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Role of TNF-α in ethanol-induced hyperhomocysteinemia and murine alcoholic liver injury

Authors

  • Cheng Ji,

    Corresponding author
    1. Research Center for Liver Disease, USC/UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Los Angeles, CA
    • GI/Liver Division, USC Keck School of Medicine, HMR-101, 2011 Zonal Ave., Los Angeles, CA 90033
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    • fax: (323) 442-5425

  • Qinggao Deng,

    1. Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
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  • Neil Kaplowitz

    1. Research Center for Liver Disease, USC/UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Los Angeles, CA
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Abstract

We previously reported a link between ethanol-induced elevation of homocysteine, endoplasmic reticulum (ER) stress, and alcoholic liver injury in the murine model of intragastric ethanol feeding. We studied the role of TNFα in this setting by using TNFR1 knockout mice (C57 BL/6). There was a 7.4-fold increase of homocysteine in wild-type and a 6-fold increase in TNFR1 knockout mice with intragastric alcohol exposure for 4 weeks. Plasma TNFα increased in the wild-type (18.4 ± 3.3 pg/mL vs. 8.4 ± 1.3 pg/mL (control)) and in the knockouts (12.9 ± 1.4 pg/mL vs. 7.2 ± 1.6 pg/mL (control)). Similar extent of fatty liver was observed in both types. Increased ALT was observed in both groups. Necroinflammatory foci were increased significantly in ethanol-fed knockouts but not to the same extent as in the ethanol-fed wild type. Increase of hepatic apoptosis and reduction of S-adenosyl-L-methionine was detected in both types of animals fed ethanol. ER stress demonstrated by RT-PCR of mRNA of selective ER stress markers GRP78, CHOP, and SREBP1 was increased equivalently in both types of mice. Betaine administration decreased ER stress in conjunction with attenuation of the elevated plasma homocysteine in both types of animals. Betaine increased hepatic S-adenosyl-L-methionine by 28 fold in the knockouts and by 24-fold in wild type. In conclusion, TNFα makes a moderate contribution to the ALT elevation, necroinflammation, apoptosis, a small contribution to the fatty liver and no contribution to hyperhomocysteinemia and ER stress in intragastric alcohol fed mice. (HEPATOLOGY 2004;40:442–451.)

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