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Lipoproteins Metabolism

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Lipid compounds are relatively water insoluble. Therefore, they are transported in plasma (aqueous) as lipoproteins Introduction

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Lipoproteins and Related Clinical Problems Atherosclerosis Atherosclerosis Hypertension Hypertension Coronary heart diseases Coronary heart diseases Lipoproteinemias (hypo- and hyper-) Lipoproteinemias (hypo- and hyper-) Fatty liver Fatty liver

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Lipoprotein Structure Protein part: Apoproteins or apolipoproteins structuraltransferred Apoproteins proteins may be structural or transferred Lipid part: Each lipoprotein contains different types of lipids in various combinations Type of lipids Type of lipids in a lipoprotein is governed according to the type of lipoprotein

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Lipoprotein Structure Spherical molecules of lipids and proteins (apoproteins) = amphipathic molecules Outer coat: Proteins Proteins - Apoproteins Lipids Lipids (amphipathic) (PL) - Phospholipids (PL) - free Cholesterol Inner core: Lipids Lipids (hydrophobic) - Triglycerides (TG) - Cholesterol ester (CE)

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Apolipoproteins (Apoproteins) Five major classes (A-E) divided by structure & function Each class has subclasses as Apo A, Apo CII Functions: structural proteins Some are required as structural proteins (i.e. they are essential structural components of the lipoprotein particles & can not be produced without them) activators Some are activators for enzymes of lipoprotein metabolism recognition sites Some are recognition sites for cell-surface receptors

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Types of Lipoproteins Types of lipoproteins are different in lipid & protein composition & therefore, they differ in: Size & density - Size & density Electrophoretic mobility - Electrophoretic mobility

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Types and CompositionofLipoproteins Chylomicrons Very low density Lipoprotein (VLDL) Low density Lipoprotein (LDL) High density Lipoprotein (HDL)

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Size & Density ofLipoproteins

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Lipoprotein Electrophoresis

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Plasma Lipoproteins For triacylglycerol transport (TG-rich): For triacylglycerol transport (TG-rich): Chylomicronsdietary - Chylomicrons: TG of dietary origin VLDLendogenous - VLDL: TG of endogenous (hepatic) synthesis For cholesterol transport (cholesterol-rich): For cholesterol transport (cholesterol-rich): LDL - LDL: Mainly free cholesterol HDL - HDL: Mainly esterified cholesterol

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Chylomicrons Synthesis Synthesis: in intestinal mucosal cells Function Function: dietary lipids Transport dietary lipids from GIT to tissues (& liver). Responsible for physiological milky appearance of plasma (up to 2 hours after meal) Structure Structure: density Lowest density size Largest size lipids proteins Highest % of lipids and lowest % proteins triacylglyceroldietary Highest triacylglycerol (dietary origin)

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Apo E mediates uptake Type I hyperlipoprotemia Chylomicrons metabolism

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Lipoprotein Lipase most tissue Extracellular enzyme anchored by heparan sulphate to the capillary walls of most tissue especially those of adipose tissue, cardiac & skeletal muscles not BUT: Adult liver does not have this enzyme Its synthesis & transfer to luminal surface of the capillary is stimulated by insulin (in fed state) Activated by apoC-II Function of lipoprotein lipase Lipoprotein lipase hydrolyses circulating TG in chylomicrons to fatty acids & glycerol Fatty acids Fatty acids are stored (in adipose) or used for energy (in muscles) Glycerol Glycerol is transferred to the liver (to be used for glycolysis, gluconeogenesis or lipid synthesis) Deficiency of lipoprotein lipase (or apo CII) : type 1 hyperlipoproteinemia (familial lipoprotein lipase deficiency) causes type 1 hyperlipoproteinemia (familial lipoprotein lipase deficiency) hypertriglyceridemia accumulation of chylomicrons in plasma (hypertriglyceridemia)

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Very Low Density Lipoproteins (VLDL) - Synthesisliver - Synthesis: in the liver Structuretriglycerides(TG) - Structure: composed predominantly of triglycerides (TG) Function : - Function : is to carry lipids (mainly TG) from the liver to tissues. lipoprotein lipase In peripheral tissues, TG are degraded by lipoprotein lipase to FA & glycerol. Fatty liver (hepatic steatosis) Occurs when TG synthesis in liver is more than VLDL secretion As in cases of As in cases of: - Obesity - Uncontrolled DM - Chronic ethanol ingestion

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Metabolism of VLDL

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Low Density Lipoproteins (LDL) LDL LDL is produced in the circulation as the end product of VLDLs Compared to VLDLs: apo B-100 It contains only apo B-100 Smaller size & more dense (less lipids) Lipid contents: Less triglycerides (TG) More cholesterol (C) & cholesterol ester (CE) Function of LDL LDL transport cholesterol from liver to peripheral tissues LDL receptor-mediated endocytosis recognized Uptake of LDL at tissue level by LDL receptor-mediated endocytosis recognized by apo B-100

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Receptor-Mediated Endocytosis LDL (through apo 100), LDL receptors 1- LDL (through apo 100), binds to LDL receptors in peripheral tissues forming a complex Internalization 2- Internalization of the complex by endocytosis to inside cells. Release 3- Release of cholesterol inside the cells for: Utilization, storage (as cholesterol ester) or excretion 4- Degradation of LDL: into amino acids, PL & FAs 5- Degradation or recycling of receptor Deficiency of functional LDL receptors: Causes elevation of LDL in blood (& therefore blood cholesterol is elevated) Type II hyperlipidemia (familial hypercholesterolemia)

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LDL: Receptor-mediated endocytosis

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LDL Receptor-Mediated Endocytosis: Regulation Cholesterol derived from LDL causes: 1-Decrease de novo synthesis of cholesterol 1- Decrease de novo synthesis of cholesterol (by inhibition of HMG CoA reductase) 2- Inhibition of LDL receptor synthesis at gene level thus, limiting further entry of LDL cholesterol into cells. 3- 3- In case cholesterol is not used immediately: Cholesterol is esterified to cholesterol esters (CE) by: acyl CoA: cholesterol acyltransferace (ACAT). Cholesterol esters can be stored in cells. ACAT is enhanced in cases of increased intracellular cholesterol.

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LDL-C = Total cholesterol [ HDL-C + TG/2.2 ] in case of mmol/L or 5 in case of mg/dL Low Density Lipoprotein Cholesterol (LDL-C) calculation

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Categories of Risk for LDL Cholesterol Goals LDL goal mg/dL < 100