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Transcript
LIPOPROTEINS A to Z Lipid Digestion & Transport Digestion & transport of lipids poses unique problems relating to the insolubility of lipids in water. Lipids, & products of their digestion, must be transported through aqueous compartments within the cell as well as in the blood & tissue spaces. Free fatty acids are transported in the blood bound to albumin Within intestinal cells (and other body cells) some of the absorbed cholesterol is esterified to fatty acids, forming cholesteryl esters. The enzyme that catalyzes cholesterol esterification is ACAT (Acyl CoA: Cholesterol Acyl Transferase). Intestinal epithelial cells synthesize triacylglycerols, cholesteryl esters, phospholipids, free cholesterol, and apoproteins, and package them into chylomicrons. Chylomicron assembly Fatty acids, 2-MAG lumen Fatty acids, 2-MAG ATP ADP intestinal epithelium Triacylglycerol Cholesterol Apolipoproteins Chylomicrons Chylomicrons lymphatics Formation of Chylomicrons : Chylomicrons are secreted by intestinal epithelial cells, and transported via the lymphatic system to the blood. Apoprotein CII on the chylomicron surface activates Lipoprotein Lipase, an enzyme attached to the luminal surface of small blood vessels. Lipoprotein Lipase catalyzes hydrolytic cleavage of fatty acids from triacylglycerols of chylomicrons. Released fatty acids & monoacylglycerols are picked up by body cells for use as energy sources. Lipoprotein Lipase, is attached to the luminal surface of small blood vessels. It catalyzes hydrolytic cleavage of fatty acids from triacylglycerols of chylomicrons. Released fatty acids & monoacylglycerols are picked up by body cells for use as energy sources. With removal of triacylglycerols and some proteins, the % weight that is cholesteryl esters increases. Chylomicron Metabolism As triacylglycerols are removed by hydrolysis, chylomicrons shrink in size, becoming chylomicron remnants with lipid cores having a relatively high concentration of cholesteryl esters. Chylomicron remnants are taken up by liver cells, via receptor-mediated endocytosis . The process involves recognition of apoprotein E of the chylomicron remnant by receptors on the liver cell surface. Chylomicrons Biosynthesis of membrane lipids and steroids 1 10 Deliver dietary TG and PL to cells dietary CHOL to liver . . . apoCII is ligand to activate lipoprotein lipase for removal of fatty acids in tissues . . . apoE & apoB-48 are ligands for liver uptake of remnants . . . Lipoprotein content of the chylomicron changes as it circulates throughout the body - acquiring the apo E & C2 from HDL Questions What are the lipids carried by CM? Where is CM formed? What is the source for lipids in CM? How does the CM release FFA? What is the fate of the FFA and Glycerol? Where is the LPL found? What are the components of Remnant CM? . Liver cells produce, and secrete into the blood, very low density lipoprotein (VLDL). • The VLDL core has a relatively high triacylglycerol content. • VLDL has several apoproteins, including apoB-100. As VLDL particles are transported in the bloodstream, Lipoprotein Lipase catalyzes triacylglycerol removal by hydrolysis. With removal of triacylglycerols and some proteins, the % weight that is cholesteryl esters increases. VLDL are converted to IDL, and eventually to LDL. VLDL IDL LDL VLDL Assembly Plasma Dietary Carbohydrate glucose B48 LDL receptor TG/CE LIVER pyruvate Acetyl CoA Acetyl CoA mitochondria E TG Cholesterol (endogenous) CMr cholesterol (exogenous) FFA FFA B100 TG CE/TG VLDL VLDL Control of VLDL production: VLDL assembly is dependent on availability of lipids. Transcription of genes for enzymes that catalyze lipid synthesis is controlled by SREBP. Availability of apoprotein B-100 for VLDL assembly depends at least in part on regulated transfer of B-100 out of the ER for degradation via the proteasome. Nascent VLDL (B-100) + HDL (apo C & E) = VLDL LPL hydrolyzes TG forming IDL IDL loses apo C-II (reduces affinity for LPL) 75% of IDL removed by liver through Apo E and Apo B mediated receptors 25% of IDL converted to LDL by hepatic lipase VLDL Biosynthesis of membrane lipids and steroids 1 17 VLDL Metabolism • Nascent VLDL (B-100) + HDL (apo C & E) = VLDL • LPL hydrolyzes TG forming IDL – IDL loses apo C-II (reduces affinity for LPL) • 75% of IDL removed by liver – Apo E and Apo B mediated receptors • 25% of IDL converted to LDL by hepatic lipase – Loses apo E to HDL • Very Low Density Lipoprotein (VLDL) – Synthesized in liver – Transport endogenous triglycerides – 90% lipid, 10% protein – Apo B-100 • Receptor binding – Apo C-II • LPL activator – Apo E • Remnant receptor binding Delivers endogenous TG and PL to cells . . . apoE is ligand for liver uptake & apoB-100 is ligand for tissue uptake . . . apoCII is ligand to activate Lipoprotein lipase for removal of fatty acids Delivers CHOL to cells . . . VLDL Triglycerides 3 Fatty Acids Adipose Skeletal (storage) Muscle (energy) Glycerol Heart (energy) Blood Liver Once VLDL looses much of its TG’s it becomes LDL QUESTIONS Where is VLDL formed? What are the lipids Carried by VLDL? Which lipid is delivered by VLDL? What is the mechanism of FFA release from VLDL? What is the fate of Remnant VLDL? What are the lipids present in excess when VLDL becomes VLDLR? • Low Density Lipoprotein (LDL) – Synthesized from IDL – Cholesterol transport – Apo B-100 • Receptor binding • 30% degraded in extra hepatic tissues while 70% in liver The lipid core of LDL is predominantly cholesteryl esters. Whereas VLDL contains 5 apoprotein types (B100, C-I, C-II, C-III, & E), only one protein, apoprotein B-100, is associated with the surface monolayer of LDL. LDL Metabolism • LDL receptor-mediated endocytosis – LDL receptors on ‘coated pits’ • Clathrin: a protein polymer that stabilizes pit – Endocytosis • Loss of clathrin coating • uncoupling of receptor, returns to surface – Fusing of endosome with lysosome • Frees cholesterol & amino acids Cells take up LDL by receptormediated endocytosis, involving formation of a clathrin-coated pit & pinching off of a vesicle incorporating the receptor & LDL cargo. After the clathrin coat disassembles, the vesicle fuses with an endosome . LDL is released from the receptor within the acidic environment of the endosome, and the receptor is returned to the plasma membrane. After LDL is transferred to a lysosome, cholesterol is released & may be used, e.g., for membranes synthesis. LDL Receptor (apoB-E receptor) Regulates cholesterol synthesis and plasma cholesterol levels HMG-CoA reductase LDL-Receptors LDL Receptors Cholesteryl ester (storage) ACAT Cholesterol LDL LDL Endosome Lysosome Amino acids LDL 28 Control of LDL Receptor activity: Synthesis of LDL Receptor is suppressed by high intracellular cholesterol. This process involves decreased release of SREBP. Members of the SREBP family of transcription factors activate transcription of genes for the LDL receptor, as well as for enzymes essential to cholesterol synthesis such as HMG-CoA Reductase. The decreased synthesis of LDL receptor prevents excessive cholesterol uptake by cells. It has the deleterious consequence that excess dietary cholesterol remains in the blood as LDL. Mutations affecting the LDL receptor are associated with the most common form of the disease familial hypercholesterolemia (high blood cholesterol). Cells lacking functional LDL receptors cannot take up LDL. As a result, the amount of circulating LDL increases, leading to enhanced risk of developing atherosclerosis. Other hereditary hypercholesterolemias relate to genetic defects in structure of apolipoproteins. E.g., familial defective apoprotein B100 leads to impaired binding of LDL to cell surface receptors, with elevated levels of circulating LDL. Summary of Control of Cholesterol Uptake and Synthesis • Increased uptake of LDL-cholesterol results in: • inhibition of HMG-CoA reductase – reduced cholesterol synthesis • stimulation of acyl CoA:cholesterol acyl transferase (ACAT) – increased cholesterol storage – TG + C -> DG + CE • decreased synthesis of LDL-receptors – “down-regulation” – decreased LDL uptake • High Density Lipoprotein (HDL) – Synthesized in liver and intestine – Reservoir of apoproteins – Reverse cholesterol transport – Apo A • Activates lecithin-cholesterol acyltransferase (LCAT) – Apo C • Activates LPL – Apo E • Remnant receptor binding HDL (high density lipoprotein) is secreted as a small protein-rich particle by liver (and intestine). One HDL apoprotein, A-1, activates LCAT (LecithinCholesterol Acyl Transferase), which catalyzes synthesis of cholesteryl esters using fatty acids cleaved from the membrane lipid lecithin. The cholesterol is scavenged from cell surfaces & from other lipoproteins. HDL may transfer cholesteryl esters to other lipoproteins. Some remain associated with HDL, which may be taken up by liver & degraded. HDL thus transports cholesterol from tissues & other lipoproteins to the liver, which can excrete excess cholesterol as bile acids. High blood levels of HDL ("good" cholesterol) correlate with low incidence of atherosclerosis. Bacterial & viral infections, & some inflammatory disease states decrease HDL & increase VLDL production by the liver. These & other changes associated with inflammation can lead to increased risk of atherosclerosis if prolonged. HDL (high density lipoprotein) is secreted as a small protein-rich particle by liver (and intestine). One HDL apoprotein, A-1, activates LCAT (LecithinCholesterol Acyl Transferase), which catalyzes synthesis of cholesteryl esters using fatty acids cleaved from the membrane lipid lecithin. The cholesterol is scavenged from cell surfaces & from other lipoproteins. HDL Metabolism: Functions • Apoprotein exchange – provides apo C and apo E to/from VLDL and chylomicrons • Reverse cholesterol transport HDL Biosynthesis of membrane lipids and steroids 1 37 Reverse cholesterol transport • Uptake of cholesterol from peripheral tissues (binding by apo-A-I) • Esterification of HDL-C by LCAT – LCAT activated by apoA1 • Transfer of CE to lipoprotein remnants (IDL and CR) by CETP • removal of CE-rich remnants by liver, converted to bile acids and excreted Reverse Cholesterol Transport Delivery of peripheral tissue cholesterol to the liver for catabolism Requires HDL, apoA-I and LCAT Peripheral Cell UC diffusion HDL UC HDL Macrophage/ Foam cell ABCA1 UC LCAT PL LCAT Nascent HDL HDL CE CE CE apoA-I SR-B1 TG UC = unesterified cholesterol CE = esterified cholesterol PL = phospholipid LDLr = LDL receptor ABC = ATP Binding Cassette transporter VLDL or LDL apoB CE Liver LDLr Chol Bile acids Bile to gut