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 reg ulators of hepatic cholesterol biosynthesis. However, the regulatory e ffects of these oxysterols on cholesterol 7 alpha-hydroxylase, the rat e-limiting enzyme in bile acid biosynthesis, is not clearly elucidated . We administered 0.1% 7-ketocholesterol (15 mg/day), a strong inhibit or of sterol synthesis, to rats orally for 6 days. Then, the levels of accumulated oxysterols in liver microsomes and microsomal 7 alpha-hyd roxylase activity were determined. The results were compared to those in the groups of rats treated with either control diet or diets contai ning 0.1 or 1% cholesterol, 0.1% butylated hydroxytoluene, 3% cholesty ramine or 1% taurocholate. 7-Ketocholesterol feeding resulted in signi ficant increase of both 7-ketocholesterol and 7 beta-hydroxycholestero l in microsomal fraction (449.4 +/- 36.8 and 438.2 +/- 46.8 ng/mg prot ein, respectively; mean +/- S.E.). Hepatic microsomal 7 alpha-hydroxyl ase activity in the rats fed 7-ketocholesterol was significantly eleva ted 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 stimula tory effect of 7-ketocholesterol on 7 alpha-hydroxylase activity was s uppressed. Our results demonstrate that oxysterols do not inhibit but rather stimulate hepatic microsomal 7 alpha-hydroxylase.