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Lipoproteins Metabolism

Lipoproteins Metabolism. Introduction. Lipid compounds are relatively water insoluble. Therefore, they are transported in plasma (aqueous) as lipoproteins. Lipoproteins and Related Clinical Problems. Atherosclerosis H ypertension Coronary heart diseases

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Lipoproteins Metabolism

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  1. LipoproteinsMetabolism

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

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

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

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

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

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

  8. Chylomicrons Very low density Lipoprotein (VLDL) Low density Lipoprotein (LDL) High density Lipoprotein (HDL) Types and Composition of Lipoproteins

  9. Size & Density of Lipoproteins

  10. Lipoprotein Electrophoresis

  11. Plasma Lipoproteins • For triacylglycerol transport (TG-rich): • - Chylomicrons: TG ofdietaryorigin • - VLDL: TG ofendogenous(hepatic) synthesis • For cholesterol transport (cholesterol-rich): • - LDL: Mainly free cholesterol • - HDL: Mainly esterified cholesterol

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

  13. Type I hyperlipoprotemia Apo E mediates uptake Chylomicrons metabolism

  14. Lipoprotein Lipase Extracellular enzyme anchored by heparan sulphate to the capillary walls of most tissue especially those of adipose tissue, cardiac & skeletal muscles 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 are stored (in adipose) or used for energy (in muscles) Glycerol is transferred to the liver (to be used for glycolysis, gluconeogenesis or lipid synthesis) Deficiency of lipoprotein lipase (or apo CII) : causes type 1 hyperlipoproteinemia(familial lipoprotein lipase deficiency) accumulation of chylomicrons in plasma (hypertriglyceridemia)

  15. Very Low Density Lipoproteins (VLDL) - Synthesis: in the liver - Structure: composed predominantly of triglycerides(TG) - Function: is to carry lipids (mainly TG) from the liver totissues. 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: - Obesity - Uncontrolled DM - Chronic ethanol ingestion

  16. Metabolism of VLDL

  17. Low Density Lipoproteins (LDL) LDLis produced in the circulation as the end product of VLDLs Compared to VLDLs: 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 Uptake of LDL at tissue level by LDL receptor-mediated endocytosis recognizedby apo B-100

  18. Receptor-Mediated Endocytosis 1- LDL (through apo 100), binds to LDL receptors in peripheral tissues forming a complex 2- Internalization of the complex by endocytosis to inside cells. 3- Releaseof 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)

  19. LDL: Receptor-mediated endocytosis

  20. LDL Receptor-Mediated Endocytosis: Regulation Cholesterol derived from LDL causes: 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-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.

  21. 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

  22. High Density Lipoproteins (HDL) Synthesis: by intestine and liver Nascent HDL: Disk-shaped Contains apo A-I, C-II and E Contains primarily phospholipid (PC) Mature HDL (HDL2):First, the HDL3 collects cholesterol (C) from peripheral tissues & other lipoproteins. Then, Cholesterol is converted to CE (by PCAT)to form HDL2. CE is transported to liver by HDL2.

  23. HDL Metabolism

  24. Composition of LDL and HDL Low density lipoprotein (LDL) Mostly free cholesterol • High density lipoprotein (HDL) • Mostly cholesterol ester • More % protein • More % phospholipids

  25. Functions of HDL Reservoir of apoproteinse.g. Apo C-II and E to VLDL Uptake of cholesterol:From peripheral tissue (& other lipoproteins) Esterification of cholesterol:Enzyme: PCAT/LCAT Activator: Apo A-I Substrate: Cholesterol, Co-substrate: PC Product: Cholesterol ester (& Lyso-PC) Reverse cholesterol transport transports cholesterol from peripheral tissues to liver

  26. VLDL CE PL ,TAG HDL Cholesteryl Ester Transfer Protein

  27. Why Is HDL a Good Cholesterol carrier? Inverse relation between plasma HDL levels and atherosclerosis …. How? Reverse cholesterol transport involves:Efflux of cholesterol from peripheral tissues and other lipoproteins to HDL3 Esterification of cholesterol & binding of HDL2 to liver (and steroidogenic cells) by scavenger receptor class B (SR-B1) Selective transfer of cholesterol ester into these cells Release of lipid-depleted HDL3

  28. Lp (a) Simulates LDL but apo(a) covalently linked to apo B-100 Competes with plasminogen to plasminogen activator Genetical element Estrogen decreases it while trans fats increases it

  29. Hyperlipoprotenemias 1- Type I hyperlipoproteinemia: Familial lipoprotein lipase deficiency - Due deficiency of lipoprotein lipase or apo C-II - Slow clearance of TG–rich lipoproteins in plasma (chylomicrons & VLDL) - Hypertriacylglyceremia(increased TG in blood) - Treated by reducing fat in diet 2- Type II hyperlipoproteinemia: Familial hypercholesterolemia - Due to deficiency of functional LDL receptors - Reduced clearance of LDL - Elevation of plasma cholesterol (but plasma TG remains normal) - Predispose to atherosclerosis & CHD Abnormalities in lipoprotein metabolism

  30. Abnormalities in lipoprotein metabolism cont. 3- Type III hyperlipoproteinemia familial dysbetalipoproteinemia or broad B disease - Due to abnormal apo E (on chylomicrons) - Reduction of clearance of chylomicron remnants by liver - Accumulation of chylomicron remnants in plasma. - Hyperchloesterolemia - Predispose to atherosclerosis & CHD 4- Type IV hyperlipoproteinemia Familial hypertriacylglycerolemia - Increased production of VLDL - Commonly associated with type II DM & obesity - Elevated blood TG & cholesterol - Predispose to atherosclerosis & CHD.

  31. Abnormalities in lipoprotein metabolism cont. Hypolipoproteinemia 1- Abetalipoproteinemia - defect in triacylglycerol transfer protein (MTP) responsible for loading of apo-100 with lipid with no chylomicrons & no VLDL synthesis - Nochylomicrons synthesis in intestine  ↓blood TG - No VLDL synthesis in liver  ↑TG in liver - NoVLDL synthesis  no LDL  ↓blood cholesterol 2- Familial hypobetalipoproteinanemia - ↓apo B-100 synthesis - ↓ VLDL  ↓ blood TG & ↑ TG in liver - ↓ LDL  ↓ blood cholesterol

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