Absorption of dietary fats, lipoproteins/apolipoproteins, lipoprotein metabolism, regulation of plasma cholesterol, LDL receptor pathway, lysosomal processing of cholesterol, HDL, reverse cholesterol transport, bilirubin metabolism, jaundice/icterus

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Biomedical Science
BMS 460
D.Rao Veeramachaneni

14 October Absorption of dietary fats: bile and pancreatic lipase Choleresis: liver cells secrete bile that contains bile salts, cholesterol, lecithin, bilirubin, electrolytes, and water Bile salts emulsify fats Exocrine pancreas secretes enzymes Colipase: amphipathic protein makes fat droplets covered with emulsifying agents accessible to water soluble lipase Lipase: breaks down triglycerides Chylomicrons (triglycerides, phospholipids, cholesterol, apolipoproteins) carry fat from intestine to liver via general circulation In lumen of small intestine Fat droplet → emulsion droplets Via colipase, bile salts, phospholipids Emulsion droplets → micelles Via bile salts, pancreatic lipase Micelles ↔ free molecules of fatty acids and monoglycerides Diffuse into epithelial cell In epithelial cell Triglyceride synthetic enzymes in endoplasmic reticulum Droplets of triglyceride enclosed by membrane from the endoplasmic reticulum Excreted to lacteal as chylomicron Lipoproteins Lipoproteins transport cholesterol and other lipids between tissues Binding to lipoproteins to receptors is mediated through apoproteins, which are acquired as lipoproteins are assembled in enterocytes and hepatocytes Apoliporotein Characteristics Apoprotein Lipoprotein Source Biological role association A-1 HDL, Liver, intestine Activates lecithin chylomicrons – cholesterol transferase in HDL B-48 Chylomicrons Intestine Serves as structural protein for chylomicrons B-100 VLDL, LDL Liver Serves as structural protein for VLDL and LDL; contains LDL receptor- binding domain C-11 HDL, VLDL, Liver Activates chylomicrons extrahepatic lipoprotein lipase E VLDL, Liver Mediates uptake chylomicrons of chylomicron remnants by the liver Chylomicron: 80 – 1000 nm, 85% triglyceride, 5% cholesterol Very-low-density lipoprotein (VLDL): 30 – 80 nm, 55% triglyceride, 20% cholesterol Intermediate-density lipoprotein (IDL): 25 – 40 nm, 30% triglyceride, 40% cholesterol Low-density lipoprotein (LDL): 15 – 20 nm, 5% triglyceride, 55% cholesterol, 20% protein High-density lipoprotein (HDL): 5 – 10 nm, 5% triglyceride, 20% cholesterol, 50% protein Lipoprotein Metabolism Chylomicrons enter the bloodstream via thoracic duct. Once in the blood, chylomicrons are subject to delipidation by lipoprotein lipase. Eventually, enough lipid has been lost and additional apolipoproteins gained, that the resulting particle, now referred to as a chylomicron remnant, is taken up by the liver. In the liver chylomicron remnants and low-density lipoprotein (LDL) are resynthesized into high-density lipoprotein (HDL) and very-low-density lipoprotein (VLDL) and put back into circulation. In circulation, triglycerides are removed for tissue use from VLDL, which becomes intermediate-density lipoprotein (IDL). More triglyceride removal leads to the formation of low-density lipoprotein (LDL) LDL is taken up by peripheral tissues to obtain cholesterol About 70% of the circulating LDL returns to the liver In abeta-lipoproteinemia, a genetic defect in the synthesis of beta apolipoprotein B, lipids are not properly absorbed because chylomicrons cannot be formed and transported normally. Role of liver in the synthesis and clearance of LDL and cholesterol thereby regulating the amount of plasma cholesterol Chylomicron remnants in blood are taken up by liver The first step in this sequence is the secretion of very-low-density lipoprotein (VLDL) by the liver into the bloodstream. When a VLDL particle reaches the capillaries of adipose tissue or muscle, it is cleaved by lipoprotein lipase, a process that extracts most of the triglycerides resulting in intermediate-density lipoprotein (IDL), which is enriched in cholesterol esters, but it retains two of the three apoproteins (B-100 and E) present in the parent VLDL. ~50% newly formed plasma IDL is recycled by liver to generate VLDL The IDL not taken up by liver is further metabolized to remove most of the remaining triglycerides yielding cholesterol-rich LDL particles. Like IDL, 70% of plasma LDL is taken up by the liver by receptor-mediated transport via LDL receptor that recognizes both ApoE and ApoB-100. A deficiency of LDL receptor results in hypercholesterolemia. Familial Hypercholesterolemia (Dyslipidemia) LDL receptor pathway and regulation of cholesterol homeostasis Although many cell types, including fibroblasts, lymphocytes, smooth muscle, hepatocytes, and adrenocortical cells, possess high-affinity LDL receptors, ~70% of the plasma LDL seems to be cleared by the liver, using a sophisticated transport process LDL endocytosed through clathrin-coated pit Lysosome degrades to amino acids and cholesterol Cholesterol → cell membrane, steroid hormones, and bile acids; storage of cholesterol ethers An oversupply of cholesterol Stimulates storage of cholesterol ethers Inhibits HMG CoA reductase (synthesizes cholesterol) Inhibits synthesis of LDL receptors Lysosomal Processing of Cholesterol: Sequelae of Dysfunction The LDL molecule is enzymatically degraded in the lysosomes The apoprotein part is hydrolyzed to amino acids, whereas the cholesteryl esters are broken down to free cholesterol This free cholesterol, in turn, crosses the lysosomal membrane to enter the cytoplasm, where it is used for membrane synthesis and as a regulator of c
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