Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice.
OBJECTIVE
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.
USC/UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Research Center for Liver Disease and Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, 90033, USA. chengji@hsc.usc.edu
Cheng
C
Ji
Neil
N
Kaplowitz
D000818:Animals; D001622:Betaine / Q000494:pharmacology*; D002492:Central Nervous System Depressants / Q000494:pharmacology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology; D005235:Fatty Liver, Alcoholic / Q000378:metabolism* / Q000473:pathology; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006710:Homocysteine / Q000378:metabolism; D020138:Hyperhomocysteinemia / Q000188:drug therapy* / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008715:Methionine / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis
D002492:Central Nervous System Depressants; D005765:Gastrointestinal Agents; D006710:Homocysteine; D000431:Ethanol; D001622:Betaine; D008715:Methionine