Scutellarin, a modulator of mTOR, attenuates hepatic insulin resistance by regulating hepatocyte lipid metabolism via SREBP-1c suppression

High levels of consumption of saturated lipids have been largely associated with the increasing prevalence of metabolic diseases. In particular, saturated fatty acids such as palmitic acid (PA) have been implicated in the development of insulin resistance (IR). Scutellarin (Scu) is one of the effective traditional Chinese medicines considered beneficial for liver diseases and diabetes. In this study, we investigated the effect of Scu on IR and lipid metabolism disorders in vitro and in high fat diet (HFD)-fed mice. In vitro, we found that Scu decreased insulin-dependent lipid accumulation and the mRNA expression of CD36, Fasn, and ACC in PA-treated HepG2 cells. Additionally, Scu upregulated Akt phosphorylation and improved the insulin signalling pathway. Moreover, Scu downregulated mammalian target of rapamycin (mTOR) phosphorylation and the n-SREBP-1c protein level and also reduced lipid accumulation via the mTOR-dependent pathway, as confirmed by the molecular docking of Scu to mTOR. In HFD-fed C57BL/6 mice, Scu improved oral glucose tolerance, pyruvate tolerance and the IR index and also increased the Akt phosphorylation level. Moreover, Scu reduced hepatocyte steatosis, decreased lipid accumulation and triglyceride levels, inhibited mTOR phosphorylation, and decreased the SREBP-1c level in the liver. Taken together, these findings suggest that Scu ameliorates hepatic IR by regulating hepatocyte lipid metabolism via the mTOR-dependent pathway through SREBP-1c suppression.