title: The genetic architecture of NAFLD among inbred strains of mice.
abstract: To identify genetic and environmental factors contributing to the pathogenesis of non-alcoholic fatty liver disease, we examined liver steatosis and related clinical and molecular traits in more than 100 unique inbred mouse strains, which were fed a diet rich in fat and carbohydrates. A &gt;30-fold variation in hepatic TG accumulation was observed among the strains. Genome-wide association studies revealed three loci associated with hepatic TG accumulation. Utilizing transcriptomic data from the liver and adipose tissue, we identified several high-confidence candidate genes for hepatic steatosis, including Gde1, a glycerophosphodiester phosphodiesterase not previously implicated in triglyceride metabolism. We confirmed the role of Gde1 by in vivo hepatic over-expression and shRNA knockdown studies. We hypothesize that Gde1 expression increases TG production by contributing to the production of glycerol-3-phosphate. Our multi-level data, including transcript levels, metabolite levels, and gut microbiota composition, provide a framework for understanding genetic and environmental interactions underlying hepatic steatosis.
authors.affiliation: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Simon T
authors.initials: ST
authors.lastname: Hui
authors.affiliation: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Parks
authors.affiliation: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Elin
authors.initials: E
authors.lastname: Org
authors.affiliation: Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
authors.forename: Frode
authors.initials: F
authors.lastname: Norheim
authors.affiliation: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Nam
authors.initials: N
authors.lastname: Che
authors.affiliation: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Calvin
authors.initials: C
authors.lastname: Pan
authors.affiliation: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Castellani
authors.affiliation: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Sarada
authors.initials: S
authors.lastname: Charugundla
authors.affiliation: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Darwin L
authors.initials: DL
authors.lastname: Dirks
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Psychogios
authors.affiliation: Department of Computational Genomics, Bristol-Myers Squibb, Princeton, United States.
authors.forename: Isaac
authors.initials: I
authors.lastname: Neuhaus
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Gerszten
authors.affiliation: Department of Cardiovascular Drug Discovery, Bristol-Myers Squibb, Princeton, United States.
authors.forename: Todd
authors.initials: T
authors.lastname: Kirchgessner
authors.affiliation: Department of Computational Genomics, Bristol-Myers Squibb, Princeton, United States.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Gargalovic
authors.affiliation: Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D015870:Gene Expression; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D055106:Genome-Wide Association Study; D008099:Liver / Q000473:pathology; D008815:Mice, Inbred Strains; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000662:veterinary*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics*; D012376:Rodent Diseases / Q000235:genetics*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D014280:Triglycerides; D010727:Phosphoric Diester Hydrolases; C038133:glycerophosphodiester phosphodiesterase
keywords: chromosomes; evolutionary biology; genes; genome-wide association; genomics; hepatic steatosis; metabolome; microbiome; mouse; transcriptome