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Molecular and Cellular Biology, December 2007, p. 8330-8339, Vol. 27, No. 23
0270-7306/07/$08.00+0     doi:10.1128/MCB.00852-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Compromised Intestinal Lipid Absorption in Mice with a Liver-Specific Deficiency of Liver Receptor Homolog 1{triangledown}

Chikage Mataki,1,{dagger} Benjamin C. Magnier,1,{dagger} Sander M. Houten,1,2 Jean-Sébastien Annicotte,1 Carmen Argmann,1 Charles Thomas,1 Henk Overmars,2 Wim Kulik,2 Daniel Metzger,1 Johan Auwerx,1,3,4 and Kristina Schoonjans1*

Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 67404 Illkirch Cedex, France,1 Laboratory Genetic Metabolic Diseases, Academic Medical Center, Amsterdam, The Netherlands,2 Institut Clinique de la Souris, 67404 Illkirch, France,3 Hôpitaux Universitaires de Strasbourg, Laboratoire de Biochimie Générale et Spécialisée, 67000 Strasbourg, France4

Received 15 May 2007/ Returned for modification 19 June 2007/ Accepted 12 September 2007

Bile acids (BAs) are water-soluble end products from cholesterol metabolism and are essential for efficient absorption of dietary lipids. By using targeted somatic mutagenesis of the nuclear receptor liver receptor homolog 1 (LRH-1) in mouse hepatocytes, we demonstrate here that LRH-1 critically regulates the physicochemical properties of BAs. The absence of LRH-1 and subsequent deficiency of Cyp8b1 eliminate the production of cholic acid and its amino acid conjugate taurocholic acid and increase the relative amounts of less amphipathic BA species. Intriguingly, while the expression of Cyp8b1 is almost extinguished in the livers of mice that lack LRH-1, the expression of the rate-limiting enzyme of BA synthesis, i.e., Cyp7a1, remains unchanged. The profound remodeling of the BA composition significantly reduces the efficacy of intestinal absorption of lipids and reuptake of BAs and facilitates the removal of lipids from the body. Our studies unequivocally demonstrate a pivotal role for LRH-1 in determining the composition of BAs, which, in turn has major consequences on whole-body lipid homeostasis.

* Corresponding author. Mailing address: Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 Rue Laurent Fries, Parc d'Innovation, 67404 Illkirch, France. Phone: 33-3-88653215. Fax: 33-3-88653201. E-mail: schoonja{at}igbmc.u-strasbg.fr

{triangledown} Published ahead of print on 1 October 2007.

{dagger} Both authors contributed equally.

Molecular and Cellular Biology, December 2007, p. 8330-8339, Vol. 27, No. 23
0270-7306/07/$08.00+0     doi:10.1128/MCB.00852-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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