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.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bile Acids and Salts / biosynthesis
  • Bile Acids and Salts / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • Cholesterol 7-alpha-Hydroxylase / metabolism*
  • Enterocytes / metabolism
  • Enterohepatic Circulation
  • Fibroblast Growth Factors / metabolism*
  • Humans
  • Intestinal Mucosa / metabolism
  • Intestine, Small / metabolism
  • Lipid Metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Molecular Sequence Data
  • Protein Structure, Tertiary
  • Signal Transduction

Substances

  • Bile Acids and Salts
  • Carrier Proteins
  • Diet1 protein, mouse
  • fibroblast growth factor 15, mouse
  • Fibroblast Growth Factors
  • Cholesterol 7-alpha-Hydroxylase
  • Cyp7a1 protein, mouse

Associated data

  • GENBANK/KC836882
  • GENBANK/KC843478
  • GENBANK/KC843480
  • GENBANK/KC843481
  • GENBANK/KC843482
  • GENBANK/KC845479