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-alpha (TNF-alpha) in the development of non-alcoholic steatohepatitis remains unclear. Aims: We evaluated the role of TNF-alpha and NSMAF gene product factor associated with neutral sphingomyelinase activation, a protein adaptor of the TNF-alpha receptor-1, in a mouse model of non-alcoholic steatohepatitis. Methods: Mice deficient either for TNF-alpha 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-beta, peroxisome proliferator-activated receptor-gamma(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-alpha 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. (C) 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.