2. Academic Validation
  3. Diet1 functions in the FGF15/19 enterohepatic signaling axis to modulate bile acid and lipid levels

Diet1 functions in the FGF15/19 enterohepatic signaling axis to modulate bile acid and lipid levels

  • Cell Metab. 2013 Jun 4;17(6):916-928. doi: 10.1016/j.cmet.2013.04.007.
Laurent Vergnes 1,  Jessica M Lee 1,  Robert G Chin 1,  Johan Auwerx 2,  Karen Reue 3
Affiliations

Affiliations

  • 1 Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 2 Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
  • 3 Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: [email protected].
PMID: 23747249 DOI: 10.1016/j.cmet.2013.04.007
Abstract

We identified a mutation in the Diet1 gene in a mouse strain that is resistant to hyperlipidemia and atherosclerosis. Diet1 encodes a 236 kD protein consisting of tandem low-density lipoprotein receptor and MAM (meprin-A5-protein tyrosine Phosphatase mu) domains and is expressed in the enterocytes of the small intestine. Diet1-deficient mice exhibited an elevated bile acid pool size and impaired feedback regulation of hepatic Cyp7a1, which encodes the rate-limiting Enzyme in bile acid synthesis. In mouse intestine and in cultured human intestinal cells, Diet1 expression levels influenced the production of Fibroblast Growth Factor 15/19 (FGF15/19), a hormone that signals from the intestine to liver to regulate Cyp7a1. Transgenic expression of Diet1, or adenoviral-mediated Fgf15 expression, restored normal Cyp7a1 regulation in Diet-1-deficient mice. Diet1 and FGF19 proteins exhibited overlapping subcellular localization in cultured intestinal cells. These results establish Diet1 as a control point in enterohepatic bile acid signaling and lipid homeostasis.

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