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

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Title: Diet1, bile acid diarrhea, and FGF15/19: mouse model and human genetic variants
Authors: Lee, JM
Ong, JR
Vergnes, L
De Aguiar Vallim, TQ
Nolan, J
Cantor, RM
Walters, JRF
Reue, K
Item Type: Journal Article
Abstract: Diet1 modulates intestinal production of the hormone fibroblast growth factor 15 (FGF15), which signals in liver to regulate bile acid synthesis. C57BL/6ByJ mice with a spontaneous Diet1 null mutation are resistant to hypercholesterolemia compared to 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 C57BL6/J 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.
Issue Date: 2-Jan-2018
Date of Acceptance: 2-Jan-2018
URI: http://hdl.handle.net/10044/1/56154
DOI: https://dx.doi.org/10.1194/jlr.M078279
ISSN: 0022-2275
Publisher: American Society for Biochemistry and Molecular Biology
Start Page: 429
End Page: 438
Journal / Book Title: Journal of Lipid Research
Volume: 59
Copyright Statement: © 2018, The American Society for Biochemistry and Molecular Biology
Sponsor/Funder: Bardhan Research and Education Trust of Rotherham Ltd
Bardhan Research and Education Trust of Rotherham Ltd
Funder's Grant Number: N/A
N/A
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
intestine
fibroblast growth factor 15/19
Hybrid Mouse Diversity Panel
GROWTH-FACTOR 19
IRRITABLE-BOWEL-SYNDROME
CORONARY HEART-DISEASE
SEHCAT RETENTION
MALABSORPTION
DIAGNOSIS
CHOLESTEROL
METABOLISM
TRANSPORT
7-ALPHA-HYDROXY-4-CHOLESTEN-3-ONE
Bile acids and salts/Metabolism
Cell biology
Cholesterol
Genes in lipid dysfunction
Genetics
Intestine
Lipids
Mouse model
0601 Biochemistry And Cell Biology
1101 Medical Biochemistry And Metabolomics
Publication Status: Published
Appears in Collections:Department of Surgery and Cancer