Abstract
Tumor necrosis factor -alpha (TNFa) 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 TNFa directly regulates lipid metabolism in liver in the mutant peroxisome-proliferator activated receptor-alpha (PPARa-/-) mouse model with robust hepatic lipid accumulation. At 10 weeks of age, TNFa and TNF receptor 1 expression are increased in livers of PPARa-/- mice compared to wild type. PPARa-/- mice were then crossed with mice lacking the receptor for TNFa receptor 1 (TNFR1-/-). Wild type, PPARa-/-, TNFR1-/-, PPARa-/- 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 PPARa ablation were largely blunted when PPARa-/- 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 TNFa, could have important clinical implications to reduce hepatosteatosis and progression of severe liver disease.