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.


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.
Kavanagh
Kylie
K
Department of Pathology, Section on Comparative Medicine, Wake Forest University School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157, USA. kkavanag@wfubmc.edu
Davis
Matthew A
MA
Zhang
Li
L
Wilson
Martha D
MD
Register
Thomas C
TC
Adams
Michael R
MR
Rudel
Lawrence L
LL
Wagner
Janice D
JD
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
D004966:Estrogens, Conjugated (USP); D008077:Lipoproteins, LDL; D002785:Sterol O-Acyltransferase; D014280:Triglycerides; D000097587:Sterol O-Acyltransferase 2