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Diet1, bile acid diarrhea, and FGF15/19: mouse model and human genetic variants.

Abstract
Diet1 modulates intestinal production of the hormone, fibroblast growth factor (FGF)15, which signals in liver to regulate bile acid synthesis. C57BL/6ByJ mice with a spontaneous Diet1-null mutation are resistant to hypercholesterolemia compared with wild-type C57BL/6J mice through enhanced cholesterol conversion to bile acids. To further characterize the role of Diet1 in metabolism, we generated Diet1-/- mice on the C57BL/6J genetic background. C57BL/6J Diet1-/- mice had elevated bile acid levels, reduced Fgf15 expression, and increased gastrointestinal motility and intestinal luminal water content, which are symptoms of bile acid diarrhea (BAD) in humans. Natural genetic variation in Diet1 mRNA expression levels across 76 inbred mouse strains correlated positively with Ffg15 mRNA and negatively with serum bile acid levels. This led us to investigate the role of DIET1 genetic variation in primary BAD patients. We identified a DIET1 coding variant (rs12256835) that had skewed prevalence between BAD cases and controls. This variant causes an H1721Q amino acid substitution that increases the levels of FGF19 protein secreted from cultured cells. We propose that genetic variation in DIET1 may be a determinant of FGF19 secretion levels, and may affect bile acid metabolism in both physiological and pathological conditions.
AuthorsJessica M Lee, Jessica R Ong, Laurent Vergnes, Thomas Q de Aguiar Vallim, Jonathan Nolan, Rita M Cantor, Julian R F Walters, Karen Reue
JournalJournal of lipid research (J Lipid Res) Vol. 59 Issue 3 Pg. 429-438 (03 2018) ISSN: 1539-7262 [Electronic] United States
PMID29295820 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2018 by the American Society for Biochemistry and Molecular Biology, Inc.
Chemical References
  • Bile Acids and Salts
  • Carrier Proteins
  • Diet1 protein, mouse
  • Fibroblast Growth Factors
Topics
  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Bile Acids and Salts (genetics, metabolism)
  • Carrier Proteins (genetics, metabolism)
  • Diarrhea (genetics, metabolism)
  • Disease Models, Animal
  • Female
  • Fibroblast Growth Factors (blood, genetics, metabolism)
  • Genetic Variation (genetics)
  • Genotype
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Young Adult

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