The pro-inflammatory action of tumour necrosis factor-α in non-alcoholic steatohepatitis is independent of the NSMAF gene product

BackgroundThe role of tumour necrosis factor-α (TNF-α) in the development of non-alcoholic steatohepatitis remains unclear.AimsWe evaluated the role of TNF-α and NSMAF gene product factor associated with neutral sphingomyelinase activation, a protein adaptor of the TNF-α receptor-1, in a mouse model of non-alcoholic steatohepatitis.MethodsMice deficient either for TNF-α or factor associated with neutral sphingomyelinase activation, as well as control animals, were fed a methionine and choline-deficient diet for 5 weeks. Liver histology, serum glucose, triglycerides, cholesterol and alanine aminotransferase levels were compared between groups.ResultsWeight loss, decrease of serum triglyceride and glucose levels and increase of alanine aminotransferase levels were attenuated in TNF−/− mice. Similarly, we found a significantly lower lobular inflammation in TNF−/− mice. Liver expression of transforming growth factor-β, peroxisome proliferator-activated receptor-γ1, 2 and monocyte chemoattractant protein-1 was attenuated in TNF−/− mice. In addition, the phosphatidylcholine/phosphatidylethanolamine liver ratio decrease was less important in TNF−/− mice. The increase in hepatic sphingomyelin and ceramide levels was less pronounced in TNF−/− animals.ConclusionWhereas TNF-α modulates the inflammatory process that underlies methionine and choline-deficient diet-induced non-alcoholic steatohepatitis, its effects are not mediated by factor associated with neutral sphingomyelinase activation. Whether changes in liver lipids, like phosphatidylcholine and ceramide, are causally involved in tumour necrosis factor-mediated liver inflammation remains an open issue.