Non-alcoholic steatoheopatitis (NASH) is a liver condition associated with the metabolic syndrome and a precursor to cirrhosis and hepatocarcinoma with no successful treatment to date. The pro-inflammatory cytokine interleukin-6 (IL-6) has been implicated in the pathogenesis and development of NASH in rodent models and humans. However, work from our laboratory and others have highlighted that ablation of IL-6 can lead to deleterious metabolic consequences such as glucose intolerance, obesity and more importantly liver damage. Consequently, this would make IL-6 a poor candidate to target for the treatment of NASH. Interestingly, it appears that IL-6 can signal in 2 distinct manners referred to as “classical” and “trans-signalling”. These distinct signalling cascades lead to different effects with the classical signalling responsible for the positive metabolic effects of IL6 and trans-signalling leading to the pro-inflammatory actions of the cytokine. We currently have a transgenic mouse model (Tg) allowing for IL6 trans-signalling inhibition without affecting IL6 classical signalling and we hypothesize these animals will be protected from NASH without exhibiting the deleterious effects observed in the global IL6 knock-out.

We induced NASH by feeding 8 weeks old Tg and wild type (WT) littermate control mice with a methionine and choline deficient diet (MCDD) for 4 weeks before animals were sacrificed and liver and blood analysed for markers of NASH. MCDD induced a strong NASH phenotype with elevated transaminase enzymes, dyslipidemia, liver inflammation and ER stress. Interestingly, there was no reduction of the NASH severity in the transgenic animals. More surprisingly, the Tg animals showed an identical hepatic recruitment of macrophages as the WT mice. This finding is contradicting our previous studies where the IL6-driven chemotaxis was abolished in Tg mice, leading us to question the role of IL6 in this model. Indeed, in opposition to previous data, we did not see an increase in IL-6 mRNA in the NASH livers of control animals but observed an increase in the expression of the cytokine TNFα. These results lead us to conclude that the MCDD model is inappropriate for studying human NASH as it lacks the critical feature of IL-6 elevation observed in the human pathology.