1. Chromosomes and Gene Expression
  2. Genetics and Genomics
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The genetic architecture of NAFLD among inbred strains of mice

  1. Simon T Hui  Is a corresponding author
  2. Brian W Parks
  3. Elin Org
  4. Frode Norheim
  5. Nam Che
  6. Calvin Pan
  7. Lawrence W Castellani
  8. Sarada Charugundla
  9. Darwin L Dirks
  10. Nikolaos Psychogios
  11. Isaac Neuhaus
  12. Robert E Gerszten
  13. Todd Kirchgessner
  14. Peter S Gargalovic
  15. Aldons J Lusis
  1. University of California, Los Angeles, United States
  2. University of Oslo, Norway
  3. Harvard Medical School, United States
  4. Bristol-Myers Squibb, United States
Research Article
  • Cited 44
  • Views 2,727
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Cite this article as: eLife 2015;4:e05607 doi: 10.7554/eLife.05607

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 >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.

Article and author information

Author details

  1. Simon T Hui

    Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    sthui@mednet.ucla.edu
    Competing interests
    The authors declare that no competing interests exist.
  2. Brian W Parks

    Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Elin Org

    Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Frode Norheim

    Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway
    Competing interests
    The authors declare that no competing interests exist.
  5. Nam Che

    Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Calvin Pan

    Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Lawrence W Castellani

    Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Sarada Charugundla

    Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Darwin L Dirks

    Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Nikolaos Psychogios

    Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Isaac Neuhaus

    Department of Computational Genomics, Bristol-Myers Squibb, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Robert E Gerszten

    Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Todd Kirchgessner

    Department of Cardiovascular Drug Discovery, Bristol-Myers Squibb, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Peter S Gargalovic

    Department of Computational Genomics, Bristol-Myers Squibb, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Aldons J Lusis

    Department of Medicine/Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#92-169) of the University of California at Los Angeles.

Reviewing Editor

  1. Christopher Glass, University of California, San Diego, United States

Publication history

  1. Received: November 13, 2014
  2. Accepted: June 11, 2015
  3. Accepted Manuscript published: June 12, 2015 (version 1)
  4. Version of Record published: July 7, 2015 (version 2)

Copyright

© 2015, Hui et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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