RT Journal Article SR Electronic T1 Apigenin ameliorates insulin resistance and lipid accumulation by endoplasmic reticulum stress and SREBP-1c/SREBP-2 pathway in palmitate-induced HepG2 cells and high-fat diet-fed mice JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP JPET-AR-2020-000162 DO 10.1124/jpet.120.000162 A1 wu, liling A1 guo, tingdong A1 deng, ranxi A1 liu, lusheng A1 yu, yongxiong YR 2021 UL http://jpet.aspetjournals.org/content/early/2021/01/28/jpet.120.000162.abstract AB Insulin resistance (IR) is the common basis of diabetes and cardiovascular diseases, and its development is closely associated with lipid metabolism disorder. Flavonoids have definite chemical defense effects, including anti-inflammatory effects, anti-cancer effects, and anti-mutation effects. However, the function and mechanism of apigenin (AP, a kind of flavonoids) on IR are still unclear. In our study, intracellular fat accumulation model cells and high-fat diet (HFD) fed model mice were established using palmitate (PA) and HFD. Mechanistically, we first demonstrated that AP could notably downregulate sterol regulatory element-binding protein 1c (SREBP-1c), sterol regulatory element-binding protein 2 (SREBP-2), fatty acid synthase (FAS), stearyl-CoA desaturase 1 (SCD-1), and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCOR) in PA-induced hyperlipidemic cells and mice. Functionally, we verified that AP could markedly reduce lipid accumulation in PA-induced hyperlipidemic cells and decrease the body weight, visceral fat weight, IR, and lipid accumulation in HFD-induced hyperlipidemic mice. Besides, we disclosed that PA could significantly downregulate ERS-related proteins and inhibit ERS. Furthermore, we proved that AP could reduce blood lipids by inhibiting ERS in PA-induced hyperlipidemic cells. Meanwhile, ERS alleviator (4-PBA), like AP, could significantly reduce blood lipids and alleviate IR in HFD fed model mice. Therefore, we concluded that AP could substantially improve the disorder of lipid metabolism, and its mechanism might be related to the decrease of SREBP-1c, SREBP-2, and downstream genes, the inhibition of ERS, and the reduction of blood lipids and IR. Significance Statement Apigenin,a non-toxic and naturally-sourced flavonoid, exerts anti-hyperlipidemia properties in mice and hepatocyte. Our study highlights a new mechanism of Apigenin that this hypolipidemic effects is associated with the mitigation of endoplasmic reticulum stress and insulin resistance in diet-induced obesity. This study might provide tranlational insight for the prevention and treatment of AP in hyperlipidemia related diseases.