M1760 Bifidobacteria Attenuate the Development of Non-Alcoholic Fatty Liver in Obese Mice

Abstract

Our laboratory has previously shown that ethanol causes defects in methionine metabolism which result in higher levels of two toxic metabolites, homocysteine and S-adenosylhomocysteine (SAH). These metabolites, in turn, contribute to the development of characteristic features of alcoholic liver injury via impairments in crucial transmethylation reactions. We have further reported that dietary betaine supplementation alleviates ethanol-induced changes in intracellular SAH levels to mitigate steatosis, apoptosis and damaged protein accumulation, thereby preventing the progression to fibrosis and cirrhosis. We have data that shows that this protective effect of betaine is due to its ability to donate methyl groups to homocysteine via reactions catalyzed by the betaine homocysteine methyltransferase (BHMT) enzyme to generate methionine. In our search for alternates to betaine, we found that sulphur-containing analogs of betaine called thetins are alternative methyl-donor substrates of BHMT. The purpose of this study therefore was to compare the efficacy of betaine and one such analog, dimethylacetothetin (DMAT) in preventing alcoholic liver injury. The chronic ethanol feeding model which shows characteristic features of alcoholic liver injury after 4-5 weeks of ethanol exposure was utilized. Male Wistar rats (180-200 g BW) were fed the control or ethanol diet. Additional groups were fed the ethanol diet-supplemented with 1% betaine or 0.5% DMAT. All rats were sacrificed at the end of 4-5 weeks of feeding. Blood was collected and livers were excised and freeze-clamped and stored at -70°C until analyzed. We observed that while both compounds, betaine and DMAT, were effective in reducing fat accumulation in the liver, DMAT was more effective than betaine in preventing alcoholic steatosis (p < 0.05). Betaine supplemented as 1% in ethanol diet reduced the elevated liver triglycerides by ~50% (p < 0.05). However, DMAT at only a 0.5% supplementation reduced the liver triglycerides to levels seen in the control diet-fed animals. The blood ethanol levels were similar in ethanol-fed rats as compared to the betaine or DMAT-supplemented ethanol diet fed groups. We further showed that DMAT is a an exceptionally good substrate for BHMT, is 20 times more effective than betaine in remethylating homocysteine (p < 0.05) and also more efficacious in preventing methionine-induced hyperhomocysteinemia (p < 0.05). To conclude, DMAT should be considered as an alternative therapeutic agent to betaine for the treatment of alcoholic and non-alcoholic liver disease.