Liver receptor homolog-1 regulates bile acid homeostasis but is not essential for feedback regulation of bile acid synthesis.
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.
Lee
Youn-Kyoung
YK
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9041, USA.
Schmidt
Daniel R
DR
Cummins
Carolyn L
CL
Choi
Mihwa
M
Peng
Li
L
Zhang
Yuan
Y
Goodwin
Bryan
B
Hammer
Robert E
RE
Mangelsdorf
David J
DJ
Kliewer
Steven A
SA
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000378:metabolism; D025461:Feedback, Physiological / Q000235:genetics* / Q000502:physiology; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics*; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009928:Organ Specificity / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C431936:Nr5a2 protein, mouse