Tumor necrosis factor-alpha can provoke cleavage and activation of sterol regulatory element-binding protein in ethanol-exposed cells via a caspase-dependent pathway that is cholesterol insensitive.
Ethanol induces the development of hepatic steatosis, increasingly recognized as causing vulnerability to subsequent liver injury. Ethanol has been shown to activate SREBP-1 (sterol regulatory element-binding protein) processing through the conventional cholesterol-sensitive pathway (1). The present study demonstrates that ethanol can also bring about SREBP-1 cleavage and activation through a novel pathway dependent on the endoplasmic reticulum-localized caspases-4 and -12. Evidence is presented that tumor necrosis factor can stimulate caspase-4 and -12 activation in ethanol-exposed cells, which cleaves SREBP-1 to a transcriptionally active form to induce the synthesis of lipogenic enzymes and triglycerides. Moreover, the caspase-4 and -12-dependent activation of SREBP-1 is insensitive to the normal negative feedback exerted by cholesterol and is mediated by the translocation of the scaffolding protein, TRAF-2, to the endoplasmic reticulum.
Pastorino
John G
JG
Department of Molecular Biology, School of Osteopathic Medicine, University of Medicine and Dentistry of New Jersey, Stratford, New Jersey 08084. Electronic address: pastorjg@umdnj.edu.
Shulga
Nataly
N
Department of Molecular Biology, School of Osteopathic Medicine, University of Medicine and Dentistry of New Jersey, Stratford, New Jersey 08084.
D000818:Animals; D053454:Caspase 12 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism*; D053471:Caspases, Initiator / Q000378:metabolism; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D006801:Humans; D008954:Models, Biological; D051381:Rats; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D014280:Triglycerides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D051779:Sterol Regulatory Element Binding Proteins; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D002784:Cholesterol; C093516:CASP4 protein, human; D053454:Caspase 12; D020169:Caspases; D053471:Caspases, Initiator