Liver receptor homolog 1 is a negative regulator of the hepatic acute-phase response

N Venteclef, JC Smith, B Goodwin… - Molecular and cellular …, 2006 - Taylor & Francis
N Venteclef, JC Smith, B Goodwin, P Delerive
Molecular and cellular biology, 2006Taylor & Francis
The orphan nuclear receptor liver receptor homolog 1 (LRH-1) has been reported to play an
important role in bile acid biosynthesis and reverse cholesterol transport. Here, we show that
LRH-1 is a key player in the control of the hepatic acute-phase response. Ectopic expression
of LRH-1 with adenovirus resulted in strong inhibition of both interleukin-6 (IL-6)-and IL-1β-
stimulated haptoglobin, serum amyloid A, and fibrinogen β gene expression in hepatocytes.
Furthermore, induction of the hepatic inflammatory response was significantly exacerbated …
The orphan nuclear receptor liver receptor homolog 1 (LRH-1) has been reported to play an important role in bile acid biosynthesis and reverse cholesterol transport. Here, we show that LRH-1 is a key player in the control of the hepatic acute-phase response. Ectopic expression of LRH-1 with adenovirus resulted in strong inhibition of both interleukin-6 (IL-6)- and IL-1β-stimulated haptoglobin, serum amyloid A, and fibrinogen β gene expression in hepatocytes. Furthermore, induction of the hepatic inflammatory response was significantly exacerbated in HepG2 cells expressing short hairpin RNA targeting LRH-1 expression. Moreover, transient-transfection experiments and electrophoretic mobility shift and chromatin immunoprecipitation assays revealed that LRH-1 regulates this cytokine-elicited inflammatory response by, at least in part, antagonizing the CCAAT/enhancer binding protein β signaling pathway. Finally, we show, by using LRH-1 heterozygous mice, that LRH-1 is involved in the control of the inflammatory response at the hepatic level in vivo. Taken together, our results outline an unexpected role for LRH-1 in the modulation of the hepatic acute-phase response.
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