The genetic architecture of NAFLD among inbred strains of mice

Abstract
Article and author information
Metrics

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

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.
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.
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.
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.
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.
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.
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.
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.
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.
Nikolaos Psychogios

Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, United States

Competing interests
The authors declare that no competing interests exist.
Isaac Neuhaus

Department of Computational Genomics, Bristol-Myers Squibb, Princeton, United States

Competing interests
The authors declare that no competing interests exist.
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.
Todd Kirchgessner

Department of Cardiovascular Drug Discovery, Bristol-Myers Squibb, Princeton, United States

Competing interests
The authors declare that no competing interests exist.
Peter S Gargalovic

Department of Computational Genomics, Bristol-Myers Squibb, Princeton, United States

Competing interests
The authors declare that no competing interests exist.
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.

Copyright

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.