Post-transcriptional regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase and cholesterol 7α-hydroxylase in rats with subtotal nephrectomy

Pandak, William M.; Vlahcevic, Z. Reno; Heuman, D. M.; Krieg, Richard J.; Hanna, James D.; Chan, James C. M.
August 1994
Kidney International;Aug1994, Vol. 46 Issue 2, p358
Academic Journal
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 7α-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 (1.33 ± 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% of 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 7α-hydroxylase (240 ± 559% of controls, P < 0.05). There was no concomitant increase in cholesterol 7α-hydroxylase steady-state mRNA levels or gene transcriptional activity. The factors responsible for the observed increases in HMG-CoA reductase and cholesterol 7α-hydroxylase specific activity in renal failure remain to he determined. In summary, renal failure induced by subtotal nephrectomy results in a twofold increase in HMG-CoA reductase activity (cholesterol synthesis), an increase which is coupled with a twofold increase in cholesterol 7α-hydroxylase activity (bile acid synthesis). The contribution of altered hepatic cholesterol metabolism to the elevated serum cholesterol levels observed in renal failure, and the net effect of increase of activity of these two enzymes on hepatic cholesterol homeostasis have not been ascertained in this study.


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