POSTTRANSCRIPTIONAL REGULATION OF 3-HYDROXY-3-METHYLGLUTARYL COENZYME-A REDUCTASE AND CHOLESTEROL 7-ALPHA-HYDROXYLASE IN RATS WITH SUBTOTALNEPHRECTOMY

Chronic renal failure is associated with hyperlipidemia and atheroscle rosis. The mechanism responsible for the observed increase of serum ch olesterol in chronic renal disease is not certain. The objective of th e present study was to characterize the effect of induced renal failur e on 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductas e) and cholesterol 7 alpha-hydroxylase, the two rate determining enzym es of the cholesterol and bile acid biosynthetic pathways, respectivel y. Studies were carried out in rats with subtotal (75%) nephrectomy, w hich 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 trigly cerides (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 presenc e of elevated hepatic microsomal cholesterol concentrations (150 +/- 1 3% of controls, P < 0.01). Surprisingly, the increase in HMG-CoA reduc tase specific activity was not associated with parallel increases in H MC-CoA reductase steady-state mRNA levels and gene transcriptional act ivity. These uremic rats also exhibited a marked increase in the speci fic activity of cholesterol 7 alpha-hydroxylase (240 +/- 559% of contr ols, P < 0.05). There was no concomitant increase in cholesterol 7 alp ha-hydroxylase steady-state mRNA levels or gene transcriptional activi ty. The factors responsible for the observed increases in HMG-CoA redu ctase and cholesterol 7 alpha-hydroxylase specific activity in renal f ailure remain to be determined. In summary, renal failure induced by s ubtotal nephrectomy results in a twofold increase in HMG-CoA reductase activity (cholesterol synthesis), an increase which is coupled with a twofold increase in cholesterol 7 alpha-hydroxylase activity (bile ac id synthesis). The contribution of altered hepatic cholesterol metabol ism to the elevated serum cholesterol levels observed in renal failure , and the net effect of increase of activity of these two enzymes on h epatic cholesterol homeostasis have not been ascertained in this study .