Betaine Treatment Attenuates Chronic Ethanol-Induced Hepatic Steatosis and Alterations to the Mitochondrial Respiratory Chain Proteome

Abstract

Introduction. Mitochondrial damage and disruption in oxidative phosphorylation contributes to the pathogenesis of alcoholic liver injury. Herein, we tested the hypothesis that the hepatoprotective actions of betaine against alcoholic liver injury occur at the level of the mitochondrial proteome. Methods. Male Wister rats were pair-fed control or ethanol-containing liquid diets supplemented with or without betaine (10 mg/mL) for 4-5 wks. Liver was examined for triglyceride accumulation, levels of methionine cycle metabolites, and alterations in mitochondrial proteins. Results. Chronic ethanol ingestion resulted in triglyceride accumulation which was attenuated in the ethanol plus betaine group. Blue native gel electrophoresis (BN-PAGE) revealed significant decreases in the content of the intact oxidative phosphorylation complexes in mitochondria from ethanol-fed animals. The alcohol-dependent loss in many of the low molecular weight oxidative phosphorylation proteins was prevented by betaine supplementation. This protection by betaine was associated with normalization of SAM : S-adenosylhomocysteine (SAH) ratios and the attenuation of the ethanol-induced increase in inducible nitric oxide synthase and nitric oxide generation in the liver. Discussion/Conclusion. In summary, betaine attenuates alcoholic steatosis and alterations to the oxidative phosphorylation system. Therefore, preservation of mitochondrial function may be another key molecular mechanism responsible for betaine hepatoprotection.

Role of defective methylation reactions in ethanol-induced dysregulation of intestinal barrier integrity

“…Our laboratory has made seminal contribution in demonstrating that ethanol-induced defects in hepatic transmethylation reactions play a causal role in the pathogenesis of ALD [17][18][19][21][22][23]34]. We have further shown that dietary betaine supplementation, which normalize methylation reactions, protects the liver from many of the ethanol-induced anomalies [17][18][19][20][21][22][35][36][37]. Here, we present novel findings that the alcohol-induced decrease in essential methylation reaction(s) may be a causal factor in disrupting TJ integrity and in promoting intestinal permeability.…”

Betaine chemistry, roles, and potential use in liver disease

“…A separate proteomic study in livers of alcohol-fed rats detected decreases in several mitochondrial proteins involved in oxidative phosphorylation complexes. These decreases were prevented by co-feeding betaine with the ethanol, suggesting that preservation of mitochondrial function may be an additional mechanism by which betaine protects the liver from alcoholic injury [87].…”

B-Vitamin dependent methionine metabolism and alcoholic liver disease

“…When MS expression and activity are inhibited by alcohol exposure, betaine becomes an alternate substrate for betaine homocysteine methyltransferase (BHMT) that converts homocysteine to methionine and produces dimethylglycine (DMG) [9] . Recent work in ethanol-fed rats showed that the co-administration of betaine specifically prevented the development of oxidative injury processes through reduction in homocysteine and preservation of normal SAM levels [10] . Methionine, the product of either MS or BHMT, is the substrate for hepatic methionine adenosyl transferase (MAT) which exists in gene form predominantly as MAT1A in progressive alcoholic liver injury and as MAT2A after malignant transformation [8] .…”