Liver Receptor Homolog-1 Regulates Bile Acid Homeostasis but Is Not Essential for Feedback Regulation of Bile Acid Synthesis

Author:

Lee Youn-Kyoung1,Schmidt Daniel R.2,Cummins Carolyn L.2,Choi Mihwa1,Peng Li1,Zhang Yuan23,Goodwin Bryan4,Hammer Robert E.5,Mangelsdorf David J.23,Kliewer Steven A.12

Affiliation:

1. Departments of Molecular Biology (Y.-K.L., M.C., L.P., S.A.K.), Dallas, Texas 75390

2. Pharmacology (D.R.S., C.L.C., Y.Z., D.J.M., S.A.K.), Dallas, Texas 75390

3. the Howard Hughes Medical Institute (D.R.S., C.L.C., Y.Z., D.J.M.), University of Texas Southwestern Medical Center, Dallas, Texas 75390

4. GlaxoSmithKline Research and Development (B.G.), Research Triangle Park, North Carolina 27709

5. Biochemistry (R.E.H.), Dallas, Texas 75390

Abstract

AbstractLiver receptor homolog 1 (LRH-1), an orphan nuclear receptor, is highly expressed in liver and intestine, where it is implicated in the regulation of cholesterol, bile acid, and steroid hormone homeostasis. Among the proposed LRH-1 target genes in liver are those encoding cholesterol 7α-hydroxylase (CYP7A1) and sterol 12α-hydroxylase (CYP8B1), which catalyze key steps in bile acid synthesis. In vitro studies suggest that LRH-1 may be involved both in stimulating basal CYP7A1 and CYP8B1 transcription and in repressing their expression as part of the nuclear bile acid receptor [farnesoid X receptor (FXR)]-small heterodimer partner signaling cascade, which culminates in small heterodimer partner binding to LRH-1 to repress gene transcription. However, in vivo analysis of LRH-1 actions has been hampered by the embryonic lethality of Lrh-1 knockout mice. To overcome this obstacle, mice were generated in which Lrh-1 was selectively disrupted in either hepatocytes or intestinal epithelium. LRH-1 deficiency in either tissue changed mRNA levels of genes involved in cholesterol and bile acid homeostasis. Surprisingly, LRH-1 deficiency in hepatocytes had no significant effect on basal Cyp7a1 expression or its repression by FXR. Whereas Cyp8b1 repression by FXR was also intact in mice deficient for LRH-1 in hepatocytes, basal CYP8B1 mRNA levels were significantly decreased, and there were corresponding changes in the composition of the bile acid pool. Taken together, these data reveal a broad role for LRH-1 in regulating bile acid homeostasis but demonstrate that LRH-1 is either not involved in the feedback regulation of bile acid synthesis or is compensated for by other factors.

Publisher

The Endocrine Society

Subject

Endocrinology,Molecular Biology,General Medicine

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