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 phenobarbital treatment with increased activity of hepatic cholesterol 7 alpha-hydroxylase. This effect was maximal after 2-3 days of treatment and was then reduced. Interestingly the increased cholesterol 7 alpha-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 paralleled 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 the responding strain of rats by lymph fistulation also was associated with a parallel increase in levels of HMG-CoA reductase activity and mRNA. 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 cholesterol substrate. This consumption may result in a compensatory increase in the activity of the HMG-CoA 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
E
Department of Clinical Chemistry, Karolinska Institute, Huddinge Hospital, Sweden.
Eggertsen
G
G
Björkhem
I
I
D000818:Animals; D015152:Blotting, Northern; D002784:Cholesterol / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000032:analysis / Q000502:physiology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000032:analysis / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology*; D012313:RNA / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013347:Subcellular Fractions
D012313:RNA; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase; D010634:Phenobarbital