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J. Biol. Chem., Vol. 282, Issue 23, 17078-17089, June 8, 2007

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Inhibiting Proteasomal Degradation of Microsomal Triglyceride Transfer Protein Prevents CCl₄-induced Steatosis^*

Xiaoyue Pan, Farah N. Hussain, Jahangir Iqbal, Miriam H. Feuerman, and M. Mahmood Hussain^¶1

From the Departments of Anatomy and Cell Biology, ^¶Pediatrics, and Biochemistry, SUNY Downstate Medical Center, Brooklyn, New York 11203

Carbon tetrachloride (CCl₄) interferes with triglyceride secretion and causes steatosis, fibrosis, and necrosis. In mice, CCl₄ decreased plasma triglyceride-rich lipoproteins, increased cellular lipids, and reduced microsomal triglyceride transfer protein (MTP) without diminishing mRNA levels. Similarly, CCl₄ decreased apoB-lipoprotein production and MTP activity but had no effect on mRNA levels in primary enterocytes and colon carcinoma and hepatoma cells. CCl₄ did not affect MTP synthesis but induced post-translational degradation involving ubiquitinylation and proteasomes in McA-RH7777 cells. By contrast, MTP inhibitor increased cellular lipids without affecting MTP protein. MTP was covalently modified when cells were incubated with ¹⁴CCl₄. This modification was prevented by the inhibition of P450 oxygenases, indicating that CCl₃^· generated by these enzymes targets MTP for degradation. To determine whether inhibition of proteolysis could prevent CCl₄ toxicity, mice were fed with CCl₄ with or without lactacystin. Lactacystin increased ubiquitinylated MTP and prevented lipid accumulation in tissues. Thus, CCl₄ induces post-translational degradation without affecting lipid transfer activity, whereas MTP antagonist inhibits lipid transfer activity without causing its destruction. These studies identify MTP as a major target of CCl₄ and its degradation as a novel mechanism involved in the onset of steatosis, suggesting that inhibition of proteolysis may prevent some forms of steatosis.

Received for publication, February 28, 2007 , and in revised form, April 3, 2007.

^* This work was supported by National Institutes of Health Grant HL-64272 (to M. M. H.) and a postdoctoral fellowship from the American Heart Association, Heritage Affiliate (to X. P.). 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: SUNY Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203. E-mail: mhussain{at}downstate.edu.

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