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Mol. Cell. Biol. doi:10.1128/MCB.00852-07
Copyright (c) 2007, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Compromised intestinal lipid absorption in mice with a liver-specific deficiency of the Liver Receptor Homolog 1

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

^* To whom correspondence should be addressed. Email: schoonja{at}igbmc.u-strasbg.fr.

	Abstract

Bile acids (BAs) are water-soluble end products from cholesterol metabolism and essential for efficient absorption of dietary lipids. Using targeted somatic mutagenesis of the nuclear receptor LRH-1 in mouse hepatocytes, we demonstrate here that LRH-1 critically regulates the physico-chemical properties of BAs. The absence of LRH-1 and subsequent deficiency of Cyp8b1 eliminates the production of cholic acid (CA) and its amino acid conjugate taurocholic acid (TCA) and increases the relative amounts of less amphipathic BA species. Intriguingly, while Cyp8b1 is almost extinguished in the liver 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 reduces significantly the efficacy of intestinal absorption of lipids and re-uptake of BAs and facilitates the removal of lipids from the body. Our studies hence 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.

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