STIMULATION OF HMG-COA REDUCTASE AS A CONSEQUENCE OF PHENOBARBITAL-INDUCED PRIMARY STIMULATION OF CHOLESTEROL 7-ALPHA-HYDROXYLASE IN RAT-LIVER

Among nine strains of rat, two were found that responded to phenobarbi tal treatment with increased activity of hepatic cholesterol 7 alpha-h ydroxylase. This effect was maximal after 2-3 days of treatment and wa s then reduced. Interestingly the increased cholesterol 7 alpha-hydrox ylase activity was associated with increased activity of hepatic HMG-C oA reductase in the two responding strains but not in the non-respondi ng strains. In tissues other than the liver, HMG-CoA reductase activit y was unaffected in responding rats. Most of the above stimulation occ urred at a pretranslatory level and the mRNA levels corresponding to t he 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 7 alpha- hydroxylase activity. It was shown that depletion of cholesterol in th e responding strain of rats by lymph fistulation also was associated w ith a parallel increase in levels of HMG-CoA reductase activity and mR NA. The findings are discussed in relation to the link between HMG-CoA reductase and cholesterol 7 alpha-hydroxylase. A primary upregulation of the cholesterol 7 alpha-hydroxylase by the cytochrome P450 inducer phenobarbital can be expected to lead to increased consumption of cho lesterol substrate. This consumption may result in a compensatory incr ease in the activity of the HMG-CoA reductase. It is suggested that su ch a mechanism is responsible for part of the covariation of the two e nzyme systems under different conditions.