The interaction between disrupted lipid homeostasis and immune response is implicated in the pathogenesis of several diseases, but the molecular bridges between the major players are still a matter of controversy. Our systemic study of the inflammatory cytokine tumor necrosis factor alpha (TNF-) in the livers of mice exposed to 20 h-cytokine/fasting for the first time shows that TNF- interferes with adaptation to fasting and activates harmful pro-atherogenic pathways, partially through the interaction with the insulin-Insig-Srebp (sterol regulatory element binding protein) signaling pathway. In addition to the increased expression of acute phase inflammatory genes, the most prominent alterations represent modified lipid homeostasis observed on the gene expression and metabolite levels. These include reduction of HDL-cholesterol, increase of LDL cholesterol, elevated expression of cholesterolgenic genes, accompanied by increase of potentially harmful pre-cholesterol metabolites and suppression of cholesterol elimination through bile acids, likely by Fxr-independent mechanisms. On the transcriptional level, a shift from fatty oxidation towards fatty acid synthesis is observed. The concept of TNF- influence on the Srebp regulatory network, followed by downstream effects on sterol metabolism, is novel. Observed acute alterations in lipid metabolism are in agreement with chronic disturbances found in patients.