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.
journal_name
Proc Natl Acad Sci U S Aauthors
Willner EL,Tow B,Buhman KK,Wilson M,Sanan DA,Rudel LL,Farese RV Jrdoi
10.1073/pnas.0336398100keywords:
subject
Has Abstractpub_date
2003-02-04 00:00:00pages
1262-7issue
3eissn
0027-8424issn
1091-6490pii
0336398100journal_volume
100pub_type
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