This Article Full Text Full Text (PDF) Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Kavanagh, K. Articles by Wagner, J. D. PubMed Articles by Kavanagh, K. Articles by Wagner, J. D. Related Collections Animal models of human disease Pathophysiology Lipid and lipoprotein metabolism

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1471.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Estrogen Decreases Atherosclerosis in Part by Reducing Hepatic Acyl-CoA:Cholesterol Acyltransferase 2 (ACAT2) in Monkeys

Kylie Kavanagh; Matthew A. Davis; Li Zhang; Martha D. Wilson; Thomas C. Register; Michael R. Adams; Lawrence L. Rudel; Janice D. Wagner

From the Department of Pathology, Section on Comparative Medicine (K.K., L.Z., T.C.R., M.R.A., J.D.W.) and the Department of Pathology, Section on Lipid Sciences (M.A.D., M.D.W., L.L.R.), Wake Forest University School of Medicine, Winston-Salem, NC.

Correspondence to Kylie Kavanagh, Department of Pathology, Section on Comparative Medicine, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157. E-mail kkavanag{at}wfubmc.edu

Objective— Estrogens decrease atherosclerosis progression, mediated in part through changes in plasma lipids and lipoproteins. This study aimed to determine estrogen-induced changes in hepatic cholesterol metabolism, plasma lipoproteins, and the relationship of these changes to atherosclerosis extent.

Methods and Results— Ovariectomized monkeys (n=34) consumed atherogenic diets for 30 months which contained either no hormones (control, n=17) or conjugated equine estrogens (CEE, n=17) at a human dose equivalent of 0.625 mg/d. Hepatic cholesterol content, low-density lipoprotein (LDL) receptor expression, cholesterol 7-hydroxylase and acyl-coenzyme A:cholesterol acyltransferase (ACAT) activity, and expression levels were determined. CEE treatment resulted in lower plasma concentrations of very-low- and intermediate- density lipoprotein cholesterol (V+IDLC; P=0.01), smaller LDL particles (P=0.002), and 50% lower hepatic cholesterol content (total, free, and esterified; P<0.05 for all). Total ACAT activity was significantly lower (P=0.01), explained primarily by reductions in the activity of ACAT2. Estrogen regulation of enzymatic activity was at the protein level as both ACAT1 and 2 protein, but not mRNA levels, were lower (P=0.02 and <0.0001, respectively). ACAT2 activity was significantly associated with hepatic total cholesterol, plasma V+IDLC cholesterol, and atherosclerosis.

Conclusions— Atheroprotective effects of estrogen therapy may be related to reduced hepatic secretion of ACAT2-derived cholesteryl esters in plasma lipoproteins.

Estrogen inhibits atherogenesis. We demonstrate in ovariectorized monkeys that estrogen therapy led to lower hepatic and circulating lipoprotein cholesterol, and lower ACAT2 protein and associated activity levels as compared to controls. Hepatic ACAT2 activity was highly correlated with, and was an independent predictor of, coronary artery atherosclerosis extent.

Key Words: ACAT2 • coronary artery atherosclerosis • estrogen • hepatic cholesterol • lipoproteins