Abstract
Increasing evidence showed that hyperhomocysteinemia plays an important role in the development of steatosis. In this study we evaluated the effects of L-serine (L-ser) on the ethanol-induced steatosis and elucidated the possible mechanisms of action in terms of the inhibition of the maturation of SREBP-1c through suppression of hyperhomocysteinemia. In vitro studies showed that treatment of AML-12 murine hepatocytes with methionine and homocysteine increased the intracellular homocysteine levels and triglyceride contents, whereas cotreatment with L-ser decreased the homocysteine and triglyceride accumulation. L-ser treatment increased the expression of insulin-induced gene-1 (INSIG-1) and inhibited the maturation and translocation of SREBP-1c to the nucleus. Transfection of the cells with siRNA for betaine homocysteine S-methyltransferase (BHMT) or cystathionine beta-synthase (CBS) increased cellular homocysteine and triglyceride level possibly due to the increase in the activation of SREBP-1. L-ser treatment reversed the SREBP-1 activation and triglyceride accumulation in BHMT siRNA-transfected cells, but not in CBS siRNA transfected cells. Male C57BL/6 mice received ethanol (5g/kg body weight) by gavage every 12 hours for a total 3 times. L-ser (200mg/kg body weight) was administrated by gavage for the last two ethanol treatment. L-Ser treatment significantly attenuated hyperhomocysteinemia. Ethanol-induced activation of SREBP-1 and accumulation of triglyceride in the liver were reversed by L-ser. These results demonstrate that L-ser inhibits hyperhomocysteinemia by accelerating the conversion of homocysteine to cystathionine which results in the amelioration of SREBP-1 activation and fatty liver.
