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

more »

... t 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. Alcoholic liver disease is one of the most serious medical consequences of chronic ethanol use in the USA and worldwide. In our on-going investigation to understand the mechanism of alcohol-induced liver injury, we have shown that ethanol causes alterations in many specific steps involved in methionine metabolism. Ethanol consumption predominantly inhibits the activity of a vital cellular enzyme, methionine synthase, involved in remethylating homocysteine. By way of compensation in some species, ethanol increases the activity of the enzyme, betaine homocysteine methyltransferase. This enzyme catalyzes an alternate pathway in methionine metabolism and utilizes hepatic betaine to remethylate homocysteine to form methionine and maintain levels of S-adenosylmethionine (SAM), the key-methylating agent. Under extended periods of ethanol feeding, however, this alternate pathway cannot be maintained resulting in a decrease in the hepatocyte level of SAM and increases in two toxic metabolites, S-adenosylhomocysteine (SAH) and homocysteine ultimately causing a reduction in the hepatocellular SAM:SAH ratio. This ethanol-induced reduction in the SAM:SAH ratio is a profound metabolic stressor and affects many crucial methylation reactions catalyzed by diverse methyltransferases in the liver. The reduced activities of the methyltransferases results in the generation of many hallmark features of alcoholic liver injury, including increased triglyceride accumulation, increased apoptosis, enhanced accumulation of damaged proteins, decreased creatine synthesis, impaired proteasome activity and altered protein-protein interactions. We have further shown that the impaired methylation also alters cytoplasmic lipid droplet dynamics disrupting normal VLDL assembly and secretion contributing to the development of alcoholic steatosis. Treatment with betaine by virtue of its ability to remethylate homocysteine increases hepatic SAM levels and lowers SAH preserving normal SAM:SAH ratios to maintain crucial methylation reactions. Overall, betaine supplementation offers an exciting therapeutic option to prevent and protect against the development of alcoholic liver injury.