Homozygous disruption of Pctp modulates atherosclerosis in apolipoprotein E-deficient mice

Juan M Baez,Wen-Jun Wang,David E Cohen,Hayes M Dansky,Rie Maurer

doi:10.1194/jlr.m600277-jlr200

Abstract

Phosphatidylcholine transfer protein (PC-TP) is a cytosolic phospholipid binding protein and a member of the steroidogenic acute regulatory-related transfer domain superfamily. Its tissue distribution includes liver and macrophages. PC-TP regulates hepatic lipid metabolism, and its absence in cholesterol-loaded macrophages is associated with reduced ATP binding cassette transporter A1-mediated lipid efflux and increased susceptibility to apoptosis induced by unesterified cholesterol. To explore a role for PC-TP in atherosclerosis, we prepared PC-TP-deficient/apolipoprotein E-deficient (Pctp(-/-)/Apoe(-/-)) mice and littermate Apoe(-/-) controls. At 16 weeks, atherosclerosis was increased in chow-fed male, but not female, Pctp(-/-)/Apoe(-/-) mice. This effect was associated with increases in plasma lipid concentrations. By contrast, no differences in atherosclerosis were observed between male or female Pctp(-/-)/Apoe(-/-) mice and Apoe(-/-) controls fed a Western-type diet for 16 weeks. At 24 weeks, atherosclerosis in chow-fed male Pctp(-/-)/Apoe(-/-) mice tended to be reduced in proportion to plasma cholesterol. The attenuation of atherosclerosis in female Pctp(-/-)/Apoe(-/-) mice fed chow or the Western-type diet for 24 weeks was not attributable to changes in plasma cholesterol or triglyceride concentrations. These findings suggest that PC-TP modulates the development of atherosclerosis, in part by regulating plasma lipid concentrations.

Highlights

Phosphatidylcholine transfer protein (PC-TP) is a cytosolic phospholipid binding protein and a member of the steroidogenic acute regulatory-related transfer domain superfamily
At 24 weeks, lesion area tended to decrease by 21% and 23% in aortas of chow-fed Pctp2/2/Apoe2/2 male and female mice, respectively, compared with their littermate Apoe2/2 controls (Fig. 1B)
The absence of PC-TP expression reduced aortic atherosclerosis by 22% in Western-type diet-fed female Pctp2/2/Apoe2/2 mice compared with gender-matched Apoe2/2 controls (Fig. 1B–D)

Summary

Introduction

Phosphatidylcholine transfer protein (PC-TP) is a cytosolic phospholipid binding protein and a member of the steroidogenic acute regulatory-related transfer domain superfamily. Consistent with a role in reverse cholesterol transport, in vivo studies using Pctp2/2 mice have demonstrated that PC-TP expression regulates the size and hepatic uptake of HDL particles [8] as well as the response of biliary lipid secretion to dietary cholesterol [5] and that the absence of PC-TP expression leads to compensatory alterations in hepatic cholesterol metabolism [9] These apparent roles in cholesterol efflux from macrophages and in the biliary elimination of plasma cholesterol suggest that PC-TP expression may influence the development of atherosclerosis. Compared with Apoe2/2 controls at 16 weeks, atherosclerosis in chow-fed male Pctp2/2/Apoe2/2 mice was increased These differences did not persist when the comparison was adjusted for plasma lipid concentrations and were not observed in Western-type diet-fed mice. In female mice, adjustment for plasma lipids did not entirely eliminate the influence of PC-TP expression on atherosclerotic lesion area, suggesting that PC-TP expression within the arterial wall predisposes to atherosclerosis after extended periods of hyperlipidemia

Methods

Results

Conclusion