Differences in betaine-homocysteine methyltransferase expression, endoplasmic reticulum stress response, and liver injury between alcohol-fed mice and rats.
Chronic ethanol infusion resulted in greater serum alanine aminotransferase elevation, lipid accumulation, necroinflammation, and focal hepatic cell death in mice than rats. Mice exhibited a remarkable hyperhomocysteinemia but no increase was seen in rats. Similarly, a high-methionine low-folate diet (HMLF) induced less steatosis, serum alanine aminotransferase increase, and hyperhomocysteinemia in rats than in mice. Western blot analysis of betaine homocysteine methyltransferase (BHMT) expression showed that rats fed either ethanol or HMLF had significantly increased BHMT expression, which did not occur in mice. Nuclear factor-kappaB p65 was increased in mouse in response to alcohol feeding. The human BHMT promoter was repressed by homocysteine in mouse hepatocytes but not rat hepatocytes. BHMT induction was faster and greater in primary rat hepatocytes than mouse hepatocytes in response to exogenous homocysteine exposure. Mice fed ethanol intragastrically exhibited an increase in glucose-regulated protein 78 and inositol-requiring enzyme 1, which was not seen in the rat, and sterol regulatory element binding protein 1 was increased to a greater extent in mice than rats. Thus, rats are more resistant to ethanol-induced steatosis, endoplasmic reticulum stress, and hyperhomocysteinemia, and this correlates with induction of BHMT in rats.


CONCLUSIONS
These findings support the hypothesis that a critical factor in the pathogenesis of alcoholic liver injury is the enhanced ability of rat or impaired ability of mouse to up-regulate BHMT which prevents hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury.
Shinohara
Masao
M
University of Southern California Research Center for Liver Disease, USC/University of California Los Angeles Research Center for Alcoholic Liver and Pancreas Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Ji
Cheng
C
Kaplowitz
Neil
N
D000818:Animals; D050940:Betaine-Homocysteine S-Methyltransferase / Q000096:biosynthesis*; D004721:Endoplasmic Reticulum / Q000502:physiology*; D000431:Ethanol / Q000008:administration & dosage; D008107:Liver Diseases / Q000201:enzymology*; D008108:Liver Diseases, Alcoholic / Q000201:enzymology / Q000209:etiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017208:Rats, Wistar; D013312:Stress, Physiological / Q000502:physiology*
D000431:Ethanol; D050940:Betaine-Homocysteine S-Methyltransferase