Deficiency of acyl CoA:cholesterol acyltransferase 2 prevents atherosclerosis in apolipoprotein E-deficient mice.

Abstract:

:Deficiency of acyl CoA:cholesterol acyltransferase 2 (ACAT2) in mice results in a reduction in cholesterol ester synthesis in the small intestine and liver, which in turn limits intestinal cholesterol absorption, hepatic cholesterol gallstone formation, and the accumulation of cholesterol esters in the plasma lipoproteins. Here we examined the contribution of ACAT2-derived cholesterol esters to atherosclerosis by crossing ACAT2-deficient (ACAT2(-/-)) mice with apolipoprotein (apo) E-deficient (ApoE(-/-)) mice, an atherosclerosis-susceptible strain that has impaired apoE-mediated clearance of apoB-containing lipoproteins. ACAT2(-/-) ApoE(-/-) mice and ACAT2(+/+) ApoE(-/-) (control) mice had similar elevations of plasma apoB and total plasma lipids; however, the lipid cores of the apoB-containing lipoproteins in ACAT2(-/-) ApoE(-/-) mice contained primarily triglycerides rather than cholesterol esters. At 30 wk of age, only the control mice had significant atherosclerosis, which was nearly absent in ACAT2(-/-) ApoE(-/-) mice. ACAT2 deficiency in the apoE-deficient background also led to a compensatory increase in the activity of lecithincholesterol acyltransferase, the major plasma cholesterol esterification enzyme, which increased high-density lipoprotein cholesterol esters. Our results demonstrate the crucial role of ACAT2-derived cholesterol esters in the development of atherosclerosis in mice and suggest that triglyceride-rich apoB-containing lipoproteins are not as atherogenic as those containing cholesterol esters. Our results also support the rationale of pharmacological inhibition of ACAT2 as a therapy for atherosclerosis.

authors

Willner EL,Tow B,Buhman KK,Wilson M,Sanan DA,Rudel LL,Farese RV Jr

doi

10.1073/pnas.0336398100

keywords:

subject

Has Abstract

pub_date

2003-02-04 00:00:00

pages

1262-7

issue

3

eissn

0027-8424

issn

1091-6490

pii

0336398100

journal_volume

100

pub_type

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