| First Author | Ji C | Year | 2003 |
| Journal | Gastroenterology | Volume | 124 |
| Issue | 5 | Pages | 1488-99 |
| PubMed ID | 12730887 | Mgi Jnum | J:83221 |
| Mgi Id | MGI:2658791 | Doi | 10.1016/s0016-5085(03)00276-2 |
| Citation | Ji C, et al. (2003) Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice. Gastroenterology 124(5):1488-99 |
| abstractText | BACKGROUND & AIMS: Alcohol-induced hyperhomocysteinemia has been reported in rats and humans. Hyperhomocysteinemia has been associated with endoplasmic reticulum (ER) stress leading to the activation of ER-dependent apoptosis or up-regulation of lipid synthesis. This novel ER stress mechanism of alcoholic liver injury was studied in the model of intragastric alcohol-fed mice. METHODS: Effects of alcohol on gene expression were analyzed using cDNA microarrays, RT-PCR, and Western blots over a period of 6 weeks. Liver injury was examined by histologic staining and TUNEL. RESULTS: We observed fatty liver, increased hepatic necroinflammation and apoptosis, and hyperhomocysteinemia. Of 1176 toxicology-related genes, glucose-regulated proteins (GRP-78 and -94), growth arrest/DNA damage-inducible protein 153 (CHOP/GADD153), and caspase-12 indicative of an ER stress response were among the alcohol-responsive genes. Sterol regulatory element binding protein (SREBP-1) and HMG-CoA reductase also were enhanced with alcohol administration. RT-PCR and selective Western blots confirmed the alcohol-induced expression of ER stress-related apoptosis and lipid synthesis genes. Addition of 0.5% and maximal 1.5% betaine to the alcohol diet reduced the elevated level of plasma homocysteine by 54% and more than 80% accompanied by a decrease in hepatic lipids and ER stress response. Betaine did not attenuate the ethanol-induced increase in tumor necrosis factor alpha or CD14 mRNA. CONCLUSIONS: The results strongly suggest that alcohol may modulate both apoptotic and fat synthetic gene expression through homocysteine-induced ER stress in chronic alcoholic mouse liver and that correction of hyperhomocysteinemia by betaine or other approaches may be useful to prevent alcoholic liver disease. |
