TRANSCRIPTIONAL REGULATION OF HEPATIC STEROL 27-HYDROXYLASE BY BILE-ACIDS

The study objective was to determine whether and to what extent sterol 27-hydroxylase, the initial step in the ''acidic'' pathway of bile ac id biosynthesis, is regulated by bile acids. Rats were fed diets suppl emented with cholestyramine (CT, 5%), cholate (CA, 1%), chenodeoxychol ate (CDCA, 1%), or deoxycholate (DCA, 0.25%). When compared with paire d controls, sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase specific activities increased after CT administration by 188 +/- 20% ( P < 0.05) and 415 +/- 36% (P < 0.01), respectively. Similarly, mRNA le vels increased by 159 +/- 14% (P < 0.05) and 311 +/- 106% (P < 0.05), respectively. Feeding CA, CDCA, or DCA decreased sterol 27-hydroxylase specific activity to 57 +/- 6, 61 +/- 8, and 74 +/- 8% of controls, r espectively (P < 0.05). By comparison, the specific activity of choles terol 7 alpha-hydroxylase decreased to 46 +/- 7, 32 +/- 10, and 26 +/- 8% (P < 0.001). mRNA levels and transcriptional activities for sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase transcriptional ac tivity were changed to the same extent as the specific activities afte r CT or bile acid feeding. We conclude that sterol 27-hydroxylase and cholesterol 7 alpha-hydroxylase are subject to negative feedback regul ation by hydrophobic bile acids at the level of transcription. However , the responses of sterol 27-hydroxylase to manipulation of the bile a cid pool are less prominent than those of cholesterol 7 alpha-hydroxyl ase. During the diurnal cycle the specific activities of sterol 27-hyd roxylase and cholesterol 7 alpha-hydroxylase changed in tandem, sugges ting that both may be under control of glucocorticoids.