L35 Lipoprotein Remodelling (2).docx

35 Lipoprotein Remodelling: ILOs By the end of this lecture, students will be able to Differentiate types of lipoproteins. Describe endogenous circulation of lipids in association to lipoproteins Correlate defects in lipoproteins to clinical conditions Deduce role of lipoproteins in dyslipidaemia Wh...

35 Lipoprotein Remodelling: ILOs By the end of this lecture, students will be able to Differentiate types of lipoproteins. Describe endogenous circulation of lipids in association to lipoproteins Correlate defects in lipoproteins to clinical conditions Deduce role of lipoproteins in dyslipidaemia What are Lipoproteins? About 90% of the dietary lipids are composed of triglycerides, the rest is made up of phospholipids, cholesterol, cholesterol esters and free fatty acids. In Plasma, Lipids are combined with apolipoproteins to form Lipoproteins. Lipoproteins are classified into four subgroups: Chylomicrons, Very Low Density Lipoproteins, Low Density Lipoproteins, and High Density Lipoproteins. They differ in lipid and protein composition, size, and site of origin Lipoproteins function both to keep their component lipids soluble as they transport them in the plasma and to provide an efficient mechanism for transporting their lipid contents to (and from) the tissues. Plasma lipoproteins have the central core formed of non-polar lipids (triacylglycerols and esterified cholesterol). The outer layer contains the more polar lipids (phospholipids and non-esterified cholesterol), and proteins (apoproteins). Apoproteins: Apoproteins are proteins that bind to lipids, they are either peripheral (can be transferred) or integral (cannot be transferred). Functions of apolipoproteins: Solubilizing lipids in aqueous environment. Recognition sites for receptors e.g. LDL-receptors. Activators for certain enzymes involved in lipoprotein metabolism e.g. apo-CII activates lipoprotein lipase and apo-AI activates LCAT. Types of apoproteins include Apolipoprotein-A, Apoprotein-B (apo-B48 and apo-B100), Apoprotein-C (apo-CI, apo-CII and apo-CIII) Apoprotein E. Chylomicrons: Synthesis: Intestinal mucosal cells secrete nascent chylomicrons Composition: Nascent chylomicrons are rich in TG (>90%)(dietary exogenous lipids),few cholesterol and contain only 1-2% protein (apoproteins). (Fig4) Apoproteins: Nascent chylomicrons contain Apo B48 which is unique to chylomicrons then they acquire apo C and apo E. Nascent chylomicrons leave the intestine to the lymphatics, through the thoracic duct and then to the blood stream. When it reaches the plasma, the particle is rapidly modified, receiving apo E and apo C from HDL to become a mature chylomicron (Fig1).(Fig 3) Apo-CII activates lipoprotein lipase (LPL= clearing factor), located in the capillaries of adipose and other peripheral tissues as cardiac and skeletal muscles. Triglycerides in chylomicrons are then hydrolyzed into glycerol and FFA. As the chylomicron circulates, and >90% of the TAG in its core is degraded by LPL, the particle decreases in size and increases in density. In addition, the C apolipoproteins (but not apo B or E) are returned to HDL. The remaining particle, called a chylomicron remnant, is rapidly removed from the circulation by the liver, whose cell membranes contain lipoprotein receptors that recognize apo E. Very-low-density lipoprotein metabolism (VLDL): Synthesis: VLDL are produced in the liver. Composition: They are composed predominantly of endogenous TAG (~60%), 20% cholesterol, few phospholipids and 5% proteins (apoproteins) Apoproteins: Apo B-100 then they acquire Apo C and Apo E Their function is to carry endogenous TG from the liver (site of synthesis) to the peripheral tissues. (Fig 4) VLDL are secreted directly into the blood by the liver as nascent particles containing apo B-100. They must obtain apo CII and apo E from circulating HDL. As VLDL pass through the circulation, TAG is degraded by LPL, causing the VLDL to decrease in size and become denser and become small dense Low density Lipoproteins (LDL) (Fig 3) Surface components, including the apo C and E are returned to HDL, but the particles retain apo B-100. Additionally, some TAG are transferred from VLDL to HDL in an exchange reaction that concomitantly transfers cholesteryl esters from HDL to VLDL. This exchange is accomplished by cholesteryl ester transfer protein (CETP) (Fig 2) Clinical Implications: Non-alcoholic fatty liver occurs in conditions in which there is an imbalance between hepatic TAG synthesis and the secretion of VLDL. Such conditions include obesity and type 2 diabetes mellitus. Low-density lipoprotein metabolism (LDL): Production: Produced from VLDL after most of their TAG has been degraded by LPL (Fig3) Composition: LDL particles contain much less TAG than their VLDL predecessors and have a higher concentration of cholesterol (about 50%), they also contain phospholipids and proteins (20%) (Apolipoproteins). (Fig4) Apolipoproteins: Apo-B100 is the only apolipoprotein in LDL particles. About 70% of plasma cholesterol is in LDL. The primary function of LDL particles is to provide cholesterol to the peripheral tissues (or return it to the liver). They do so by binding to plasma membrane LDL receptors that recognize apo B-100 (but not apo B-48). The cholesterol content of the cells that have active LDL pathway is regulated in 2 ways: The released cholesterol suppresses the formation of HMG CoA reductase there-by inhibiting de novo synthesis of cholesterol. LDL receptors are subjected to feedback regulation. New receptors are not synthesized and so the uptake of additional cholesterol from the plasma LDL is blocked. Clinical Implications: Since LDL transports cholesterol particles throughout the body and builds up in the walls of arteries, making them hard and narrow (atherosclerosis), it is known as “Bad Cholesterol” Normal levels of LDL should be less than 110 mg/dl High LDL levels are seen with low physical activity, unhealthy diets, and obesity. Defects in the synthesis of functional LDL receptors causes a significant elevation in plasma LDL-Cholesterol. Patients with such deficiencies have familial hypercholesterolemia [FH] and premature atherosclerosis. High-density lipoprotein metabolism HDL particles serve as a circulating reservoir of apo C-II (the apolipoprotein that is transferred to VLDL and chylomicrons and is an activator of LPL) and apo E (the apolipoprotein required for the receptor-mediated endocytosis of chylomicron remnants). Synthesis: Nascent HDL are disc-shaped particles synthesized mainly by the liver Composition: HDL contains primarily proteins (apoproteins) (40%) and phospholipids (30%) (fig4) Apolipoproteins: Apo A, C, and E. HDL take up cholesterol from non-hepatic (peripheral) tissues and return it to the liver as cholesteryl esters. HDL particles are excellent acceptors of non-esterified cholesterol as a result of their high concentration of phospholipids, which are important solubilizers of cholesterol. The cholesterol taken up by HDL is immediately esterified by the plasma enzyme lecithin:cholesterol acyltransferase (LCAT). This enzyme is synthesized and secreted by the liver. LCAT binds to nascent HDL and is activated by apo A. The produced hydrophobic cholesteryl ester is sequestered in the core of the HDL and carries these esters to the liver This in known as “Reverse cholesterol transport (RCT)” which is an important process by which selective transfer of cholesterol from peripheral cells to HDL and from HDL to the liver occurs, this is important for bile acid synthesis or disposal via the bile which is a key component of cholesterol homeostasis. Clinical Implications: The process of reverse cholesterol transport (RCT) is, in part, the basis for the inverse relationship seen between plasma HDL concentration and atherosclerosis, for this reason HDL is known as the “good” cholesterol. Normal HDL levels should be above 40 mg/dL in males, while in females it should be above 50 mg/dL It is believed that determining the non-HDL cholesterol, Total cholesterol/HDL ratio or even the LDL/HDL ration levels may be more useful than calculating the total cholesterol. Non-HDL cholesterol, as its name implies, simply subtracts HDL "good" cholesterol from the total cholesterol. So it contains all the "bad" types of cholesterol.