This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Venteclef, N. Articles by Delerive, P. Search for Related Content PubMed PubMed Citation Articles by Venteclef, N. Articles by Delerive, P.

Liver Receptor Homolog 1 Is a Negative Regulator of the Hepatic Acute-Phase Response

GlaxoSmithKline, Cardiovascular & Urogenital Center of Excellence for Drug Discovery, 25 Avenue du Quebec, 91951 Les Ulis, France,¹ GlaxoSmithKline, Laboratory Animal Sciences, The Frythe, United Kingdom,² GlaxoSmithKline, High Throughput Biology, Research Triangle Park, North Carolina 27709³

Received 3 April 2006/ Returned for modification 26 April 2006/ Accepted 29 June 2006

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-1ß-stimulated haptoglobin, serum amyloid A, and fibrinogen ß 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 ß 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.

This article has been cited by other articles:

• Kopec, A. K., Boverhof, D. R., Burgoon, L. D., Ibrahim-Aibo, D., Harkema, J. R., Tashiro, C., Chittim, B., Zacharewski, T. R. (2008). Comparative Toxicogenomic Examination of the Hepatic Effects of PCB126 and TCDD in Immature, Ovariectomized C57BL/6 Mice. Toxicol Sci 102: 61-75 [Abstract] [Full Text]  
• Venteclef, N., Haroniti, A., Tousaint, J.-J., Talianidis, I., Delerive, P. (2008). Regulation of Anti-atherogenic Apolipoprotein M Gene Expression by the Orphan Nuclear Receptor LRH-1. J. Biol. Chem. 283: 3694-3701 [Abstract] [Full Text]  
• Coste, A., Dubuquoy, L., Barnouin, R., Annicotte, J.-S., Magnier, B., Notti, M., Corazza, N., Antal, M. C., Metzger, D., Desreumaux, P., Brunner, T., Auwerx, J., Schoonjans, K. (2007). LRH-1-mediated glucocorticoid synthesis in enterocytes protects against inflammatory bowel disease. Proc. Natl. Acad. Sci. USA 104: 13098-13103 [Abstract] [Full Text]  
• Matsukuma, K. E., Wang, L., Bennett, M. K., Osborne, T. F. (2007). A Key Role for Orphan Nuclear Receptor Liver Receptor Homologue-1 in Activation of Fatty Acid Synthase Promoter by Liver X Receptor. J. Biol. Chem. 282: 20164-20171 [Abstract] [Full Text]  
• Venteclef, N., Delerive, P. (2007). Interleukin-1 Receptor Antagonist Induction as an Additional Mechanism for Liver Receptor Homolog-1 to Negatively Regulate the Hepatic Acute Phase Response. J. Biol. Chem. 282: 4393-4399 [Abstract] [Full Text]