TNF-alpha interferes with lipid homeostasis and activates acute and proatherogenic processes

• Published in: Physiological genomics 2007-10, Vol.31 (2), p.216-227
• Main Authors: Fon Tacer, Klementina, Kuzman, Drago, Seliskar, Matej, Pompon, Denis, Rozman, Damjana
• Format: Article
• Language: English
• Subjects: Acute-Phase Reaction - genetics; Animals; Bile Acids and Salts - biosynthesis; Cholesterol - biosynthesis; Fasting - physiology; Fatty Acids - metabolism; Feedback, Physiological; Homeostasis - genetics; Humans; Hydroxymethylglutaryl CoA Reductases - metabolism; Inflammation - genetics; Inflammation - metabolism; Inflammation - physiopathology; Insulin - physiology; Intracellular Signaling Peptides and Proteins - metabolism; Lipid Metabolism - genetics; Lipid Metabolism - physiology; Liver - drug effects; Male; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Recombinant Proteins - pharmacology; Steroid Hydroxylases - biosynthesis; Steroid Hydroxylases - genetics; Sterol Regulatory Element Binding Proteins - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Tumor Necrosis Factor-alpha - physiology
• ISSN: 1094-8341; 1531-2267
• DOI: 10.1152/physiolgenomics.00264.2006

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-alpha) in the livers of mice exposed to 20-h cytokine/fasting for the first time shows that TNF-alpha interferes with adaptation to fasting and activates harmful proatherogenic pathways, partially through interaction with the insulin-Insig-sterol regulatory element binding protein (Srebp) 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, and elevated expression of cholesterogenic genes, accompanied by increase of potentially harmful precholesterol metabolites and suppression of cholesterol elimination through bile acids, likely by farnesoid X receptor-independent mechanisms. On the transcriptional level, a shift from fatty oxidation toward fatty acid synthesis is observed. The concept of the influence of TNF-alpha 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.