Interstrain differences in susceptibility to non‐alcoholic steatohepatitis

Abstract

The pathophysiological mechanisms leading to the development of non-alcoholic steatohepatitis (NASH) remain unclear. There are differences in the susceptibility to NASH between the different species and sexes. The investigation of the precise mechanism of interstrain differences may provide new means by which the pathophysiological mechanisms of NASH may be understood. C57BL/6N and C3H/HeN mice were administered a methionine- and choline-deficient (MCD) diet to establish a dietary model of NASH. An elevation of the serum alanine aminotransferase and increased infiltration of inflammatory cells were predominant in C57BL/6N mice at 8 weeks. The increase in the steatosis and lipid contents in the liver was greater in C57BL/6N mice than in C3H/HeN mice. The indices of lipid peroxidation demonstrated by F2-isoprostanes or 8-hydroxy-2'-deoxyguanosine also increased in the livers of C57BL/6N mice. Furthermore, Sirius red staining revealed an increase in the degree of fibrosis in C57BL/6N mice given the MCD diet. As a result, the C57BL/6N strain had a higher susceptibility to NASH than the C3H/HeN mice. The carnitine palmitoyltransferase 1A (in beta-oxidation) mRNA and mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (in ketogenesis) mRNA were downregulated in the C57BL/6N mice in comparison with C3H/HeN mice. There were no differences in the expression of microsomal triglyceride transfer protein or sterol regulatory element binding protein 1 between the C57BL/6N and C3H/HeN mice. There were interstrain differences in susceptibility to NASH observed in a rodent dietary model. Further evaluations of the precise molecular mechanism of this interstrain difference may provide some indications of the pathophysiological mechanisms of NASH in humans.