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Keywords:

  • MCD;
  • NASH;
  • QTL;
  • steatohepatitis

Abstract: Background: Nonalcoholic steatohepatitis (NASH) is a common disease with a poorly understood etiology, and the methionine–choline-deficient (MCD) diet is a nutritional model of NASH. Quantitative trait loci (QTL) analysis is a standard method for chromosomal mapping of polygenic disease traits. The purpose of this study is to administer mice an MCD diet in order to determine the strain-specific susceptibility for developing steatohepatitis, and to apply a computational methodology of QTL analysis to identify associated chromosomal susceptibility loci.

Methods: Inbred mice were fed an MCD diet and alanine aminotransferase (ALT), hepatic triglycerides, liver weight, and weight loss were measured as phenotypic markers of steatohepatitis.

Results: A/J mice developed the highest ALT and hepatic triglyceride levels. Using linear regression analysis, gene loci affecting serum ALT levels were identified on four chromosomes, and four loci that affect liver weight were also identified. In contrast, no QTLs for hepatic triglycerides or body weight were identified. Of note, loci for ALT and liver weight co-localized to proximal segments of chromosomes 2 and 15, in regions previously identified as QTLs for liver fibrosis.

Conclusions: These data indicate that experimental steatohepatitis is a polygenic disease with genes determining ALT, liver weight, and liver fibrosis.