Studies of alteration of hepatic cholesterol metabolism in puromycin-induced nephrotic syndrome in rats.
Hypercholesterolemia frequently accompanies the nephrotic syndrome, but the mechanism responsible for elevation of plasma cholesterol is poorly understood. Specifically, the contribution of abnormal hepatic cholesterol metabolism to elevated concentrations of serum cholesterol has never been studied in depth. The objective of the present study was to define the alteration of hepatic cholesterol metabolism in puromycin induced nephrotic syndrome in rats. Studies involved measurements of specific activities of four enzymes participating in the maintenance of hepatic cholesterol metabolism: HMG-CoA-reductase, the rate limiting enzyme of cholesterol synthesis; cholesterol 7 alpha-hydroxylase, the rate limiting enzyme in bile acid synthesis; acyl CoA: cholesterol acyltransferase, the enzyme responsible for esterification of cholesterol; and cholesterol ester hydrolase (CEH), an enzyme which hydrolyzes cholesterol. Multiple injections of puromycin resulted in a production of nephrotic syndrome with massive proteinuria, hypoalbuminemia, hypercholesterolemia, ascites and edema. HMG-CoA-reductase (nmol/hr/mg protein) and cholesterol 7 alpha-hydroxylase activities (nmol/hr/mg protein) in rats with nephrotic syndrome were not statistically significant as compared to control rats (4.0 +/- 0.7 and 2.0 +/- 0.6 vs. 3.3 +/- 0.4 and 1.6 +/- 0.2), respectively. Our results also demonstrate, for the first time, that the normal diurnal rhythm in HMG-CoA reductase activity is no longer present in the nephrotic animals. The activities in the nephrotics in the day was 4.0 nmol/hr/mg and at night, 3.9 nmol/hr/day, compared to the control values of 3.3 nmol/hr/mg in the day and 6.9 nmol/hr/mg at night. ACAT activities were 428 +/- 78 versus 302 +/- 64 pmol/min/mg/protein (P = NS).(ABSTRACT TRUNCATED AT 250 WORDS)
Thabet
M A
MA
Department of Pediatrics, Children's Medical Center, Medical College of Virginia, Richmond.
Challa
A
A
Chan
J C
JC
Pandak
W M
WM
Heuman
D M
DM
Vlahcevic
Z R
ZR
D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D002940:Circadian Rhythm; D005260:Female; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008099:Liver / Q000378:metabolism* / Q000648:ultrastructure; D009404:Nephrotic Syndrome / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism*; D011691:Puromycin; D051381:Rats; D017207:Rats, Sprague-Dawley; D002787:Sterol Esterase / Q000378:metabolism; D002785:Sterol O-Acyltransferase / Q000378:metabolism
D011691:Puromycin; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase; D002785:Sterol O-Acyltransferase; D002787:Sterol Esterase