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.