Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c

Mitsuhiro Watanabe

Sander Houten

Li Wang

Antonio Moschetta

^{Institut de Génétique et Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/ULP, Illkirch, France.}^{Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, USA.}^{Howard Hughes Medical Institute and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.}^{X-ceptor Therapeutics, San Diego, California, USA.}^{Institut Clinique de la Souris, Illkirch, France.}

Address correspondence to: Johan Auwerx, Institut de Génétique et Biologie Moléculaire et Cellulaire, 1 Rue Laurent Fries, Parc d’Innovation, 67404 Illkirch, France. Phone: 33-388653425; Fax: 33-388653201; E-mail: rf.gbsarts-u.cmbgi@xrewua.

Received 2004 Jan 9; Accepted 2004 Mar 23.

Abstract

We explored the effects of bile acids on triglyceride (TG) homeostasis using a combination of molecular, cellular, and animal models. Cholic acid (CA) prevents hepatic TG accumulation, VLDL secretion, and elevated serum TG in mouse models of hypertriglyceridemia. At the molecular level, CA decreases hepatic expression of SREBP-1c and its lipogenic target genes. Through the use of mouse mutants for the short heterodimer partner (SHP) and liver X receptor (LXR) α and β, we demonstrate the critical dependence of the reduction of SREBP-1c expression by either natural or synthetic farnesoid X receptor (FXR) agonists on both SHP and LXRα and LXRβ. These results suggest that strategies aimed at increasing FXR activity and the repressive effects of SHP should be explored to correct hypertriglyceridemia.

Abstract

Acknowledgments

Work in the laboratories of the authors is supported by grants of CNRS, INSERM, ULP, Hôpital Universitaire de Strasbourg, NIH (1P01 DK59820-01), EMBO, and the EU (QLG1CT-1999-00674 and QLRT-2001-00930). D.J. Mangelsdorf is an investigator and A. Moschetta is an associate of the Howard Hughes Medical Institute, which partly funded this work. The authors thank Pierre Chambon, Elisabeth Fayard, Osamu Ezaki, and Jurgen Lehmann for helpful discussions, and Marie-France Champy and the staff of the Institut Clinique de la Souris for technical assistance.

Acknowledgments

Footnotes

Nonstandard abbreviations used: acetyl-CoA carboxylase (ACC); acetyl-CoA synthetase (AceCS); angiopoietin-like protein 3 (ANGPTL3); carnitine palmitoyltransferase I (CPT-I); chenodeoxycholic acid (CDCA); cholesterol 7α-hydroxylase (CYP7A1); cholic acid (CA); farnesoid X receptor (FXR); fatty acid synthase (FAS); LDL receptor (LDL-R); liver receptor homolog-1 (LRH-1); liver receptor homolog-1 response element (LRH-1RE); liver X receptor (LXR); liver X receptor response element (LXRRE); long-chain acyl-CoA dehydrogenase (LCAD); malic enzyme (ME); medium-chain acyl-CoA dehydrogenase (MCAD); retinoid X receptor (RXR); short heterodimer partner (SHP); stearoyl-CoA desaturase-1 (SCD-1); triglyceride (TG).

Conflict of interest: The authors have declared that no conflict of interest exists.

Footnotes

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