Lipoproteins PDF

Lippincott’s illustrated reviews Chapter 18 – Page 219 Lectures 31 Lipoproteins 1  Specific Objectives By the end of this lecture students can be able to: Understand the composition of the different types of plasma lipoproteins. Explain the ef...

Lippincott’s illustrated reviews Chapter 18 – Page 219 Lectures 31 Lipoproteins 1  Specific Objectives By the end of this lecture students can be able to: Understand the composition of the different types of plasma lipoproteins. Explain the effect of lipoproteins in heart diseases. 2  Plasma lipoproteins The plasma lipoproteins are spherical macromolecular complexes of lipids and specific proteins (apolipoproteins or apoproteins). The lipoprotein particles include chylomicrons (CM), very- low-density lipo-proteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). They differ in lipid and protein composition, size, density, and 3 site of origin. Lipoproteins function: Keep their component lipids soluble as they transport them in the plasma Provide an efficient mechanism for transporting their lipid contents to (and from) the tissues. 4  In humans, the transport system is less perfect than in other animals and, as a result, humans experience a gradual deposition of lipid—especially cholesterol—in tissues. The lipid deposition contributes to plaque formation, causing the narrowing of blood vessels (atherosclerosis). 5 6  Composition of plasma lipoproteins Lipoproteins are composed of a neutral lipid core (containing triacylglycerol and cholesteryl esters) surrounded by a shell of amphipathic apolipoproteins, phospholipid, and nonesterified (free) cholesterol. The triacylglycerol and cholesterol carried by the lipoproteins are obtained either from the diet (exogenous source) or from de novo synthesis (endogenous source). 7  Size and density of lipoprotein particles: Chylomicrons are the lipoprotein particles lowest in density and largest in size, and contain the highest percentage of lipid and the lowest percentage of protein. VLDLs and LDLs are successively denser, having higher ratios of protein to lipid. HDL particles are the densest. 8  Apo-lipoproteins The protein part of lipoprotein is called apolipoprotein (apo-Lp) or apoprotein. All apoproteins are mainly synthesised in liver; but small quantities are produced from almost all organs. Intestinal cells produce small quantities of apo-A. Types of apolipoproteins: 1. Apo-A-I. It activates lecithin-cholesterol acyl transferase (LCAT). It is the ligand for HDL receptor. It is anti-atherogenic. 2. 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. It is synthesized in liver. 3. Apo-B-48. It is synthesized in intestinal cells. It is the structural component of chylomicrons. It is named because it is only 48% of the size9of B-100. 4. Apo-C-II. It activates lipoprotein lipase. 5. Apo-E. It is an arginine-rich protein. It is present in chylomicrons, LDL and VLDL. Astrocytes also make apo-E; it is involved in cellular transport of lipids in CNS. Apo-E has I, II, III and IV isoforms, due to 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. 10  1. CHYLOMICRONS Synthesis of chylomicrons Chylomicrons are formed in the intestinal mucosal cells. They are rich in triglyceride. They contain only apo-B-48 and apo-A but apo-C and apo- E are added from HDL in blood during transport 11 Function of Chylomicrons Chylomicrons are the transport form of dietary triglycerides from intestines to the adipose tissue for storage; and to muscle or heart for their energy needs. Metabolism of Chylomicrons i. Main sites of metabolism of chylomicrons are adipose tissue and skeletal muscle. The half-life of chylomicrons in blood is about 1 hour. ii. The enzyme lipoprotein lipase (LpL) is located at the endothelial layer of capillaries of adipose tissue, muscles and heart; but not in liver. 12  Apo C-II present in the chylomicrons activates the LpL. The LpL hydrolyses triglycerides present in chylomicrons into fatty acids and glycerol. Muscle or adipose tissue cells take up the liberated fatty acids. Lack of C-II leads to decreased activity of LpL and consequent accumulation of chylomicrons and VLDL in blood. iii. Following injection of heparin, the LpL is released from the tissues and lipemia is thus cleared. This is called post- heparin lipolytic activity. Insulin also increases LpL activity. 13 C. Metabolism of VLDL VLDLs are synthesized in the liver. They are composed predominantly of endogenous triacylglycerol (approximately 60%), along with hepatic cholesterol, apo-B- 100, C-II and E. Apo-B-100 is the major lipoprotein present in VLDL when it is secreted. Apo-E and C-II are obtained from HDL in plasma. VLDL function is to carry this lipid from the liver (site of synthesis) to the peripheral tissues for energy need. 14  “Fatty liver” (hepatic steatosis) occurs in conditions in which there is an imbalance between hepatic triacylglycerol synthesis and the secretion of VLDL. Such conditions include obesity, uncontrolled diabetes mellitus, and chronic ethanol ingestion. 15 Metabolism of VLDL The half-life of VLDL in serum is only 1 to 3 hours. When they reach the peripheral tissues, apo-C-II activates LpL which liberates fatty acids that are taken up by adipose tissue and muscle. The remnant is now designated as IDL (intermediate density lipoprotein) (or VLDL remnants) and contains less of TAG and more of cholesterol. The major fraction of IDL further loses triglyceride, so as to be converted to LDL (low density lipoprotein). This conversion of VLDL to IDL and then to LDL is referred to as lipoprotein cascade pathway. 16 17 D. Metabolism of LDL LDL particles contain much less triacylglycerol than their VLDL predecessors, and have a high concentration of cholesterol and cholesteryl esters. 18 Function of LDL About 75% of the plasma cholesterol is incorporated into the LDL particles. LDL transports cholesterol from liver to the peripheral tissues. The cholesterol thus liberated in the cell has three major fates: i. It is used for the synthesis of other steroids like steroid hormones. ii. Cholesterol may be incorporated into the membranes. iii. Cholesterol may be esterified to a 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. 19 LDL and Clinical Applications LDL concentration in blood has positive correlation with incidence of cardiovascular diseases. LDL infiltrates through arterial walls, and is taken up by macrophages or scavenger cells. This is the starting event of atherosclerosis leading to myocardial infarction. When these cells become engorged with cholesterol, foam cells are formed, that get deposited in the subendothelial space triggering formation of atheromatous plaque. 20  Procoagulant changes are induced in the endothelium resulting in increased chances of thrombosis and coronary artery disease. Since LDL-cholesterol is thus deposited in tissues, the LDL (low density lipoprotein) variety is called “bad cholesterol” and LDL as “Lethally Dangerous Lipoprotein” in common parlance. 21 E. Metabolism of HDL HDL particles are formed in blood by the addition of lipid to apo A-1, an apolipo protein made by the liver and intestine and secreted into blood. The major apoproteins in HDL are Apo-A1 (70%), with some Apo-A2, Apo-C and Apo-E. HDL serves as a plasma reservoir of Apo-C and Apo-E which can be transferred to VLDL and chylomicrons and back. 22 Functions of HDL i. HDL is the main transport form of cholesterol from peripheral tissue to liver, which is later excreted through bile. This is called reverse cholesterol transport by HDL. ii. The only excretory route of cholesterol from the body is the bile. iii. Excretion of cholesterol needs prior esterification with PUFA. Thus PUFA will help in lowering of cholesterol in the body, and so PUFA is anti-atherogenic. 23 Clinical Significance of HDL The level of HDL in serum is inversely related to the incidence of myocardial infarction. As it is “antiatherogenic” or “protective” in nature, HDL is known as “good cholesterol” in common parlance. It is convenient to remember that "H" in HDL stands for "Healthy". HDL level below 35 mg/dl increases the risk, while level above 60 mg/dl protects the person from coronary artery 24 diseases. F. Role of lipoprotein (a) in heart disease Lipoprotein (a), or Lp(a), is a particle that, when present in large quantities in the plasma, is associated with an increased risk of coronary heart disease. Lp(a) is very strongly associated with myocardial infarction and is sometimes called the “little rascal”. If the Lp(a) concentration in blood is more than 30 mg/dl; and these persons are susceptible for heart attack at a younger age. 25  Lp(a) is nearly identical in structure to an LDL particle. However, factors such as diet may play some role, as trans fatty acids have been shown to increase Lp(a), and estrogen decreases both LDL and Lp(a). 26 27 Reference Book: Vasudevan, D. M., Sreekumari, S., and Kannan, V.., 2011. Textbook of biochemistry for medical students, 6th Edition. 28