S24S-ADENOSYLMETHIONINE IN THE PATHOGENESIS AND TREATMENT OF ALCOHOLIC LIVER DISEASES24.1THE ROLE OF ALTERED SAME METABOLISMn IN ALCOHOL-INDUCED ER STRESS AND LIVER INJURYS24.2RESCUE OF ALTERED METHYLATION REACTIONS BY BETAINE: A THERAPEUTIC APPROACHn FOR THE TREATMENT OF ALCOHOLIC LIVER INJURYS24.3ROLE OF SAME IN HEPATOCELLULAR CARCINOMAS24.4THE EFFECTS OF SAME ON METHIONINEn METABOLISM AND TREATMENT OF ALD

摘要

ER stress is a condition under which unfolded or malfolded proteins accumulate in the endoplasmic reticulum. ER stress triggers the unfolded protein response (UPR) which can either result in the recovery of ER homeostasis or activate a cascade of events which result in inflammation and steatosis and ultimately cell death. Alcohol-induced alterations of molecular markers of the UPR were first revealed by microarray analysis in the liver of mice with intragastric alcohol infusion (French-Tsukamoto model) in 2001. The role of ER stress in alcohol-induced liver disease (ALD) has since been investigated using genomic and proteomic profiling as well as a series of transgenic or gene-knockout cell and animal models. Robust support for a contributing as opposed to a secondary role for ER stress response is seen in ALD. Potential mechanisms that trigger alcohol-induced ER stress response include alcohol-induced hyperhomocysteinemia (HHcy) causing protein homocysteinylation, alcohol metabolite acetaldehyde forming protein adducts and alcohol-induced reduction in the ratio of liver S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) increasing hepatic exposure to homocysteine as well as causing epigenetic regulations of the UPR signaling pathway. Mice with liver-specific deletion of the major chaperone GRP78/BiP was recently created. The GRP78 loss exacerbated ER stress and liver injury in the knockout mice fed orally low doses of alcohol at which minimal HHcy, ER stress or fatty liver injury were induced in wild-type mice. The evidence support the existence of a complex interplay between impaired SAMe/Hcy metabolism, continuous high alcohol consumption that promotes it and ER stress responses that result from it. Such a vicious cycle may be the key pathophysiologic concept in ALD. Therapeutic approaches aimed at interrupting the cycle may dampen the stress response and the ensuing injury. (This study was supported by US NIH/NIAAA grants R01AA018846 and R01AA018612.)