BIOC 460 DR. TISCHLER LECTURE 36  LIPID TRANSPORT

OBJECTIVES Common lipid components of the diet. Describe the five steps of digestion and absorption of lipids including the important enzymes and location where each step occurs. Describe the general structure of a lipoprotein Name the 4 main classes of lipoproteins and a) indicate whether each is in the exogenous or the endogenous system. b) identify the major lipid component in each. c) describe their lipid-transport functions. d) list their key apoproteins and the functions of these apoproteins

OBJECTIVES Discuss the function of lipoprotein lipase. Outline the steps in the processing of: a) chylomicrons from their synthesis in the intestinal cell to the delivery of cholesterol in chylomicron remnants to the liver. b) VLDL from its synthesis in the liver to the delivery of cholesterol to cells via the low-density-lipoprotein (LDL) receptor including the cellular uptake and processing of cholesterol via LDL. Describe how defects in the LDL receptor are associated with familial hypercholesterolemia and atherosclerosis

Figure 1 Five steps of lipid digestion and absorption Lipids: Triacylglycerol Cholesterol esters Phospholipids Lingual Lipase Gastric Lipase STEP 1 stomach STEP 2 Pancreas releases: Lipase (+colipase) cholesterol esterase phospholipase A2 small intestine pancreas STEP 4 Lipids absorbed from micelles into epithelial cells STEP 3 Liver releases bile acids to solubilize lipid products in mixed micelles liver STEP 5 Chylomicrons form and travel through lymphatics

Table 1. Steps of lipid digestion and absorption Location Enzymes 1. Minor digestion (TAGs  DAGs + FFA) mouth and stomach lingual/ gastric lipase 2. Major digestion (all) TAG  MAG + 2FFA (PL) CE  chol. + ester (CE) PL  FA + lysoPL (PLA) lumen of the small intestines pancreatic lipase (+colipase) cholesterol esterase phospholipase A2 3. Formation of mixed micelles (uses bile salts as biological detergent) N/A 4. Passive absorption of lipolytic products into intestinal epithelial cell 5. Assembly and export of chylomicrons from intestinal cells to the lymphatics

Figure 2. Model of low density lipoprotein Figure 2. Model of low density lipoprotein. Other lipoproteins have a similar structure differing in the core content of lipid and the type of apoproteins on the surface of the molecule

Table 2. The major classes of lipoproteins and their relative content of triacylglycerol, cholesterol and protein Class Triacylglycerol Cholesterol Protein Chylomicrons >95% 3% 2% Very Low Density Lipoprotein (VLDL) 70% 20% 10% Low Density 55% 25% High Density 15% 35% 50%

chylomicron interacts with lipoprotein lipase removing FFA Lymph system: INTEST INE chylomicrons acquire apo CII (C) and E (E) from HDL non-hepatic tissues CE CE CE C E chylomicron remnants travel in blood to liver C E ApoB48 helps with chylomicron E Liver: apo E chylo remnants bind receptor Cholesterol from remnants deposited in liver LIVER Figure 3. Exogenous pathway of lipid transport. Chylomicrons carry dietary fatty acids to tissues and remnants take cholesterol to the liver

VLDL acquires apo CII (C) and E (E) from HDL B100 (B) helps assemble and export nascent VLDL VLDL interacts with LPL Produce LDL non-hepatic tissues LIVER CE C E CE B CE C E C E bile acids B LDL travels to tissues B100 binds to receptors B Apo E binds to receptor B LDL into cell delivers cholesterol HDL scavenges cholesterol Figure 4. Endogenous pathway of lipid transport.

ACAT CE stored in droplets Recycling of clathrin and receptor Recycling of clathrin Ligand/receptor dissociate in sorting endosome LDL receptor transport vesicle- lysosome fuse forming late endosome lysosome clathrin- coated pit ooo late endosome Golgi NPC-1 mediated transfer ooo free pool of cholesterol ACAT CEcholesterol B100  a. acids endocytosis CE stored in droplets vesicle CE CE LDL CE Figure 5. Steps in the cellular uptake of cholesterol via the LDL receptor.

Table 3. Summary of lipoprotein functions Chylomicron deliver fatty acids as part of triacylglycerol, from dietary fat to muscle, adipose Chylomicron remnants deliver dietary cholesterol to the liver VLDL deliver fatty acids, attached to triacylglycerol, derived from liver synthesis to non-hepatic tissues (e.g., muscle, adipose) LDL from VLDL; delivers cholesterol, derived from liver synthesis to various tissues HDL collects (scavenges) cholesterol from non-hepatic tissues and delivers to the liver

Table 4. Summary of apoproteins and their characteristics Lipoprotein Apoprotein Function Chylomicron B-48 CII E chylomicron formation activates LPL transferred to remnants Chylomicron remnants binds liver receptor for remnants to enter cell VLDL B-100 assembly of VLDL binds liver receptor for VLDL to enter cell LDL binds LDL receptor for LDL to enter cell HDL A1 facilitates cholesterol efflux from cells HDL stored, transfer to chylos/VLDL binds liver receptor for HDL to enter cell