Estrogen decreases atherosclerosis in part by reducing hepatic acyl-CoA:cholesterol acyltransferase 2 (ACAT2) in monkeys

Arterioscler Thromb Vasc Biol. 2009 Oct;29(10):1471-7. doi: 10.1161/ATVBAHA.109.191825.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Atherosclerosis / prevention & control*
  • Estrogens, Conjugated (USP) / pharmacology*
  • Female
  • Lipoproteins, LDL / blood
  • Liver / enzymology*
  • Macaca fascicularis
  • Sterol O-Acyltransferase / antagonists & inhibitors*
  • Sterol O-Acyltransferase 2
  • Triglycerides / blood

Substances

  • Estrogens, Conjugated (USP)
  • Lipoproteins, LDL
  • Triglycerides
  • Sterol O-Acyltransferase