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Hepatology. 2018 Jun 16. doi: 10.1002/hep.30113. [Epub ahead of print]

The Genetic Architecture of Diet-induced Hepatic Fibrosis in Mice.

Author information

1
Department of Medicine, Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
2
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, California, USA.
3
Department of Medicine, Division of Digestive Diseases & Pfleger Liver Institute and Center for Obesity and Metabolic Health (COMET), David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
4
Department of Pathology & Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
5
Clínica Integral de Cirugía para la Obesidad y Enfermedades Metabólicas, Hospital General Dr. Rubén Lénero, Mexico City, Mexico.
6
Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico.
7
Unidad de Genómica de Poblaciones Aplicada a la Salud, Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City, Mexico.

Abstract

We report the genetic analysis of a "humanized" hyperlipidemic mouse model for progressive nonalcoholic steatohepatitis (NASH) and fibrosis. Mice carrying transgenes for human APOE*3-Leiden and CETP and fed a "Western" diet were studied on the genetic backgrounds of over 100 inbred mouse strains. The mice developed hepatic inflammation and fibrosis that was highly dependent on genetic background, with vast differences in the degree of fibrosis. Histological analysis showed features characteristic of human NASH, including macrovesicular steatosis, hepatocellular ballooning, inflammatory foci and pericellular collagen deposition. Time course experiments indicated that while hepatic triglyceride levels increased steadily on the diet, hepatic fibrosis occurred at about 12 weeks. We found that the genetic variation predisposing to NASH and fibrosis differs markedly from that predisposing to simple steatosis, consistent with a multi-step model in which distinct genetic factors are involved. Moreover, genome-wide association identified distinct genetic loci contributing to steatosis and NASH. Finally, we used hepatic expression data from the mouse panel and from 68 bariatric surgery patients with normal liver, steatosis, or NASH to identify enriched biological pathways. The pathways showed substantial overlap between our mouse model and the human disease. This article is protected by copyright. All rights reserved.

KEYWORDS:

Nonalcoholic Steatohepatitis; gene network analysis; genome-wide association; metabolome; systems genetics; transcriptome

PMID:
29907965
DOI:
10.1002/hep.30113

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