Week 2 Lecture 3 PDF

1  How are fatty acids/membrane lipids/cholesterol transported to cells and tissues? Lipoproteins The Enterohepatic circulation 2  Lipids are broadly classified as hydrophobic molecules that are soluble in organic solvents and in...

1  How are fatty acids/membrane lipids/cholesterol transported to cells and tissues? Lipoproteins The Enterohepatic circulation 2  Lipids are broadly classified as hydrophobic molecules that are soluble in organic solvents and insoluble in aqueous solution.  However, a number of lipids, including phospholipids, are amphipathic as they have distinct surfaces or domains that are charged and uncharged. ◦ Can form micelles or liposome structures in aqueous solutions.  Lipids such as sterols, sterol esters, phospholipids, triglycerides, fat-soluble vitamins, and waxes are insoluble in water, ◦ require specific transport mechanisms or carriers (e.g., lipoproteins, fatty acid binding proteins) to move them through the blood or cytoplasm.  Lipophilic molecules can passively diffuse across membranes, driven by concentration gradients, the availability of acceptors that facilitate desorption from the membrane bilayer, and by cellular metabolism. 3  Passive Diffusion  Protein-mediated transport of lipids ◦ Cell surface Transporters  Fatty acid transport molecules (FATPs)  ATP binding cassette (ABC) transporter proteins ◦ Carrier proteins  E.g. albumin  Endocytosis/exocytosis ◦ As part of lipoproteins 4 How lipids get into and out of cells 5  Integral membraneproteins Aid in moving fatty acids across membrane Some fatty acids diffuse across lipid bilayer Some are transported across Intestinal epithelial cells Cardiac muscle cells Adipocytes Fatty acid transport molecules (FATPs) – e.g. CD36 6  ATP binding cassette (ABC) transporter proteins ◦ thought to facilitate the ATP-dependent translocation of lipids or lipid- related compounds ◦ E.g. cholesterol, plant sterols, bile acids, phospholipids and sphingolipids.  Also known as primary active transporters, ◦ drive substrate flow against a concentration gradient by coupling movement to energy released by ATP hydrolysis. 7  Fatty acids and Carrier Proteins Most fatty acids have poor water solubility Therefore, fatty acids are bound to carrier proteins in cytosol or extracellular space e.g., serum albumin 8  Lipids can also be exported or imported in large well-defined lipoprotein complexes  Efficient alternative to molecule-by-molecule import/export  Packages hundreds/thousands of lipids into water soluble macromolecular carriers called lipoproteins 9  Lipoproteins are complex particles that transport lipids, such as phospholipids, triglycerides, and cholesterol, between cells  Classified according to their density and composition.  Five different types of lipoproteins ◦ chylomicrons ◦ very-low-density lipoprotein (VLDL) ◦ intermediate-density lipoprotein (IDL) ◦ low-density lipoprotein (LDL) ◦ High density lipoprotein (HDL) 10 11  Esterification of cholesterol is a universal mechanism to store and transport large quantities of cholesterol between organs and tissues and to avoid toxicity of the excess of cellular cholesterol.  Intended for transport and storage and thus to be inert  Cholesteryl esters (CEs) reside in hydrophobic cores of circulating lipoproteins and intracellular lipid droplets 12  Spherical 10-1000 nm diameter neutral lipidcore of TG and/or CE Around the core is layer of protein, PL, C oriented with polar portions exposed to surface of lipoprotein 9 Apoproteins Several enzymes Cholesteryl Ester Transfer Protein 13 14  LDLs transport cholesterol to various tissues throughout the body for use in cell membranes, hormone production, etc.  Contain a high proportion of cholesterol relative to protein  High levels are associated with an increased risk of heart disease "bad cholesterol." 15  Liver secretes VLDL VLDL TGs are hydrolysed by lipoprotein lipase (LPL) Loss of TGs and some apolipoproteins from VLDL produces IDL IDL LDL Removed from circulation by endocytosis via LDL receptors 16  Triglyceride-rich lipoproteins produced in enterocytes from dietary lipids—namely, fatty acids, and cholesterol. Main role is to transport dietary triglycerides and cholesterol from the intestines to other parts of the body, such as muscle and adipose tissue. Dietary lipids are absorbed and packaged into chylomicrons in intestinal epithelial cells Secreted into lymph…bloodstream Remodeled similarly to VLDL Form smaller cholesterol-enriched chylomicron remnants Taken up by hepatocytes through receptor-mediated endocytosis 17 Removal of triglycerides from chylomicrons results in the formation of chylomicron remnants. Remnants are mainly composed of cholesterol and are taken up by the liver via the Remnant and LDL receptors by recognition of ApoE 18  HDLs collect cholesterol from tissues and the walls of blood vessels and return it to the liver for excretion or recycling.  Has the highest density due to its higher protein content and lower lipid content.  Can remove excess cholesterol, particularly from artery walls, and transport it to the liver.  HDL is considered “good cholesterol” because high levels are associated with a lower risk of heart disease. 19  Pre β-HDL particles are formed by liver Contain Apo A but very little lipid They accept PL and cholesterol exported from cells (liver/intestine) by ABCA1 transporter forms a cholesterol-rich intermediate LCAT (lecithin:cholesterol acyltransferase) in the plasma esterifies cholesterol 20  HDL metabolism CE in core of HDL can be transferred to cells (liver/ steroidogenic cells) by receptor SRBI or to other lipoproteins by CETP (cholesteryl ester transfer protein) and subsequently to tissues, e.g. liver 21  FABPs Facilitate intracellular movement Hydrophobic pocket lined by β sheet Long chain fatty acid fitspocket Interacts non covalently with surrounding protein Expression is regulated… high in active muscles and adipocytes Genetic inactivation of cardiac muscle FABP converts heart from a muscle that burns fatty acids for energy into one that burns glucose 22 23  Enterohepatic circulation refers to the process by which bile acids, bilirubin, drugs, or other substances are secreted by the liver into bile, stored in the gallbladder, and released into the small intestine.  After aiding in digestion, especially of fats, these substances can be reabsorbed from the intestine back into the bloodstream and returned to the liver to be secreted again.  This cycle helps to conserve bile acids and efficiently regulate fat digestion.  This process is under tight regulation by nuclear receptor signalling. 24 https://www.osmosis.org/learn/Bile_se cretion_and_enterohepatic_circulation 25  Enterohepatic recycling is physiologically important for bile salt because the liver is unable to synthesise enough bile salts to meet the daily requirement for fat digestion. Bile acids (BA) facilitate digestion and absorption of lipids in the small intestine as well as regulating cholesterol homeostasis 3 ABC proteins move PLs, cholesterol and bile acids across apical surface of liver cells into small ductules ABCB4 flips phospholipids from cytosolicleaflet to exoplasmicleafletof apical membrane ABCB11 transports bile acid ABCG5/G8 exports sterols, e.g., cholesterol 26  Ileal bile acid transporter (IBAT) imports bile acids from lumen into intestinal epithelial cell Na+ linked symporter, uses energy released by movement of Na+ down concentration gradient Powers uptake of 95% of BA Move intracellularily with aid of I-BABP (intestinal bile acid-binding protein) to basolateral side Exported from basolateral side into blood by transport proteins… returned to liver by Na+ symporter NTCP Allows the cycling of BA from liver to intestine and back 27 Enterohepatic Circulation: 28  Enterohepatic Circulation (cont.) Large fraction of cholesterol on intestinal lumen comes from liver. ABCG5/8 is expressed in apical membrane of intestinal epithelial cells Helps control amount of cholesterol absorbed Pumps excess or unwanted absorbed sterols out of epithelial cells back intolumen ~1% dietary plant sterols enter bloodstream Unabsorbed bile acids, unabsorbed cholesterol and plant sterols are eventually excreted in faeces 29