Liver receptor homolog-1 regulates bile Acid homeostasis but is not essential for feedback regulation of bile Acid synthesis.

Liver receptor homolog-1 regulates bile Acid homeostasis but is not essential for feedback regulation of bile Acid synthesis. Research Abstract Details 

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Liver receptor homolog-1 regulates bile Acid homeostasis but is not essential for feedback regulation of bile Acid synthesis. Abstract Text:

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

Liver receptor homolog-1 regulates bile Acid homeostasis but is not essential for feedback regulation of bile Acid synthesis. Publishing Authors By Initials

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Liver receptor homolog-1 regulates bile Acid homeostasis but is not essential for feedback regulation of bile Acid synthesis. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: Molecular endocrinology (Baltimore, Md.)

VOLUME: 22

Page Numbers: 1345-56

Journal Abbreviation: Mol. Endocrinol.

ISSN: 0888-8809

DAY: 6

MONTH: 03

YEAR: 2008

Liver receptor homolog-1 regulates bile Acid homeostasis but is not essential for feedback regulation of bile Acid synthesis. Information

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LANGUAGE: eng

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AFFILIATION: Departments of Molecular Biology and Pharmacology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9041. steven.kliewer@utsouthwestern.edu.

Country: United States

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MEDLINETA: Mol Endocrinol

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