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

Abstract

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.

• Authors: Cheng Ji, Neil Kaplowitz
• Journal: Gastroenterology (Gastroenterology) Vol. 124 Issue 5 Pg. 1488-99 (May 2003) ISSN: 0016-5085 [Print] United States
• PMID: 12730887 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

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

Topics

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