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Semin Liver Dis 2009; 29(2): 178-187
DOI: 10.1055/s-0029-1214373
© Thieme Medical Publishers

“Second Hit” Models of Alcoholic Liver Disease

Hidekazu Tsukamoto1 , 2 , 4 , Keigo Machida1 , 3 , Alla Dynnyk1 , 2 , Hasmik Mkrtchyan1 , 2
  • 1Southern California Research Center for ALPD and Cirrhosis, Keck School of Medicine of the University of Southern California
  • 2Department of Pathology, Keck School of Medicine of the University of Southern California
  • 3Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California
  • 4Department of Veterans Affairs, Greater Los Angeles Healthcare System, Los Angeles, California
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Publication History

Publication Date:
22 April 2009 (online)

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ABSTRACT

Alcoholic liver disease (ALD) is a lifestyle disease with its pathogenesis and individual predisposition governed by gene–environment interactions. Based on the “second hit” or “multiple hits” hypothesis, patients are predisposed to progressive ALD when a magic combination of gene and environmental interactions exists. Reproduction of second or multiple hits in animal models serves to test a combination and to gain mechanistic insights into synergism achieved by such combination. Numerous environmental factors have been incorporated into animal models, largely classified into nutritional, xenobiotic/pharmacologic, hemodynamic, and viral groups. A loss or gain of function genetic model has become a popular experimental approach to test the role of a gene as a second hit. Future research will need to test more subtle or natural hits combined with excessive alcohol intake to test multiple hits in the genesis of ALD. Additionally, animal models of comorbidities are urgently needed particularly for synergistic liver disease and oncogenesis caused by alcohol, obesity, and hepatitis virus.

KEYWORDS

Gene-environment interactions - alcoholic liver disease - alcoholic steatohepatitis - nonalcoholic steatohepatitis - nonalcoholic fatty liver disease - animal models

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Hidekazu TsukamotoD.V.M. Ph.D. 

Keck School of Medicine of the University of Southern California

1333 San Pablo Street, MMR-402, Los Angeles, CA 90033

Email: htsukamo@usc.edu