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

Departments of Molecular Biology (Y.-K.L., M.C., L.P., S.A.K.), Pharmacology (D.R.S., C.L.C., Y.Z., D.J.M., S.A.K.), and Biochemistry (R.E.H.), and 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; GlaxoSmithKline Research and Development (B.G.), Research Triangle Park, North Carolina 27709

Address all correspondence and requests for reprints to: Steven A. Kliewer, Departments of Molecular Biology and Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9041. E-mail: steven.kliewer{at}utsouthwestern.edu.

Liver 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 7-hydroxylase (CYP7A1) and sterol 12-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.

NURSA Molecule Pages Link:

Nuclear Receptors:   SHP  |  LRH-1

Ligands:   GW4064

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