title: Estrogen decreases atherosclerosis in part by reducing hepatic acyl-CoA:cholesterol acyltransferase 2 (ACAT2) in monkeys.
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.
  
  
  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.
authors.affiliation: Department of Pathology, Section on Comparative Medicine, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA. kkavanag@wfubmc.edu
authors.forename: Kylie
authors.initials: K
authors.lastname: Kavanagh
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Davis
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Martha D
authors.initials: MD
authors.lastname: Wilson
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Register
authors.forename: Michael R
authors.initials: MR
authors.lastname: Adams
authors.forename: Lawrence L
authors.initials: LL
authors.lastname: Rudel
authors.forename: Janice D
authors.initials: JD
authors.lastname: Wagner
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000517:prevention & control*; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology*; D005260:Female; D008077:Lipoproteins, LDL / Q000097:blood; D008099:Liver / Q000201:enzymology*; D008252:Macaca fascicularis; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*; D014280:Triglycerides / Q000097:blood; D000097587:Sterol O-Acyltransferase 2
chemical_list: D004966:Estrogens, Conjugated (USP); D008077:Lipoproteins, LDL; D002785:Sterol O-Acyltransferase; D014280:Triglycerides; D000097587:Sterol O-Acyltransferase 2