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

Abstract

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 mTORdependent pathway, as confirmed by the molecular docking of Scu to mTOR. In HFDfed 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. K E Y W O R D Shepatic insulin resistance, lipid accumulation, mTOR, n-SREBP-1c

Maternal nicotine exposure aggravates metabolic associated fatty liver disease via PI3K/Akt signaling in adult offspring mice

“…Insulin resistance and metabolic dysfunction can promote the release of FAAs, and β‐oxidation of FFAs induces the generation of ROS and the release of pro‐inflammatory cytokines, thus promoting the progression of MAFLD 4 . During these processes, sterol regulatory element binding protein (SREBPs), important nuclear transcription factors involved in cholesterol and FA synthesis, play an important role in lipid metabolism 10 . Additionally, peroxisome proliferator‐activated receptors (PPARs), which are a group of nuclear regulatory factors involved in glucose and fat metabolism and the regulation of inflammatory cell activation and fibrotic processes, also participate in the pathogenesis of MAFLD 11 …”

“…4 During these processes, sterol regulatory element binding protein (SREBPs), important nuclear transcription factors involved in cholesterol and FA synthesis, play an important role in lipid metabolism. 10 Additionally, peroxisome proliferator-activated receptors (PPARs), which are a group of nuclear regulatory factors involved in glucose and fat metabolism and the regulation of inflammatory cell activation and fibrotic processes, also participate in the pathogenesis of MAFLD. 11 Evidence has shown that intrauterine insults, such as poor nutrition, stress, and toxin exposure, during pregnancy may make offspring prone to chronic metabolic diseases such as cardiovascular diseases, hypertension, diabetes, and obesity in their adulthood.…”

Scutellarin ameliorates hepatic lipid accumulation by enhancing autophagy and suppressing IRE1α/XBP1 pathway

“…The role of autophagy in maintaining the homeostasis of hepatocyte lipids has been continuously confirmed, and diseases with lipid metabolism disorders, such as NAFLD, are often accompanied by different degrees of autophagy impairment (Allaire et al, 2019). In our previous study, we found that Scu improved lipid metabolism profiles in the serum and liver of C57BL/6 mice fed a HFD (Luan et al, 2020). Normal autophagy helps to maintain liver lipid homeostasis; therefore, the effect of Scu on liver lipid metabolism may be related to the improvement of autophagy function.…”

“…The mice in the test drug group were orally administered Scu (50 and 150 mg/kg) and Met (200 mg/kg) dissolved in a 0.2% CMC‐Na, respectively. Oral administration continued once a day for 18 days (Luan et al, 2020).…”

“…Moreover, Scu can enhance autophagy in non‐small‐cell lung cancer cells and kidneys (Sun et al, 2018; Sun et al, 2019). Our previous study showed that Scu attenuates steatosis in high‐fat diet (HFD) mice via mTOR/SREBP‐1c suppression (Luan et al, 2020). However, the mechanisms underlying the effects of Scu on ER stress and autophagy in hepatic lipid homeostasis remain unknown.…”