Post-transcriptional regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase and cholesterol 7 alpha-hydroxylase in rats with subtotal nephrectomy.
Chronic renal failure is associated with hyperlipidemia and atherosclerosis. The mechanism responsible for the observed increase of serum cholesterol in chronic renal disease is not certain. The objective of the present study was to characterize the effect of induced renal failure on 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase) and cholesterol 7 alpha-hydroxylase, the two rate determining enzymes of the cholesterol and bile acid biosynthetic pathways, respectively. Studies were carried out in rats with subtotal (75%) nephrectomy, which resulted in a marked elevation of blood urea nitrogen (371 +/- 44% of control, P < 0.001), and was accompanied by significant increases in the levels of serum cholesterol (133 +/- 7%, P < 0.005) and triglycerides (185 +/- 25, P < 0.01). In nephrectomized rats, an increase in the specific activity of HMG-CoA reductase (219 +/- 30% above control levels, P < 0.02) was observed. This increase occurred in the presence of elevated hepatic microsomal cholesterol concentrations (150 +/- 13% of controls, P < 0.01). Surprisingly, the increase in HMG-CoA reductase specific activity was not associated with parallel increases in HMG-CoA reductase steady-state mRNA levels and gene transcriptional activity. These uremic rats also exhibited a marked increase in the specific activity of cholesterol 7 alpha-hydroxylase (240 +/- 559% of controls, P < 0.05). There was no concomitant increase in cholesterol 7 alpha-hydroxylase steady-state mRNA levels or gene transcriptional activity. The factors responsible for the observed increases in HMG-CoA reductase and cholesterol 7 alpha-hydroxylase specific activity in renal failure remain to be determined.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Medicine, Medical College of Virginia, Richmond.
W M
WM
Pandak
Z R
ZR
Vlahcevic
D M
DM
Heuman
R J
RJ
Krieg
J D
JD
Hanna
J C
JC
Chan
D000818:Animals; D001646:Bile / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics* / Q000378:metabolism; D007676:Kidney Failure, Chronic / Q000209:etiology; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D009392:Nephrectomy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic; D014280:Triglycerides / Q000097:blood
D012333:RNA, Messenger; D014280:Triglycerides; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase