestinal tract, followed by an overview of lipid transport in body fluids, uptake and distribution to body cells. No specific preparation – it will be useful to review concepts from semester 1 What you will need to do in regarding absorption of macromolecules from the GI tract. preparation Useful text: Baynes and Dominiczak, 6th Ed. Chapters 14 and 33 What you will need to bring N/A session LEARNING OBJECTIVES 01 Outline the digestion, absorption, and transport of dietary lipids through the exogenous lipoprotein pathway. 02 Describe the endogenous lipoprotein pathway, and explain the role of apolipoproteins in the regulation of this pathway. 03 Describe the mechanism of reverse cholesterol transport. Regulation of cholesterol synthesis and 04 clearance. 01 Outline the digestion, absorption, and transport of dietary lipids through the exogenous lipoprotein pathway. Bile is produced by hepatocytes in the liver and stored in the gallbladder Bile contains amphipathic bile salts that cover and emulsify dietary fats In the emulsification process, fat globules are converted to microscopic micelles Micelles contain triglycerides, cholesterol, phospholipids and fat- soluble vitamins Chylomicrons are synthesized The pancreas release bicarbonate-rich fluid inside the enterocyte and digestive enzymes into the duodenum. Emulsification increases the surface area for pancreatic lipases to act on and hydrolyse TAGs FAs, MAGs and cholesterol can then be transported into the enterocyte by specific transporters. Source: Guyton and Hall Textbook of Medical Physiology Hall, John E., PhD; Hall, Michael E., MD, MS Published January 1, 2021. Pages 853-864. © 2021.  Chylomicrons contain ApoB-48, Apo A, Apo C- II and Apo E Chylomicron synthesis *ApoB- 48* ApoE FAs and MAGs are used to re- synthesize TAGs in the enterocyte. Absorbed cholesterol is esterified to cholesterol esters (CE) by acyl- ApoC-II ApoA CoA cholesterol acyl transferase (ACAT). TAGs and CE are packaged into chylomicrons in the endoplasmic reticulum. Chylomicrons are secreted into the lymph and delivered via the thoracic The formation of chylomicrons in duct to the circulation. the endoplasmic reticulum requires the synthesis of Apo B-48 by the Newly formed chylomicrons are enterocyte. delivered to the systemic circulation and not to the liver via the portal circulation. Adapted from Source: Ferri's Clinical Advisor 2025 Intestinal lumen Enterocyte Ferri, Fred F., MD Published January 1, 2025. Pages 581- 584.e4. © 2025. Chylomicron metabolism Lipoprotein lipase (LPL) is produced in muscle cells and As TAGs are released from chylomicrons, they decrease in adipocytes and transported to the luminal surface of size forming chylomicron remnants, which are rich in capillaries. cholesterol esters. Apo C-II on chylomicrons activate LPL, leading to the Apo E on the chylomicron remnants binds to receptors on hydrolysis of the TAGs inside the chylomicrons. hepatocytes and are cleared by the liver in this way. FAs are taken up by the adjacent muscle cells and adipocytes for energy production or storage. Capillary endothelial lining LPL LPL LPL: Lipoprotein lipase Classes of lipoproteins HDL LDL VLDL There are different lipoproteins with different apolipoproteins. Chylomicron Apolipoproteins have 4 major functions: structural role guides formation of lipoproteins act as ligands for lipoprotein receptors in tissues Netter's Illustrated Pharmacology, Chapter 4, 93-128. Copyright © 2014, 2005 by Elsevier Inc serves as activators/inhibitors of enzymes involved in metabolism Classes of lipoproteins Feingold KR. 2021 Available from: https://www.ncbi.nlm.nih.gov/books/NBK305896/ KEY CONCEPTS Digestion of dietary fats and the formation of chylomicrons in the intestinal enterocytes. The role of ApoB-48 and ApoC-II in chylomicron function. The involvement of lipoprotein lipase (LPL) in triglyceride hydrolysis. The clearance of chylomicron remnants by the liver through ApoE-mediated receptor binding. 02 Describe the endogenous lipoprotein pathway, and explain the role of apolipoproteins in the regulation of this pathway VLDL synthesis In the liver, fatty acids are a produced through de novo Chylomicron Glucose fatty acid synthesis. remnants The availability of fatty acids determine the production rate of triglycerides. GLUT-2 Apo E receptor Liver cell Glycolysis Pyruvate Mitochondria Acetyl-CoA Fatty acids Triglycerides Triglycerides and cholesterol esters are *ApoB- 100* transferred onto newly ApoE synthesised Apo B-100. VLDL particles also contain Apo C- II and Apo E. ApoC-II VLDL VLDL metabolism 4. Some of the IDL particles are taken up by the liver via binding of Apo 1. The liver releases VLDL E to receptors. particles into the Capillary lumen circulation *ApoB- 100* ApoE ApoC-II Capillary endothelial lining LPL 2. VLDL particles are transported to FAs peripheral tissues where the triglycerides are hydrolysed by LPL and fatty acids are 3. The removal of released. triglycerides from VLDL Apo C-II activates LPL on the surface of the causes particles to become endothelium, in much the same way as progressively smaller (IDL). chylomicrons. Tissues take up the fatty acids for metabolism or storage. LDL metabolism 4. The levels of plasma LDL are 1. The remaining IDL particles are determined by the rate of LDL transformed into LDL. LDLs are rich in production and the rate of LDL cholesterol esters and carry 65 -75% of clearance. total plasma cholesterol. LDL lipoproteins contain mostly Apo B-100. *ApoB- 100* 2. Cells take up LDL receptor 3. The entire LDL cholesterol by receptor- particle is taken up. mediated endocytosis Cholesterol is used for (involves apoB-100 & membrane synthesis in LDL receptors) the endoplasmic reticulum.  Receptor mediated endocytosis Alberts et al. Molecular Biology of the Cell. 5th Ed.  recap ENDOGENOUS PATHWAY VLDL TRIGLYCERIDE CONVERSION TO CHOLESTEROL LDL CLEARANCE PRODUCTION DELIVERY IDL AND THEN DELIVERY LDL Key Concepts: VLDL production in the liver. The role of ApoB-100 in VLDL structure and LDL formation. The conversion of VLDL to LDL via lipoprotein lipase. LDL receptor-mediated endocytosis and its significance in cholesterol homeostasis.  Describe the mechanism of reverse cholesterol transport. 03 Reverse 3. HDL circulates back to the liver. The Apo E present on the surface of HDL binds to receptors on hepatocytes. Cholesterol may also be taken up via scavenger cholesterol receptor class B type I (SR-BI). transport Cholesterol is repackaged into VLDL lipoproteins or excreted as bile in the faeces. Cholesterol-depleted HDLs recirculate to extract more cholesterol from peripheral tissues. Apo A- I Apo C Apo E 2. Apo A-I activates ATP binding casette-1 (ABCA-1), that transfers cholesterol onto HDL. Cholesterol 1. ‘Empty’ HDL particles are produced Once in HDL, the enzyme lecithin- in the liver and intestines. Synthesis cholesterol acyltransferase (LCAT), requires the structural protein Apo A-I. converts free cholesterol into HDL also contains smaller amounts of cholesteryl esters (CE’s). Apo C and Apo E. KEY CONCEPTS The function of ApoA-I in HDL formation and cholesterol efflux. The conversion of cholesterol into cholesteryl esters by lecithin-cholesterol acyltransferase (LCAT). The hepatic uptake of HDL cholesterol via scavenger receptor class B type I (SR-BI) and subsequent excretion in bile.  Liver Summary slide Extrahepatic Intestine tissues HDL precursors Capillaries 04 Regulation of cholesterol synthesis and clearance Sources of cholesterol in the body Intake is about 500mg/day Digested and absorbed along with fat, and secreted as part of the chylomicron Synthesis is about 1 g/day – i.e. body can make sufficient amounts & most cholesterol is synthesised Needed to replenish any lost cholesterol. If intake increases, synthesis decreases and vice versa Liver is a major source of cholesterol, although significant amounts are also synthesised in skin, adrenal cortex, testis and ovary. Synthesised from acetyl CoA  Key regulatory enzyme of cholesterol synthesis Activated by insulin and thyroid hormone & inhibited by glucagon and cortisol Intracellular cholesterol concentration regulates the activity of the HMG CoA reductase enzyme and the expression of LDL receptors on (ACAT = acyl-CoA:acylcholesterol transferase) the cell membrane. HMG-CoA reductase and statins Target of statin drugs- inhibit enzyme Statins inhibit HMG CoA reductase and decrease intracellular synthesis of cholesterol Also lead to increased synthesis of LDL receptors & increased uptake of plasma cholesterol à reduces plasma cholesterol levels Hypercholesterolaemia Most frequent dyslipidaemia Elevated total plasma cholesterol Increased LDL-cholesterol, caused by single gene defects or polygenic disorders Polygenic, with diet & environmental factors A number of other dyslipidaemias have more defined genetic background… Familial hypercholesterolaemia Hypertriglyceridaemia FH is typically a monogenic genetic Increased VLDLs and chylomicrons. disorder involving a mutation in the gene Obesity, excessive consumption of sugars, for the LDL receptor or genes involved in its saturated fats, alcohol, insulin resistance regulation. and diabetes are predisposing factors. Very high plasma cholesterol and LDL- Familial forms are due to mutations in the cholesterol. lipoprotein lipase gene or apoC-ii – Reduced number of LDL receptors, resulting in massive accumulation of impaired function of LDL receptor, chylomicrons decreased clearance of LDL from plasma. Results in increased risk of CHD