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J. Biol. Chem., Vol. 283, Issue 37, 25638-25649, September 12, 2008

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Tumor Necrosis Factor- Can Provoke Cleavage and Activation of Sterol Regulatory Element-binding Protein in Ethanol-exposed Cells via a Caspase-dependent Pathway That Is Cholesterol Insensitive^*

From the Department of Molecular Biology, School of Osteopathic Medicine, University of Medicine and Dentistry of New Jersey, Stratford, New Jersey 08084

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.

Received for publication, January 9, 2008 , and in revised form, June 3, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R01CA118356 and R01AA012897. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Science Center, Rm. 316, 2 Medical Center Dr., Stratford, NJ 08084. Tel.: 856-566-6041; Fax: 856-566-6291; E-mail: pastorjg{at}umdnj.edu.

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