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

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 alpha-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. (Arterioscler Thromb Vasc Biol. 2009; 29: 1471-1477.)