Hepatic steatosis in the absence of tumor necrosis factor in mice

Tumor necrosis factor (TNF) has pleiotropic effects including on hepatic metabolism. Here we investigated the effect of high cholesterol diet (1.25%) in TNF deficient mice. TNFalpha/beta deficient mice developed hepatomegaly and extensive steatosis in the absence of steatohepatitis as compared to wild type mice. Saturated and unsaturated, prominently mono- but also poly-unsaturated fatty acids (MUFA, PUFA) prevailed in steatotic livers. Down-regulation of the cholesterol scavenger receptor B1 and reduced insulin induced phosphorylation of protein kinase B in cholesterol fed TNFalpha/beta deficient mice likely contributed to the development of hepatic steatosis, which was accompanied by increased body weight and bone length. Steatosis was only present in TNFalpha/beta double deficient mice, however not in single TNF deficient mice suggesting a redundant role of TNFalpha and TNFbeta. In conclusion, high cholesterol diet causes an abnormal metabolic phenotype in the simultaneous absence of both TNFalpha and beta signals. The presence of either TNFalpha or beta alone is sufficient to reconstitute the control of lipid homeostasis.