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J. Biol. Chem., Vol. 277, Issue 35, 31401-31406, August 30, 2002
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From the Arteriosclerosis Research Program, Department of
Pathology, Wake Forest University School of Medicine,
Winston-Salem, North Carolina 27157
The role of liver acyl-CoA:cholesterol
acyltransferase 2 (ACAT2), earlier shown to be the principal ACAT
enzyme within primate hepatocytes, as a regulator of the
hypercholesterolemia induced by dietary cholesterol was studied. At the
end of low and high cholesterol diet periods, liver biopsies were taken
from cynomolgus monkeys, a species highly responsive to dietary
cholesterol, and less responsive African green monkeys. Liver
cholesterol and cholesteryl ester concentrations were highest in
cynomolgus monkeys fed cholesterol, despite the fact that in order to
induce equivalent hypercholesterolemia, dietary cholesterol levels were
50% lower than was fed to green monkeys. Hepatic cholesteryl oleate
secretion rate, measured during liver perfusion as an indicator of ACAT
activity, was significantly higher in cynomolgus monkeys. Liver
microsomal ACAT activity was 2-3-fold higher in cynomolgus monkeys
than in green monkeys. The responses of ACAT2 were compared with those
of ACAT1 that is found primarily in Kupffer cells. ACAT2 protein mass
was significantly correlated to microsomal total ACAT activity in both
species; ACAT1 mass was less well correlated. Dietary cholesterol
induced a significant 3-fold increase of ACAT2 protein mass in
cynomolgus monkeys, a much greater increase than was found for mRNA
abundance; neither ACAT2 mRNA nor protein was diet-responsive in
green monkeys. In cynomolgus monkeys but not in green monkeys, liver
free cholesterol concentrations were elevated when cholesterol was fed
and were correlated with ACAT2 protein levels. The data suggest a
mechanism whereby the elevation of hepatic free cholesterol
concentrations by dietary cholesterol, seen only in cynomolgus monkeys,
resulted in higher ACAT2 protein levels in hepatocytes, either through increased production or stabilization of the protein. Regulation of ACAT2 gene transcription was not a factor.
Primates Highly Responsive to Dietary Cholesterol Up-regulate
Hepatic ACAT2, and Less Responsive Primates Do Not*
,
*
This work was supported by National Institutes of Health
Grants HL-49373 and HL-24736.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Pathology,
Wake Forest University School of Medicine, Medical Center Blvd.,
Winston-Salem, NC 27157. Tel.: 336-716-2821; Fax: 336-716-6279; E-mail: lrudel@wfubmc.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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