HDL and Atherosclerosis

Atherosclerosis: A Progressive Process Préparation ESC Septembre 18/09/2018 Atherosclerosis: A Progressive Process Plaque Rupture/ Fissure & Thrombosis Occlusive Atherosclerotic Plaque Fatty Streak Fibrous Plaque Unstable Angina Normal MI Coronary Death Stroke Effort Angina Claudication Clinically Silent Critical Leg Ischemia Atherosclerosis is a progressive disease, typically starting in adolescence and developing over the course of several decades until clinically manifested as heat attack, stroke or peripheral vascular disease (intermittent claudication). Information on atherosclerosis is available at : http://en.wikipedia.org/wiki/Atherosclerosis. http://www.athero.org/ Increasing Age

Préparation ESC Septembre 18/09/2018 HDL Subpopulations Particle shape Apolipoprotein composition Discoidal Spherical A-I HDL A-I/A-II HDL E HDL Particle size Lipid-poor apoA-I HDL are the smallest and densest of the plasma lipoproteins. HDL exist in the plasma as a number of subpopulations of particles of varying shape, size, density and composition. The main apolipoproteins in HDL are apolipprotein (apo)A-I (70%) and apoA-II (20%). HDL also transport additional proteins such as CETP (cholesteryl ester transfer protein), LCAT (lecithin:cholesterol acyltransferase), PLTP (phospholipid transfer protein) and PON( paraoxonase). Most of the HDL particles in the plasma are spherical. Discoid HDL particles (nascent HDL) only exist transiently before conversion to spherical HDL particles. HDL particles carry cholesterol from the body's tissues to the liver for reprocessing or excretion. Reference Barter P, Rye K-A. High density cholesterol: the new target. A handbook for clinicians. Sherborne Gibbs, Birmingham, 2007 HDL2b HDL2a HDL3a HDL3b HDL3c

Préparation ESC Septembre 18/09/2018 Apolipoproteins Apo-A I carries ”good cholesterol” ( HDL ) Apo B carries ”bad cholesterol” ( LDL ) Apolipoproteins are components of both LDL and HDL cholesterol. The main apolipoproteins in HDL are apolipopotein A-I (apoA-I) and apolipoprotein A-II (apoA-II). These comprise about 70% and 20% of the total HDL protein, respectively. Most HDL particles also contain other minor apolipoproteins.

Préparation ESC Septembre 18/09/2018 HDL particles consist of a fatty core (mainly cholesteryl esters with a small amount of triglyceride), surrounded by a surface layer of phospholipids, unesterified cholesterol and apolipoproteins. Reference Barter P, Rye K-A. High density cholesterol: the new target. A handbook for clinicians. Sherborne Gibbs, Birmingham, 2005

Préparation ESC Septembre 18/09/2018 HDL Metabolism Bile A-I A-I FC LCAT CE CE FC FC CE ABCA1 SR-BI HL, EL Macrophage Liver CETP LDLR PLTP HDL metabolism is complex and presents a variety of targets for therapeutic intervention. These include: 1. HDL cholesteryl esters may be transferred to very-low-density lipoproteins (VLDL) and low-density lipoprotein (LDL) by CETP (cholesteryl ester transfer protein) and then removed from the plasma as components of these lipoproteins. 2. HDL cholestery esters (CE) may be selectively taken up by the liver in a process involving binding of HDL to SR-B1 (scavenger receptor type B1). 3. HDL, triglycerides and phospholipids are removed by hydrolysis catalysed by hepatic lipase (HL), endothelial lipase (EL), lipoprotein lipase (LPL) and possibly secretory phospholipase A2. 4. ApoA-I is independently metabolised following its dissociation from HDL during HDL remodelling. Reference Barter P, Rye K-A. High density cholesterol: the new target. A handbook for clinicians. Sherborne Gibbs, Birmingham, 2007. CE B TG Kidney VLDL/LDL

Metabolism of HDL Lipid-poor particles originate from the liver and intestine Plasma apolipoprotein A-I (apoA-I) acquires phospholipids and cholesterol from cell membranes, resulting in discoidal A-I HDL Esterification of cholesterol, resulting in formation of spherical HDL Remodelling of spherical HDL, leading to changes in composition and size

Préparation ESC Septembre 18/09/2018 Cycling of apoA-I between HDLs and a lipid-poor pool HDL CE TG Excretion through kidney CE Discoidal HDL CETP HL Lipid-poor apoA-I PLTP SRB1 HDL also transport proteins that are involved in HDL formation and remodelling. These include cholesteryl ester transfer protein (CETP), which remodels HDL into particles of varying size. Reference Barter P, Rye K-A. High density cholesterol: the new target. A handbook for clinicians. Sherborne Gibbs, Birmingham, 2007 CE TG CE TG CE CE UC CE LCAT

Préparation ESC Septembre 18/09/2018 Antiatherogenic Actions of HDL Reverse Cholesterol Transport Cellular Cholesterol Efflux Anti- inflammatory activity HDL Anti- apoptotic activity Anti- thrombotic activity Anti- oxidative activity Anti- infectious activity In addition to their role in reverse cholesterol transport, HDL have the ability to protect against atherosclerosis via a number of different mechanisms. HDL have been shown to inhibit oxidative modification of LDL (thereby reducing their atherogenicity) and inhibit expression of endothelial cell adhesion molecules. HDL also have anti-thrombotic effects, and stimulate nitric oxide generation, thereby reducing endothelial dysfunction. HDL are also implicated in the repair of damaged endothelium. Reference Barter P, Rye K-A. High density cholesterol: the new target. A handbook for clinicians. Sherborne Gibbs, Birmingham, 2005 Endothelial Repair Vasodilatory Activity Chapman et al. Curr Med. Res Opin. 2004,20:1253-1268 Assmann G. and Nofer JR, Annu Rev Med. 2003,53 : 321-41