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

BACKGROUND:The role of tumour necrosis factor-α (TNF-α) in the development of non-alcoholic steatohepatitis remains unclear. AIMS:We 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. METHODS:Mice 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. RESULTS:Weight 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-γ(1, 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. CONCLUSION:Whereas 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.

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