Upregulation of acyl-CoA: cholesterol acyltransferase in chronic renal failure.
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, or 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 acyl-CoA:cholesterol acyltransferase (ACAT) expression. ACAT is an intracellular enzyme that 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 wk after 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 and 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.
Liang
Kaihui
K
Division of Nephrology and Hypertension, Physiology and Biophysics, University of California, Irvine, California 92697, USA.
Vaziri
N D
ND
D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism; D004195:Disease Models, Animal; D015971:Gene Expression Regulation, Enzymologic; D006949:Hyperlipidemias / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D002785:Sterol O-Acyltransferase / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology; D000097587:Sterol O-Acyltransferase 2
D012333:RNA, Messenger; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2