Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice

Gastroenterology. 2003 May;124(5):1488-99. doi: 10.1016/s0016-5085(03)00276-2.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Betaine / pharmacology*
  • Central Nervous System Depressants / pharmacology
  • Disease Models, Animal
  • Endoplasmic Reticulum / metabolism
  • Ethanol / pharmacology
  • Fatty Liver, Alcoholic / metabolism*
  • Fatty Liver, Alcoholic / pathology
  • Gastrointestinal Agents / pharmacology*
  • Gene Expression / drug effects
  • Homocysteine / metabolism
  • Hyperhomocysteinemia / drug therapy*
  • Hyperhomocysteinemia / pathology
  • Liver / metabolism*
  • Liver / pathology
  • Male
  • Methionine / metabolism
  • Methylation / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Oligonucleotide Array Sequence Analysis


  • Central Nervous System Depressants
  • Gastrointestinal Agents
  • Homocysteine
  • Ethanol
  • Betaine
  • Methionine