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

Abstract

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, anticancer effects, and antimutation effects. However, the function and mechanism of apigenin (AP, a kind of flavonoid) in 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, stearyl-CoA desaturase 1, and 3-hydroxy-3-methyl-glutaryl-CoA reductase 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 showed that PA could significantly downregulate endoplasmic reticulum stress (ERS)-related proteins and inhibit ERS. Furthermore, we proved that AP could reduce blood lipids by inhibiting ERS in PA-induced hyperlipidemic cells. Meanwhile, 4-phenyl butyric acid (also called ERS alleviator), 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 nontoxic and naturally sourced flavonoid, has antihyperlipidemic properties in mice and hepatocyte. This study highlights a new mechanism of apigenin and proposes that these hypolipidemic effects are associated with the mitigation of endoplasmic reticulum stress and insulin resistance in diet-induced obesity. This study might provide translational insight into the prevention and treatment of apigenin in hyperlipidemia-related diseases.