Ablation of Tumor Necrosis Factor Alpha Receptor 1 Signaling Blunts Steatohepatitis in Peroxisome Proliferator Activated Receptor α-Deficient Mice

Tumor necrosis factor -alpha (TNFα) is strongly associated with fatty liver disease (i.e, hepatosteatosis). Cytokine production has been thought of as a consequence of hepatic lipid accumulation which becomes a critical factor in the development of chronic liver pathologies as well as insulin resistance. The purpose of this study was to test the hypothesis that TNFα directly regulates lipid metabolism in liver in the mutant peroxisome-proliferator activated receptor-alpha (PPARα(−/−)) mouse model with robust hepatic lipid accumulation. At 10 weeks of age, TNFα and TNF receptor 1 expression are increased in livers of PPARα(−/−) mice compared to wild type. PPARα(−/−) mice were then crossed with mice lacking the receptor for TNFα receptor 1 (TNFR1(−/−)). Wild type, PPARα(−/−), TNFR1(−/−), PPARα(−/−) x TNFR1(−/−) mice were housed on ad-libitum standard chow diet for up to 40 weeks. Increases in hepatic lipid and liver injury and metabolic disruption associated with PPARα ablation were largely blunted when PPARα(−/−) mice were crossed with TNFR1(−/−) mice. These data support the hypothesis that TNFR1 signaling is critical for accumulation of lipid in liver. Therapies that reduce pro-inflammatory responses, namely TNFα, could have important clinical implications to reduce hepatosteatosis and progression of severe liver disease.