L12. Plasma Lipoproteins.pdf

PLASMA LIPOPROTEINS By Dr Mostafa Mohamed Mostafa  Lipoproteins are complex aggregates of lipids and proteins that render the lipids compatible with the aqueous environment of body fluids and enable their transport throughout the body  Lipids are transported as lipoproteins...

PLASMA LIPOPROTEINS By Dr Mostafa Mohamed Mostafa  Lipoproteins are complex aggregates of lipids and proteins that render the lipids compatible with the aqueous environment of body fluids and enable their transport throughout the body  Lipids are transported as lipoproteins with special arrangement: The most hydrophobic one is present in the core (triacylglycerol and cholesteryl-esters).These are surrounded by the amphipathic lipids (phospholipids and cholesterol) and apolipoproteins.  Apolipoproteins may be : integral (cannot be removed) e.g. apo B peripheral (can be transferred) e.g. apo-C and E.  Methods of separation of plasma lipoproteins 1) Ultracentrifugation: lipoproteins are separated by means of a very high speed centrifuge into 5 fractions. 2) Electrophoresis: lipoproteins are separated also into 5 fractions. electrophoresis depends on the molecular weight and the charges of the particles to be separated.  Metabolism of Chylomicrons Chylomicrons carry the absorbed dietary lipids to the liver and other tissues. Synthesis: in the intestine Composition: mainly triacylglycerols + apo B-48 +apo A +apo C + apo E 1-Synthesis of nascent chylomicrons by intestinal cells They are formed by the following steps: a- Synthesis of the lipid components on the smooth endoplasmic reticulum (SER). b- Synthesis of apolipoproteins by the ribosomes on the rough endoplasmic reticulum (RER). c- Assembly of both lipids and proteins occurs during transport from ER to Golgi apparatus, where they are packaged in secretory vesicles and released to intercellular space by exocytosis. 2- Conversion of nascent chylomicrons to mature chylomicrons This occurs by receiving apo C (including apo C II) and apo E from HDL 3- Degradation by plasma lipoprotein lipase enzyme This enzyme is attached to endothelial lining of the capillary walls of many tissues. Lipoprotein lipase is activated by apo C-II present in chylomicrons. The enzyme catalyzes hydrolysis of about 90% of the triacylglycerol present into glycerol and free fatty acids. Glycerol is taken by liver cells. Free fatty acids enter within the tissues. 4- Formation of chylomicron remnants After hydrolysis of TAG by the lipoprotein lipase, apo C & A are transferred to HDL. The remaining particles are termed chylomicron remnants. The remnants are endocytosed by liver cells through specific receptors for apo E. In liver cells, the different components are hydrolyzed and metabolized or reused for synthesis of lipoproteins. Metabolism of VLDL, IDL and LDL 1- Synthesis of nascent VLDL by liver cells Nascent VLDLs are formed by liver cells and contain a specific protein termed apo B-100. They are responsible for the transport of TAG from liver to extrahepatic tissues. 2- Conversion to mature VLDL Nascent VLDLs are released from liver cells into blood, where they receive apo C and apo E from HDL to form the mature VLDL. 3- Degradation by plasma lipoprotein lipase enzyme The enzyme catalyzes hydrolysis of about 50% of the TAG into glycerol and free fatty acids. 4- Formation of VLDL remnants (IDL) They are also termed intermediate density lipoproteins (IDLs). They are formed after the action of lipoprotein lipase and removal of apo C that returns back to HDL. 5- Conversion of IDL to LDL This is achieved by further hydrolysis of TAG, and removal of apo E (it returns back to HDL). Also TAG is transferred to HDL in exchange with cholesteryl esters, this is catalyzed by cholesteryl ester transfer protein (apo D). 6- Fate of LDL LDLs bind to specific apo B-100 receptors, in both extrahepatic tissues (30%) and liver (70%) where they are endocytosed and their contents are metabolized. LDLs are important source of cholesterol to extrahepatic tissues. High levels of LDL-cholesterol increase the risk of atherosclerosis. METABOLISM OF HDL  They are formed by liver cells and small intestine as discoidal HDL which are mainly formed of phospholipid bilayer, free cholesterol and apolipoproteins (A, C, E & D), then accept free cholesterol from extrahepatic tissues, where it is esterified by Lecithin cholesterol acyltransferase (LCAT). LCAT is activated by apo A present in HDLs and catalyzes transfer of acyl group from position 2 of lecithin to cholesterol to form cholesteryl esters and lysolecithin. Cholesteryl esters form a central hydrophobic core that pushes the phospholipid bilayer apart and converts the discoidal HDLs into the spherical HDLs.  HDLs act as reservoir for different apoproteins (C&E), which are important for metabolism of chylomicrons and VLDL. HDLs by the mean of CETP (apo D) provide cholesteryl esters to chylomicron remnants and LDLs in exchange with triacylglycerol. HDLs are endocytosed by liver cells, where cholesteryl esters are hydrolyzed. The free cholesterol released is either repacked into lipoproteins, converted to bile acids or secreted in bile. So, HDLs are important for removal of cholesterol from the tissues to the liver (reverse cholesterol transport) and high levels of HDL protect against atherosclerosis.  Types, composition and functions of lipoproteins Type Source Function CM Intestine Transport of dietary TAG (mainly), cholesterol & cholesterol esters from the intestine to the peripheral tissues VLDL Liver Transport of endogenous TAG from the liver to the peripheral tissues IDL VLDL Precursor of LDL LDL VLDL Transport of cholesterol from the liver to the (via IDL) peripheral tissues HDL Liver Transport of cholesterol from peripheral & intestine tissues to the liver for elimination  Primary Disorders of Plasma Lipoproteins (Dyslipoproteinemias)  Name Defect Characteristics Hyperlipoproteinemias Familial Defective apo B-100 Elevated LDL levels and hypercholesterolemia receptor. hypercholesterolemia resulting in atherosclerosis and coronary disease. Hypertriacylglycerolemia Overproduction of VLDL There is a rise of TAG and associated with glucose VLDL. Levels of LDL and intolerance HDL tend to be subnormal. and hyperinsulinemia, This type is commonly associated with type II diabetes mellitus and Obesity. Familial lipoprotein lipase Hypertriacylglycerolemia Slow clearance of deficiency due to deficiency chylomicrons and VLDL. Low levels of LDL and HDL. of LPL, abnormal LPL, or No increased risk of coronary apoC-II deficiency causing disease. inactive LPL.