Up-regulation of acyl-coenzyme A:cholesterol acyltransferase (ACAT) in nephrotic syndrome.
BACKGROUND
We have previously demonstrated that hypercholesterolemia in rats with puromycin-induced nephrotic syndrome (NS) is associated with up-regulation of hepatic 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase and relative down-regulation of cholesterol 7alpha-hydroxylase (Ch-7alpha), which represent the rate-limiting steps in cholesterol biosynthesis and catabolism. Expression of HMG-CoA reductase is inhibited and Ch-7alpha is augmented by intracellular free cholesterol, which is avidly esterified by acyl-CoA:cholesterol acyltransferase (ACAT). Therefore, we hypothesized that NS may result in up-regulation of hepatic ACAT.


METHODS
Hepatic tissue ACAT mRNA (Northern blot), protein (Western blot) and enzymatic activity were determined in rats with puromycin-induced NS, placebo-treated control rats and Nagase hypoalbuminemic (NAG) rats.


RESULTS
The NS group exhibited heavy proteinuria, hypoalbuminemia, normal creatinine clearance, severe hypercholesterolemia and hypertriglyceridemia. Despite severe hypoalbuminemia, NAG rats with inherited hypoalbuminemia exhibited only a mild elevation of plasma cholesterol and triglycerides. Severe hypercholesterolemia in the NS group was coupled with depressed liver tissue free cholesterol concentration and marked increases in hepatic ACAT mRNA, protein and enzymatic activity. In contrast, ACAT mRNA and protein contents of the liver were normal and ACAT activity was mildly elevated in the NAG group.


CONCLUSIONS
NS results in marked up-regulation of hepatic ACAT, which is primarily due to proteinuria and not hypoalbuminemia, since the latter alone, as seen in NAG rats, does not significantly impact ACAT expression. Elevated ACAT in NS can contribute to dysregulation of cholesterol biosynthesis and catabolism by limiting the normal cholesterol signaling involved in regulation of these processes.
Vaziri
Nosratola D
ND
Division of Nephrology and Hypertension, Department of Medicine, University of California, Irvine, Irvine, California, USA. ndvaziri@uci.edu
Liang
Kaihui
K
D000818:Animals; D001161:Arteriosclerosis / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006949:Hyperlipidemias / Q000378:metabolism; D007668:Kidney / Q000201:enzymology*; D008297:Male; D009404:Nephrotic Syndrome / Q000378:metabolism*; 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
D002784:Cholesterol; D012333:RNA, Messenger; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2