title: Diet1 functions in the FGF15/19 enterohepatic signaling axis to modulate bile acid and lipid levels.
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.
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Vergnes
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Chin
authors.affiliation: Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.affiliation: 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: reuek@ucla.edu.
authors.forename: Karen
authors.initials: K
authors.lastname: Reue
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism*; D020895:Enterocytes / Q000378:metabolism; D004764:Enterohepatic Circulation; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D007421:Intestine, Small / Q000378:metabolism; D050356:Lipid Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D015398:Signal Transduction
chemical_list: D001647:Bile Acids and Salts; D002352:Carrier Proteins; C585655:Diet1 protein, mouse; C108526:fibroblast growth factor 15, mouse; D005346:Fibroblast Growth Factors; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse