Transcriptional regulation of hepatic sterol 27-hydroxylase by bile
acids.
Vlahcevic, Z. Reno, Sanjeev K. Jairath, Douglas M. Heuman, R. Todd
Stravitz, Phillip B. Hylemon, Narayan G. Avadhani, and William M.
Pandak.
Section of Gastroenterology, McGuire Veterans Administration
Medical Center and the Department of Microbiology/Immunology, Medical
College of Virginia, Virginia Commonwealth University, Richmond
Virginia and Department of Animal Biology, School of Veterinary
Medicine, University of Pennsylvania, Philadelphia, PA
APStracts 2:0199G, 1995.
The study objective was to determine whether and to what extent sterol
27-hydroxylase, the initial step in the "acidic" pathway of
bile acid biosynthesis, is regulated by bile acids. Rats were fed
diets supplemented with cholestyramine (CT, 5%), cholate (CA, 1%),
chenodeoxycholate (CDCA, 1%) or deoxycholate (DCA, 0.25%). When
compared to paired controls sterol 27-hydroxylase and cholesterol
7[alpha]-hydroxylase specific activities increased following CT
administration by 188 +/- 20% (p<0.05) and by 415 +/- 36%
(p<0.01) of control rats. Similarly, mRNA levels increased by
159 +/- 14% (p<0.05) and by 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, respectively (p<0.05). By comparison, the specific
activity of cholesterol 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 activity were changed to the
same extent as the specific activities following CT or bile acid
feeding. We conclude that sterol 27-hydroxylase and cholesterol
7[alpha]-hydroxylase are subject to negative feedback regulation by
hydrophobic bile acids at the level of transcription. However, the
responses of sterol 27-hydroxylase to manipulation of bile acid pool
are less prominent than those of cholesterol 7[alpha]-hydroxylase.
During the diurnal cycle the specific activities of sterol 27
-hydroxylase and cholesterol 7[alpha]-hydroxylase changed in tandem,
suggesting that both may be under control of glucocorticoids.
Received 21 April 1995; accepted in final form 28 September 1995.
APS Manuscript Number G166-5.
Article publication pending Am. J. Physiol. (Gastrointest. Liver
Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 6 November 95