Matrine is a small molecule (MW: 248) isolated from a natural product and used as a prescribed hepatoprotective drug in humans with little adverse effect. Our recent work shows that matrine can reduce glucose intolerance in mice caused by excess lipid intake directly from diet (Bri J Pharmacol 172:4303,2015). Here, we investigated whether matrine may also be efficacious for hepatosteatosis and glucose intolerance due to hepatic de novo lipogenesis from high carbohydrate. This study was performed in high fructose-fed mice for 8 weeks with matrine treatment (100 mg/kg/d) administered in the last 2 weeks. We found that matrine markedly reduced hepatosteatosis (100% reduction in triglyceride content, pde novo lipogenesis (PlosOne 7:e30816, 2012), we examined hepatic ER stress following matrine treatment. Indeed, matrine significantly decreased IRE1 by 2 fold (pde novo lipogenesis in the liver.