Stimulation of HMG - CoA reductase as a consequence of phenobarbital - induced primary stimulation of cholesterol 7 ~ hydroxylase in rat liver

Among nine strains of rat, two were found that responded to phenobarbital treatment with increased activity of hepatic cholesterol 7a-hydroxylase. This effect was maximal after 2-3 days of treatment and was then reduced. Interestingly the increased cholesterol 7a-hydroxylase activity was associated with increased activity of hepatic HMG-CoA reductase in the two responding strains but not in the non-responding strains. In tissues other than the liver, HMG-CoA reductase activity was unaffected in responding rats. Most of the above stimulation occurred at a pretranslatory level and the mRNA levels corresponding to the two enzymes parallelled the activities. The phenobarbital treatment resulted in decreased content of free cholesterol in liver microsomes in a strain of rat that responded with increased cholesterol la-hydroxylase activity. It was shown that depletion of cholesterol in the responding strain of rats by lymph fistulation also was associated with a parallel increase in levels of HMG-CoA reductase activity and mRNA.m The findings are discussed in relation to the link between HMG-CoA reductase and cholesterol 7a-hydroxylase. A primary upregulation of the cholesterol 7a-hydroxylase by the cytochrome P450 inducer phenobarbital can be expected to lead to increased consumption of cholesterol substrate. This consumption may result in a compensatory increase in the activity of the HMGCoA reductase. It is suggested that such a mechanism is responsible for part of the covariation of the two enzyme systems under different conditions.Sudjana-Sugiaman, E., G. Eggertsen, and I. Bjorkhem. Stimulation of HMG-CoA reductase as a consequence of phenobarbital-induced primary stimulation of cholesterol 7a-hydroxylase in rat liver. J Lipid Res. 1994. 35: 319-327. Supplementary key words HMG-CoA reductase cytochrome P450 cholesterol synthesis bile acid synthesis Under most conditions the rate-limiting enzyme in cholesterol synthesis, HMG-CoA reductase, covariates with the rate-limiting enzyme in bile acid biosynthesis, cholesterol 7a-hydroxylase (for reviews, see refs. 1-3). The linkage between the two enzymes is most important for cholesterol homeostasis and an increased svnthesis of sion of HMG-CoA reductase activity and a slight upregulation of cholesterol 7a-hydroxylase. These effects would help keep the cholesterol content of the hepatocyte as constant as possible. I n order to obtain information about the link between the two enzymes, the most simple approach would be to affect the activity of one of them and then study the effect on the other. Selective inhibitors or selective stimulators must then be used. To our knowledge no specific inhibitors are known for cholesterol 7a-hydroxylase. Bile acids are potent downregulators of both cholesterol 7a-hydroxylase and HMGCoA reductase (l), and it is not known with certainty whether there is a primary effect on only one of the two