cardiovascu;arBLOOD LIPIDS 200L (1).pptx

Blood Lipids

1. BLOOD LIPIDS CHYLOMICRONS; LIPOPROTEINS

2. Learning objectives To identify components of blood lipids To understand the properties of major lipoproteins To understand the functions of lipoproteins To apply the knowledge acquired to the system in normal and disease conditions

3. Introduction Lipids are defined as organic compounds that are poorly soluble in water but miscible in organic solvents they are structural components in cells and are involved in metabolic and hormonal pathways Since lipids are insoluble in water, they need the help of carriers in plasma. Therefore, they form complexes with specific proteins to form lipoproteins Lipids and proteins associate non-covalently to form lipoproteins , which function in the blood plasma as transport vehicles for triacylglycerols and cholesterol

4. Composition of plasma Lipoproteins Lipoproteins composed of lipids and proteins. Lipid Components are : a neutral lipid core – triacylglycerols (TAG), and cholesterol esters(CE), surrounded by a shell of protein, phospholipid (PL) and non-esterified (free) cholesterol (NEC) Non polar core of triacylglycerols and cholesteryl esters forms the hydrophobic layer Surrounding coating of protein, phospholipid and free cholesterols forms the hydrophilic layer

5. Composition of plasma Lipoprotein cont’d Sources of blood lipids : The TAG and cholesterol carried by the lipoproteins are obtained from; i ) the diet (exogenous source) or de novo synthesis (endogenous source) Lipoprotein particles undergo continuous metabolic processing , so that they have variable properties and compositions Total plasma lipid is 400-600 mg/dl. Out of this, 40% is cholesterol; 30% is phospholipids; 20% is triglycerides

6. Composition of plasma Lipoprotein cont’d The protein component of lipoproteins are called apolipoproteins or apoproteins At least nine apolipoproteins are distributed in significant amounts in different human lipoproteins . Most of them are water-soluble and associate rather weakly with lipoproteins Hence, they readily transfer between lipoprotein particles via the aqueous phase

7. Composition of plasma Lipoprotein cont’d Sources of apoproteins : All apoproteins are mainly synthesized in the liver; but small quantities are produced from almost all organs Intestinal cells produce small quantities of apo -A The Apoproteins primarily function to : solubilise the lipid part, of the lipoprotein

8. Composition of plasma Lipoprotein cont’d Apo-B-100: It is a component of LDL; it binds to LDL receptor on tissues . Apo-B-100 is one of the biggest proteins, having 4536 amino acids, with a molecular weight of 550 kDa . It is synthesized in the liver Apo-B-48: It is synthesized in intestinal cells. It is the structural component of chylomicrons Apo-C-II: It activates lipoprotein lipase Apo-E: It is an arginine -rich protein. It is present in chylomicrons, LDL and VLDL. Astrocytes also makes apo -E; it is involved in cellular transport of lipids in centra nervous system(CNS)

9. Figure 1 . Apo- B-100 and Apo-B-48 are produced from the same gene. In liver, the mRNA is translated as usual (B-100). But in intestine, a particular cytosine residue is de- aminated , to become uracil . So, a stop codon is generated in the middle, and a short protein is produced in intestine (B48). Apo-B-48 is only 48% of the size of B-100

10. Classification of lipoproteins Classified into five broad categories on the basis of their functional and physical properties(densities & electrophoretic mobility) : Chylomicrons , contain apoprotein B-48; transport exogenous ( externally supplied ; ) dietary triacylglycerols and cholesterol from the intestines to the tissues Very low density lipoproteins VLDL or pre- β lipoproteins. Main apoprotein is B-100 Intermediate density lipoproteins IDL or broad β lipoprotein 4. Low density lipoproteins LDL or beta-lipoproteins. Major apoprotein in LDL is B- 100

11. Classification of lipoproteins cont’d Very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and low density lipoproteins are a group of related particles that transport endogenous (internally produced) triacylglycerols and cholesterol from the liver to the tissues (the liver synthesizes triacylglycerols from excess carbohydrates) 5. High density lipoproteins ( HDL)or alpha lipoproteins; major apoprotein in HDL is apo -A transport endogenous cholesterol from the tissues to the liver

12. Figure 2 . Generalized structure of plasma lipoprotein

13. Figure 3. Comparison of sizes of lipoproteins . Lipoprotein densities increase with decreasing particle diameter because the density of their outer coating is greater than that of their inner core

14. Classification of Lipoproteins cont’d Figure 4. Classification based on density and mobility

15. Figure 5. Structure of chylomicron

16. Figure 6. Metabolism of Chylomicrons

17. Figure 7. LDL, the major cholesterol carrier of the bloodstream . This spheroidal particle consists of some 1500 cholesteryl ester molecules surrounded by an amphiphilic coat of 800 phospholipid molecules, 500 cholesterol molecules, and a single 4536-residue molecule of apolipoprotein B-100 .

18. Figure 8. Schematic illustration of low-density lipoprotein (LDL) metabolism and the role of the liver in its synthesis and clearance. Lipolysis of very-low-density lipoprotein (VLDL) by lipoprotein lipase in the capillaries releases triglycerides, which are then stored in fat cells and used as a source of energy in skeletal muscles .

19. Characteristics of Apolipoproteins Apoproteins Components MW Source Functions Apo A-I HDL-2 29 Intestine; Liver Activation of LCAT; ligand for HDL receptor; antiatherogenic Apo A -II HDL-3 17 Intestine; Liver Inhibits LCAT; s timulate lipase Apo-B-100 LDL, VLDL 513 Liver Binds LDL receptors; cholesterol clearance Apo B-48 Chylomicron 241 Intestine Cholesterol clearance Apo C-I Chylomicron, VLDL 6.6 Liver Activation of LCAT Apo C-II Chylomicron, VLDL LDL 8.9 Liver Activate extrahepatic LPL in vessel walls ; clearance of TAG from chylomicron and VLDL Apo-C-III Chylomicron, VLDL LDL 8.8 Liver Inhibit LPL; antiatherogenic Apo E LDL,VLDL Chylomicron 19 Liver Arginine rich; ligand for hepatic uptake Apo Lp (a) Lp (a) 34 Liver Attached to B-100; impairs fibrinolysis; atherogenic

20. Functions of lipoproteins Chylomicrons are the transport form of dietary triglycerides from intestines to the adipose tissue for storage; and to muscles(skeletal and cardiac) for their energy needs The retinol is transported in chylomicrons to the liver for esterification and storage in the satellite cells VLDL carries triglycerides (endogenous triglycerides) from liver to peripheral tissues for energy About 75% of the plasma cholesterol is incorporated into the LDL particles. LDL transports cholesterol from liver to the peripheral tissues

21. Functions of lipoprotein cont’d The cholesterol thus liberated in the cell has three major fates : i . It is used for the biosynthesis of other substances/ compounds like steroid hormones, bile acid and bile salts ii. Cholesterol may be incorporated into the plasma and subcellular organelle membranes iii. Cholesterol may be esterified to a monounsaturated fatty acids MUFA by acyl cholesterol acyl transferase (ACAT) for storage The cellular content of cholesterol regulates further endogenous synthesis of cholesterol by regulating HMG CoA reductase

22. Functions of lipoprotein cont’d Transport of lipids: Mechanisms of Lipid transport 1) transport of exogenous (dietary) lipids 2) transport of endogenous lipids from the liver 3) HDL and reverse cholesterol transport Transport of exogenous (dietary) lipids: all dietary fat (exception of medium chain TG) is efficiently carried into circulation via lymphatic drainage from the intestinal mucosa TG & cholesterol combined with apo A & apo B-48 in the intestinal mucosa to form chylomicrons

23. Functions of Lipoprotein cont’d Apo-A-I, activates lecithin-cholesterol acyl transferase (LCAT); It is the ligand for HDL receptor; It is anti- atherogenic Ligand is an ion, molecule or functional group that binds to another chemical entity to form a larger complex HDL particle contribute apo C- ll to the chylomicrons during transportation; apo C- ll is required for the activation of lipoprotein lipase within the capillary endothelium of adipose, heart and skeletal muscle tissues Both phospholipids and apo C-II are required as cofactors for lipoprotein lipase activity

24. Functions of Lipoprotein cont’d Free fatty acids FFA are oxidized, reesterified for storage as TG; or released into the circulation bound to albumin for transport to the liver HDL contribute apoE to the chylomicron remnant, apoE facilitates binding of the particle to the hepatic LDL receptors Within the hepatocytes , chylomicrons has several fates: incorporated into membranes; resecreted as lipoprotein back to the circulation or secreted as bile acids All dietary fats are disposed of within 8 hrs after last meal; elevated lipid level after meal is a risk factor for atherosclerosis

25. Functions of Lipoprotein cont’d Transport of endogenous lipids from the Liver : the formation and secretion of VLDL from the liver and its catabolism to IDL & LDL particles describe the endogenous lipid pathway; Fatty acids used in the formation is derived primarily by uptake from the circulation VLDL, transported away from the liver , rapidly as it’s synthesized VLDL, consist of TG,CE,PL and apoB-100 Nascent VLDL remnant, secreted into the circulation combined with apoprotein C’s and apoE

26. Figure 9. Model for plasma triacylglycerol and cholesterol transport in humans.

27. Functions of lipoprotein cont’d HDL and Reversed cholesterol transport : as the hepatic secretion of lipid particles into bile is the only mechanism by which cholesterol can be removed from the body, transport of excess cholesterol from the peripheral cells back to liver is important The transport is mediated by HDL; HDL is laden with apoA-1, containing lipoprotein which is nonatherogenic Cholesterol-poor nascent HDL particles secreted by the liver and small intestine, are esterified to more mature HDL-2 particles by the action of lecithin cholesterol acyl transferase LCAT

28. Functions of lipoprotein cont’d LCAT , facilitates movement of chylomicrons and VLDL into the HDL core HDL-2, transfer cholesteryl ester back to apoB mediated by cholesteryl ester transfer protein (CETP) or the cholesterol-rich particle, removed from plasma by endocytosis, completing reverse cholesterol transport

29. Figure 10. HDL metabolism

30. Figure 11. Forward and Reversed transport of cholesterol

31. Clinical correlates ApoB deficiency= abetalipoproteinemia Apo-E has I, II, III and IV isoforms , (independent alleles in the genes). Apo E-IV isoform is implicated in the development of senile dementia and Alzheimer's disease. Apo-E is also associated with lipoprotein glomerulopathy Individual with the deficiency of either apo -E or hepatic triacylglycerol lipase (HTGL) accumulate IDL in the plasma Low HDL due to genetic deficiency of apoA-1 or secondary to increased plasma TG

32. Clinical correlates cont’d DISORDER LIPOPROTEIN ELEVATED GENETICS CLINICAL FINDINGS Familial hypercholesterolemia LDL AD Tendon Xanthoma , CHD Familial defective Apo B-100 LDL AR Tendon xanthomas Familial dysbetahypercholesterolemia LDL, TG AD Tubereruptive xanthoma , peripheral vascular diseases Familial hepatic lipase deficiency VLDL AR CDH

33. Assignments Enumerate the various components of lipoproteins Concisely, describe the biochemical functions of lipoproteins In a tabular form, describe the characteristic properties of lipoproteins Write sort note on: (a). reverse transport of cholesterol (b).Chylomicron ©. LDL

34. THANK YOU

35. Composition of blood lipoproteins

36. LDL reacts with receptors on various cells, is taken up by endocytosis , and is digested by lysosomal enzymes. (Step 6) a. Cholesterol, released from cholesterol esters by a lysosomal esterase, can be used for the synthesis of cell membranes or for the synthesis of bile salts in the liver or steroid hormones in endocrine tissue. b. Cholesterol inhibits HMG- CoA reductase (a key enzyme in cholesterol biosynthesis) and, thus, decreases the rate of cholesterol synthesis by the cell. c. Cholesterol inhibits synthesis of LDL receptors ( downregulation ) and, thus, reduces the amount of cholesterol taken up by cells. d. Cholesterol activates acyl:cholesterol acyltransferase (ACAT), which converts cholesterol to cholesterol esters for storage in cells.

37. LDL reacts with receptors on various cells, is taken up by endocytosis , and is digested by lysosomal enzymes. (Step 6) a. Cholesterol, released from cholesterol esters by a lysosomal esterase, can be used for the synthesis of cell membranes or for the synthesis of bile salts in the liver or steroid hormones in endocrine tissue. b. Cholesterol inhibits HMG- CoA reductase (a key enzyme in cholesterol biosynthesis) and, thus, decreases the rate of cholesterol synthesis by the cell. c. Cholesterol inhibits synthesis of LDL receptors ( downregulation ) and, thus, reduces the amount of cholesterol taken up by cells. d. Cholesterol activates acyl:cholesterol acyltransferase (ACAT), which converts cholesterol to cholesterol esters for storage in cells.