The effect of dietary 7-ketocholesterol, inhibitor of sterol synthesis, on hepatic microsomal cholesterol 7 alpha-hydroxylase activity in rat.
A group of oxygenated sterols has been identified as physiological regulators of hepatic cholesterol biosynthesis. However, the regulatory effects of these oxysterols on cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis, is not clearly elucidated. We administered 0.1% 7-ketocholesterol (15 mg/day), a strong inhibitor of sterol synthesis, to rats orally for 6 days. Then, the levels of accumulated oxysterols in liver microsomes and microsomal 7 alpha-hydroxylase activity were determined. The results were compared to those in the groups of rats treated with either control diet or diets containing 0.1 or 1% cholesterol, 0.1% butylated hydroxytoluene, 3% cholestyramine or 1% taurocholate. 7-Ketocholesterol feeding resulted in significant increase of both 7-ketocholesterol and 7 beta-hydroxycholesterol in microsomal fraction (449.4 +/- 36.8 and 438.2 +/- 46.8 ng/mg protein, respectively; mean +/- S.E.). Hepatic microsomal 7 alpha-hydroxylase activity in the rats fed 7-ketocholesterol was significantly elevated as compared with those of control rats; 44.70 +/- 5.97 vs. 16.57 +/- 2.46 pmol/min per mg protein. Addition of BHT to 7-ketocholesterol reduced the accumulation of 7 beta-hydroxycholesterol, and the stimulatory effect of 7-ketocholesterol on 7 alpha-hydroxylase activity was suppressed. Our results demonstrate that oxysterols do not inhibit but rather stimulate hepatic microsomal 7 alpha-hydroxylase.
Tamasawa
N
N
Third Department of Internal Medicine, Hirosaki University School of Medicine, Horosaki, Japan.
Tamasawa
A
A
Takebe
K
K
Hayakari
M
M
D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism*; D004032:Diet; D006888:Hydroxycholesterols / Q000378:metabolism; D007653:Ketocholesterols / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D051381:Rats; D017208:Rats, Wistar; D013261:Sterols / Q000037:antagonists & inhibitors*
D006888:Hydroxycholesterols; D007653:Ketocholesterols; D013261:Sterols; C011724:cholest-5-en-3 beta,7 alpha-diol; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; C003001:7-ketocholesterol