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Role of TNF‐α in ethanol‐induced hyperhomocysteinemia and murine alcoholic liver injury
Author(s) -
Ji Cheng,
Deng Qinggao,
Kaplowitz Neil
Publication year - 2004
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20309
Subject(s) - hyperhomocysteinemia , homocysteine , medicine , endocrinology , knockout mouse , fatty liver , chemistry , liver injury , methionine , unfolded protein response , apoptosis , alcoholic liver disease , chop , gene knockout , cyp2e1 , wild type , oxidative stress , biology , biochemistry , mutant , metabolism , cirrhosis , cytochrome p450 , receptor , disease , amino acid , gene
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. (H EPATOLOGY 2004;40:442–451.)