Unfolding new mechanisms of alcoholic liver disease in the endoplasmic reticulum.
Intragastric ethanol feeding in mice induces expression of unfolded protein response/endoplasmic reticulum (UPR/ER) stress response genes. The proximate cause appears to be hyperhomocysteinemia, a well-known cause of ER stress in other contexts. Hyperhomocysteinemia appears to be due to downregulation of methionine synthase. The importance of homocysteine and ER stress in the pathogenesis of liver disease was suggested by the prevention of the alcohol-induced changes by feeding sufficient betaine to lower homocysteine via betaine homocysteine methyl transferase. The ER stress, via CHOP, causes apoptosis and CHOP null mice exhibit no apoptosis. Alcohol-induced ER stress can activate sterol regulatory element-binding protein (SREBP)-1c and SREBP-2, which contribute to the accumulation of triglyceride and cholesterol. Hyperhomocysteinemia, ER stress and pathological changes of alcohol were minimally affected by absence of tumor necrosis factor receptor 1 (TNFR1) and the effect of betaine was also independent of TNF signaling. At present ER stress as an important factor in the pathogenesis of alcoholic liver disease is an exciting new hypothesis and ongoing research will need to further clarify its contribution. Among the issues in need of further elucidation are the role of ER stress induced by alcohol in SREBP regulation and fatty liver, as well as the precise mechanism of protection by betaine: decreased homocysteine, decreased S-adenosylhomocysteine, or increased S-adenosylmethionine.
Kaplowitz
Neil
N
USC-UCLA Research Center for Alcoholic Liver, USC Research Center for Liver Disease, Division of Gastrointestinal, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. kaplowit@usc.edu
Ji
Cheng
C
D000818:Animals; D001622:Betaine / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D005765:Gastrointestinal Agents / Q000494:pharmacology; D020869:Gene Expression Profiling; D005978:Glutathione / Q000378:metabolism; D006710:Homocysteine / Q000378:metabolism; D020138:Hyperhomocysteinemia / Q000378:metabolism* / Q000503:physiopathology; D008108:Liver Diseases, Alcoholic / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D051379:Mice; D008930:Mitochondria, Liver / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D005765:Gastrointestinal Agents; D051779:Sterol Regulatory Element Binding Proteins; D014409:Tumor Necrosis Factor-alpha; D006710:Homocysteine; D001622:Betaine; D005978:Glutathione