Role of Phospholipid Transfer Protein in HighDens

Authors: Amirfarbod Yazdanyar Calvin Yeang XianCheng Jiang

Publish Date: 2011/03/02

Volume: 13, Issue: 3, Pages: 242-248

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Abstract

Reverse cholesterol transport RCT describes the process whereby cholesterol in peripheral tissues is transported to the liver where it is ultimately excreted in the form of bile Given the atherogenic role of cholesterol accumulation within the vessel intima removal of cholesterol through RCT is considered an antiatherogenic process The major constituents of RCT include cell membrane– bound lipid transporters plasma lipid acceptors plasma proteins and enzymes and lipid receptors of liver cell membrane One major cholesterol acceptor in RCT is highdensity lipoprotein HDL Both the characteristics and level of HDL are critical determinants for RCT It is known that phospholipid transfer protein PLTP impacts both HDL cholesterol level and biological quality of the HDL molecule Recent data suggest that PLTP has a sitespecific variation in its function Moreover the RCT pathway also has multiple steps both in the peripheral tissues and circulation Therefore PLTP may influence the RCT pathway at multiple levels In this review we focus on the potential role of PLTP in RCT through its impact on HDL homeostasis The relationship between PLTP and RCT is expected to be an important area in finding novel therapies for atherosclerosisAtherogenesis is initiated by accumulation of cholesterolrich lipid strikes in the arterial wall 1 Many processes have been implicated in early atherogenesis including lipoprotein oxidation 2 3 aggregation and retention 4 5 6 7 endothelial alteration 1 monocyte recruitment and foam cell formation 1 Subsequent selfperpetuating chronic inflammatory response leads to further immune reactions and lipid deposition which lead to atherosclerosis One defense mechanism for atherosclerosis is removal of cholesterol from the vessel intima via reverse cholesterol transport RCTThe general concept of RCT involves transport of cholesterol from peripheral tissues and cells to the liver transforming it into bile acids and finally eliminating it from the body RCT may prevent the formation and development of atherosclerosis by decreasing cholesterol levels in the plasma and in the wall of arteries The RCT pathway consists of multiple factors First there are lipid transporters which efflux cholesterol from peripheral tissues 8 9 10 second there are lipid acceptors such as highdensity lipoprotein HDL and its various subclasses 8 9 10 11 which act as a mediator between peripheral tissues and the liver third there are lipoproteinassociated proteins and enzymes such as lecithin cholesterol acyltransferase LCAT 12 cholesteryl ester transfer protein CETP and phospholipid transfer protein PLTP 13 which are involved in HDL remodeling and metabolism and fourth there are liver receptors such as scavenger receptor class B type I SRBI which are important in removing cholesterol from the circulation 14There is a growing body of evidence suggesting that HDL mediates its atheroprotective effect through driving cholesterol efflux from macrophage foam cells that reside in vessel intima 11 15 16 As a plasma cholesterol acceptor both the biological activity and concentration of HDL particles are equally important to accomplish its atheroprotective effect 8 17 18 Therefore several cellular and plasma transfer proteins that are involved in the process of the formation and remodeling of HDL play a pivotal role in cholesterol efflux from macrophages Among the different transfer proteins that are active either at cell membrane or in the circulation PLTP and CETP have long been studied for their remarkable role in HDL metabolism This review is mainly focused on the latest data regarding the role of PLTP in HDLmediated RCTRCT is a potent defense mechanism against cholesterol accumulation in peripheral tissues 19 This process involves the centripetal transport of excess cholesterol and phospholipid from peripherally settled macrophages to the liver for further metabolism and excretion through the bilefecal route 11 16 The first step of RCT is efflux of free cholesterol from macrophages and other peripheral cells to extracellular cholesterol acceptors 19 20 There are four different pathways that work together to carry cholesterol out of the macrophages to plasma acceptors The major route is through ATPbinding cassette ABC A1 and ABCG1mediated unidirectional active transport of free cholesterol toward apolipoprotein AI apoAI–rich lipidpoor apolipoproteins preβHDL or HDL particles respectively 21 22 SRBI and aqueous diffusion also promote efflux of the excess cholesterol in a passive bidirectional manner to mature HDL particles 23 Macrophages and foam cells have extensive contribution in pathogenesis of the atherosclerotic lesions and efflux of cholesterol from these cells has been shown to have a significant role in regression of an existing atheroma and reversing the process of atherosclerosis 16 In order to accomplish RCT the interaction between extracellular acceptors and cell surface transporters is very critical 20 During this step of RCT free cholesterol can be transferred to preβHDL and the HDL bound cholesterol is subsequently esterified by LCAT Accumulation of cholesteryl ester in preβHDL converts it to the larger spherical mature HDL particles that are then taken up by the liver via the SRBI 14 24 Alternatively the cholesteryl ester can be transferred from HDL to lowdensity lipoprotein LDL and the later can be taken up by LDL receptors The concentration and composition of extracellular cholesterol acceptors are determinants of the rate of cholesterol efflux Furthermore plasma proteins such as PLTP CETP and lipases are essentially involved in the process of HDL formation conversion and remodeling Therefore these proteins actively maintain the plasma level and biological properties of HDL particles and potentially play an important role in RCTA high HDL cholesterol level has been mentioned as an antiatherogenic factor in progressive cohort studies and in randomized clinical trials aimed at raising HDL levels Moreover acute infusion of synthetic HDL or its principal apolipoprotein apoAI can induce the regression of atheromatous plaque in humans Indeed there has been a wealth of research demonstrating the beneficial processes in which HDL participates HDL plays a key role in RCT and importantly facilitates the removal of cholesterol from intralesion macrophages 25 In addition HDL has been shown to protect against LDLinduced monocyte migration into the subendothelial space in an endothelial cell/smooth muscle cell coculture system 26 This is consistent with the finding that HDL can blunt expression of endothelial cell adhesion molecules 27 HDL can protect against oxidation of LDL or phospholipids 28 Other aspects of HDL function that are protective against atherosclerosis include promoting endothelial function by stimulating nitric oxide synthesis 29 and preventing platelet aggregation and thrombin formation 30 There are multiple aspects of HDL function that are antiatherogenic and its role in RCT is one of them Different subclasses of HDL play major roles as cholesterol acceptors in the extracellular region and plasma 31 Interestingly a growing body of evidence has shown that fruitful cholesterol efflux is dependent both on high level of HDL cholesterol and on biological quality of different HDL particles 17 18 The biological quality refers to the size shape and composition of HDL particles which are notably various and dynamically interconvertible 32 Evidently each of the different pathways of cholesterol efflux prefers a specific subclass of the HDL particles as a cholesterol acceptor 32 Therefore the presence of different HDL subspecies and dynamic conversion between these subspecies are determinants for RCT Human and mouse studies have pointed out that preβHDL and mature HDL are the major cholesterol acceptors in plasma 32 PreβHDL is produced by interaction and subsequent lipidation of lipidpoor apoA1 by ABCA1 or by HDL particle remodeling in the circulation 19 32 One pathway for HDL particle remodeling involves plasma PLTP PLTP fuses HDL particles generating larger HDL particles with concomitant production of small preβHDL 33 Given its role in HDL metabolism PLTP’s role in reverse cholesterol transport deserves to be addressedThe relationship between PLTP structure and function is far from resolved However some progress has been made PLTP belongs to a family of lipid transfer/lipopolysaccharide binding proteins including lipopolysaccharide binding protein LBP bactericidal/permeability increasing protein BPI and CETP 34In terms of lipid transfer activity PLTP has its own characteristics It has no neutral lipid transfer activity PLTP circulates bound to HDL and mediates the net transfer of phospholipids between unilaminar vesicles into HDL and also the exchange of phospholipids between lipoproteins The net transfer of phospholipid into HDL results in the formation of larger less dense species Plasma PLTP is also a nonspecific lipid transfer protein Several studies have indicated that PLTP is capable of transferring all common phospholipids Besides phospholipids diacylglycerol αtocopherol cerebroside and lipopolysaccharides are likewise transferred efficiently 35 Although CETP also can transfer phospholipids there is no redundancy in the functions of PLTP and CETP in the mouse model 36

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