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Physiol. Genomics 31: 216-227, 2007. First published June 12, 2007; doi:10.1152/physiolgenomics.00264.2006
1094-8341/07 $8.00
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Received 4 December 2006; accepted in final form 5 June 2007.
Physiological Genomics 31:216-227 (2007)
1094-8341/07 $8.00 © 2007 American Physiological Society

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

Klementina Fon Tacer1, Drago Kuzman2, Matej Seliskar1, Denis Pompon3 and Damjana Rozman1

1 Center for Functional Genomics and Biochips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Slovenia
2 Lek Pharmaceuticals, Ljubljana, Slovenia
3 Laboratoire d'Ingénierie des Protéines Membranaires, Centre de Génétique Moléculaire, Centre National de la Recherche Scientifique, Gif-sur-Yvette, France

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.

transcriptome; inflammation; acute response; cholesterol






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