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Mouse Models of Nonalcoholic Steatohepatitis: Toward Optimization of Their Relevance to Human Nonalcoholic Steatohepatitis.

Authors
  • Farrell, Geoff1
  • Schattenberg, Jörn M2
  • Leclercq, Isabelle3
  • Yeh, Matthew M4
  • Goldin, Robert5
  • Teoh, Narci6
  • Schuppan, Detlef7, 8
  • 1 Liver Research Group, Australian National University Medical School at the Canberra Hospital, Canberra, Australian Capital Territory, Australia. , (Australia)
  • 2 I. Department of Medicine, University Medical Center, Mainz, Germany. , (Germany)
  • 3 Laboratory of Hepato-gastroenterology, Institut de Recherche Experimentale et Clinique, Université catholique de Louvain, Brussels, Belgium. , (Belgium)
  • 4 Department of Pathology, University of Washington, Seattle, WA.
  • 5 Department of Histopathology, Imperial College, London, UK.
  • 6 Department of Gastroenterology and Hepatology, Australian National University at The Canberra Hospital, Australian Capital Territory, Australia. , (Australia)
  • 7 Institute of Translational Immunology and Research Center for Immunotherapy, University Medical Center, Mainz, Germany. , (Germany)
  • 8 Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. , (Israel)
Type
Published Article
Journal
Hepatology
Publisher
Wiley (John Wiley & Sons)
Publication Date
May 01, 2019
Volume
69
Issue
5
Pages
2241–2257
Identifiers
DOI: 10.1002/hep.30333
PMID: 30372785
Source
Medline
Language
English
License
Unknown

Abstract

Nonalcoholic steatohepatitis (NASH) arises from a variable interplay between environmental factors and genetic determinants that cannot be completely replicated in animals. Notwithstanding, preclinical models are needed to understand NASH pathophysiology and test mechanism-based therapies. Among several mouse models of NASH, some exhibit the key pathophysiologic as well as histopathologic criteria for human NASH, whereas others may be useful to address specific questions. Models based on overnutrition with adipose restriction/inflammation and metabolic complications, particularly insulin resistance, may be most useful to investigate critical etiopathogenic factors. In-depth pathologic description is required for all models. Some models demonstrate hepatocyte ballooning, which can be confused with microvesicular steatosis, whereas demonstration of an inflammatory infiltrate and pattern of liver fibrosis compatible with human NASH is desirable in models used for pharmacologic testing. When mice with specific genetic strains or mutations that cause overeating consume a diet enriched with fat, modest amounts of cholesterol, and/or simple sugars ("Western diet"), they readily develop obesity with liver disease similar to human NASH, including significant fibrosis. Purely dietary models, such as high-fat/high-cholesterol, Western diet, and choline-deficient, amino acid-defined, are similarly promising. We share concern about using models without weight gain, adipose pathology, or insulin resistance/hyperinsulinemia and with inadequate documentation of liver pathology. NASH-related fibrosis is a key endpoint in trials of possible therapies. When studied for this purpose, NASH models should be reproducible and show steatohepatitis (ideally with ballooning) and at least focal bridging fibrosis, while metabolic factors/disordered lipid partitioning should contribute to etiopathogenesis. Because murine models are increasingly used to explore pharmacologic therapies for NASH, we propose a minimum set of requirements that investigators, drug companies, and journals should consider to optimize their translational value. © 2018 by the American Association for the Study of Liver Diseases.

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