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Articles in PresS, published online ahead of print June 4, 2002
Am J Physiol Endocrinol Metab, 10.1152/ajpendo.00364.2001
Submitted on August 9, 2001
Accepted on May 24, 2002
1 Division of Nephrology and Hypertension, Department of Medicine, Physiology and Biophysics, University of California Irvine, Irvine, California, USA
* To whom correspondence should be addressed. E-mail: ndvaziri{at}uci.edu.
Chronic renal failure (CRF) is associated with profound abnormalities of lipid metabolism and accelerated arteriosclerotic cardiovascular disease. In a recent study, we found marked downregulation of hepatic lecithin: Cholesterol acyltransferase (LCAT) expression which can account for impaired HDL maturation and depressed HDL cholesterol concentration in CRF. Here we report on the effect of CRF on ACAT expression. ACAT is an intracellular enzyme which catalyzes esterification of free cholesterol to cholesterol ester for storage or secretion. ACAT plays a major role in hepatic, production and release of VLDL, intestinal absorption of cholesterol, foam cell formation and atherogenesis. We examined hepatic expression of ACAT-1 and ACAT-2 mRNA (Northern Blot), and protein (Western Blot) abundance and total ACAT activity in male CRF rats (6 weeks post 5/6 nephrectomy), and sham-operated controls. The CRF animals showed a significant reduction in creatinine clearance, marked hypertriglyceridemia, modest hypercholesterolemia and significant upregulation of hepatic tissue ACAT-2 protein and mRNA abundance. In contrast, hepatic ACAT-1 mRNA and protein abundance were unaffected by CRF. Upregulation of ACAT-2 expression was accompanied by a significant increase in hepatic ACAT activity, a significant decrease in hepatic microsomal and whole liver free cholesterol concentration. Thus, CRF results in significant upregulation of hepatic ACAT-2 (but not ACAT-1) expression and ACAT activity which may, in part, contribute to the associated lipid disorders.
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