PD1/PD-L1 protects from inflammation and fibrosis in non-alcoholic steatohepatitis

The pathophysiological mechanisms leading to the development of non-alcoholic steatohepatitis (NASH) remain unclear. There are differences in the susceptibility to NASH between different species and sexes.

The aim of this study was to investigate the susceptibility of three different mouse strains to NASH.

Methods and Results: NASH was induced in C57BL/6, 129/SvJ and BALB/C male mice (8 weeks old) applying 2 different models: (i) methionine-choline deficient (MCD) diet and (ii) an atherogenic (Ath) diet that has been shown to more accurately resemble pathopyhsiological changes observed in human NASH (Matsuzawa et al. Hepatology 2007). MCD and Ath feeding induced NASH in all mouse strains, but there were dramatic strain differences regarding hepatic steatosis as assessed by histological analysis and measurement of hepatic triglycerides and total fatty acids. Hepatic lipid accumulation in BALB/C mice was more than 2-fold higher than in C57BL/6 and 129/SvJ mice. Similarly, strong differences were observed regarding liver-body-weight ratio, serum transaminases and hepatic proinflammatory gene expression (TNF, IL-1, MCP-1). Here, as well BALB/C mice revealed the highest values, and in addition, there were significant differences between 129/SvJ (higher values) than C57BL/6 mice. Finally, profibrogenic gene expression (Collagen I, TIMP-1, TGF-beta) and histological fibrosis revealed significant differences comparing individual strains (BALB/C >129/SvJ > C57BL/6).

Summary and Conclusion: There is significant mice strain-dependent variation in the susceptibility to the development of hepatic steatosis as well as consecutive inflammation and fibrogenesis in murine NASH models. Identification of the precise molecular mechanisms of this interstrain difference may provide indications of the pathophysiological mechanisms of NASH in humans.

NASH - PD-1 - PD-L1