Betaine suppresses hepatic steatosis: Inhibition of FoxO6 and PPARγ interaction

Betaine is the major water-soluble component of Lycium chinensis. Although there are reports of a protective effect of betaine on fatty liver disease, the underlying mechanisms are unclear. We investigated the effects of betaine on forkhead box O6 (FoxO6) and peroxisome proliferator-activated receptor gamma (PPARγ) expression, which are associated with hepatic lipid accumulation. In this study, we attempted to elucidate the molecular regulation of betaine on hyperglycemia-induced lipid accumulation via FoxO6 activation. HepG2 cells and liver tissue isolated from db/db mice treated with betaine at a dose of 50 mg/kg/day for 3 weeks were used. In the present study, we investigated whether betaine ameliorates hepatic steatosis by inhibiting FoxO6/PPARγ signaling in liver cells. Interestingly, betaine notably decreased lipid accumulation in FoxO6-induced mRNA expression of lipogenesis-related genes. In addition, hepatic insulin signaling was decreased; and activation of FoxO6, which is negatively regulated by Akt, was reduced by betaine treatment. Furthermore, betaine inhibited the FoxO6 interaction with PPARγ and cellular triglycerides in high-glucose- or FoxO6-overexpression-treated liver cells. In addition, we confirmed that betaine administration via oral gavage significantly ameliorated hepatic steatosis in db/db mice. The protein level of PPARγ, a lipogenic transcription factor, was decreased in the livers of db/db mice. Therefore, it has previously been shown to induce hepatic steatosis. We conclude that betaine ameliorates hepatic steatosis, at least in part, by inhibiting the interaction between FoxO6 and PPARγ, thereby suppressing lipogenic gene transcription.