Scavenger receptor type BI potentiates reverse cholesterol transport system by removing cholesterol ester from HDL

Abstract

High-density lipoprotein (HDL) plays an important role in reverse cholesterol transport by removing accumulated cholesterol from extrahepatic tissues. Subsequently, cholesterol ester (CE) on HDL in humans is transported to apolipoprotein B-containing lipoproteins by cholesteryl ester transfer protein (CETP). CETP deficiency, which is common in the Japanese population, leads to a marked increase in HDL-cholesterol levels due to impaired CE transport from HDL to LDL. It has been reported that the HDL observed in CETP deficiency is an atherogenic lipoprotein, as it contains a large amount of CE. Scavenger receptor class B type I (SR-BI) has been found to be an authentic HDL receptor that mediates the selective uptake of HDL CE and the bi-directional transfer of free cholesterol between HDL and cells. In the present study, the interaction between SR-BI and CE-rich HDL from CETP-deficient patient was studied in order to evaluate the anti-atherosclerotic role of SR-BI in relation to CE uptake and reverse cholesterol transport. When CE-rich HDL was added to the medium of SR-BI-transfected CHO (SR-BI CHO) cells, more CE accumulated in SR-BI CHO cells compared to control HDL. In contrast, the amount of cholesterol efflux from SR-BI CHO cells into HDL was almost the same between the two HDLs. Therefore, when CE-rich HDL was added to the medium of SR-BI CHO cells, the intracellular CE content increased significantly. Moreover, the particle size of HDL in CETP-deficient patient decreased significantly when the HDL was added to the medium of SR-BI CHO cells, and this HDL showed an increment of CE efflux from foam cells. These results indicate that SR-BI reduces the cholesterol content and size of the CE-rich HDL from CETP deficiency, which ultimately activate reverse cholesterol transport system.

Introduction

High-density lipoprotein (HDL) plays an important role in lipid homeostasis by removing accumulated cholesterol from extrahepatic tissues [1]. Unesterified cholesterol, removed from the extrahepatic tissues, is esterified on HDL by lecithin:cholesterol acyltransferase (LCAT) and transferred to apolipoprotein (apo) B-containing lipoproteins by cholesteryl ester transfer protein (CETP) and delivered to the liver through LDL receptors [2]. Alternatively, cholesterol transport can also occur through the direct transport of cholesterol ester (CE) on HDL, after which CE is taken up by the liver and other steroidgenic tissues [1], [2]. These processes, referred to as reverse cholesterol transport, are believed to play a major anti-atherosclerotic role in primates [3]. It has been known that the scavenger receptor class B type I (SR-BI) is a cell-surface HDL receptor that selectively takes up the CE of HDL [4], [5]. SR-BI mRNA and protein levels are highest in the liver, adrenal gland, ovary, and testis, tissues which has great selective CE uptake from HDL [6], [7]. Additionally, it has been reported that SR-BI also plays a role in HDL-mediated cholesterol efflux from SR-BI-transfected cells [8]. Recently, in studies of transgenic mice, it has been revealed that the overexpression of hepatic SR-BI increases reverse cholesterol transport and plays an anti-atherosclerotic role, despite low HDL cholesterol concentrations [9], [10].

On the other hand, a marked increase of the HDL cholesterol contents has been observed in a patient with CETP deficiency [11], [12], [13]. It has been discussed whether the high HDL cholesterol observed in CETP deficiency plays an anti-atherosclerotic role [14], [15], [16]. Some studies have suggested that the large HDLs observed in CETP deficiency are atherogenic lipoproteins and that CETP-deficient patients show signs of progressed atherosclerosis [17], [18], [19]. In the present study, we examined the interaction between SR-BI and HDLs from CETP deficiency to evaluate the anti-atherosclerotic role of SR-BI in relation to CE uptake and reverse cholesterol transport.