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Nonalcoholic fatty liver disease is the most prevalent liver disease characterized by excessive lipid accumulation in hepatocytes. Endoplasmic reticulum (ER) stress and autophagy play an important role in lipid accumulation. In this study, scutellarin (Scu) was examined in palmitic acid–treated HepG2 cells and C57/BL6 mice fed a high‐fat diet (HFD). Scu reduced intracellular lipid content and inhibited sterol regulatory element binding protein‐1c (SREBP‐1c)‐mediated lipid synthesis and fatty acid translocase‐mediated lipid uptake in HepG2 cells. Additionally, Scu restored impaired autophagy and inhibited excessive activation of ER stress in vivo and in vitro. Moreover, Scu upregulated forkhead box O transcription factor 1–mediated autophagy by inhibiting inositol‐requiring enzyme 1α (IRE1α)/X‐box‐binding protein 1 (XBP1) branch activation, while XBP1s overexpression exacerbated the lipid accumulation and impaired autophagy in HepG2 cells and also weakened the positive effects of Scu. Furthermore, Scu attenuated ER stress by activating autophagy, ultimately downregulating SREBP‐1c‐mediated lipid synthesis, and autophagy inhibitors offset these beneficial effects. Scu inhibited the crosstalk between autophagy and ER stress and downregulated saturated fatty acid–induced lipid accumulation in hepatocytes. These findings demonstrate that Scu ameliorates hepatic lipid accumulation by enhancing autophagy and suppressing ER stress via the IRE1α/XBP1 pathway. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]