Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan 70101.
J Nutr Biochem. 2012 Oct;23(10):1264-70. doi: 10.1016/j.jnutbio.2011.07.006. Epub 2011 Dec 29.
Nonalcoholic fatty liver disease is frequently associated with type 2 diabetes; however, this idea is challenged by recent studies because hepatic steatosis is not always associated with insulin resistance (IR). Oleic acid (OA) is known to induce hepatic steatosis with normal insulin sensitivity; however, the mechanism is still unknown. Previous studies depict that activation of peroxisome proliferator-activated receptor δ (PPARδ) improves hepatic steatosis and IR, whereas the role of PPARδ in the improvement of insulin sensitivity by OA is unknown. Here we induced steatosis in HepG2 cells by incubation with OA and OA significantly increased the expression of PPARδ through a calcium-dependent pathway. OA also induced the expression of G protein-coupled receptor 40 (GPR40), and deletion of GPR40 by small interfering ribonucleic acid transfection partially reversed the effect of OA on PPARδ. Inhibition of phospholipase C (PLC) by U73122 also reversed OA-induced PPARδ expression. Otherwise, deletion of PPARδ augmented the OA-induced steatosis in HepG2 cells. Furthermore, IR was developed in OA-treated HepG2 cells with PPARδ deletion, while insulin-related signals and insulin-stimulated glycogen synthesis were reduced through increase of phosphatase and tensin homolog (PTEN) expression. In conclusion, OA activates GPR40-PLC-calcium pathway to increase the expression of PPARδ and PPARδ further decreased the expression of PTEN to regulate insulin sensitivity in hepatic steatosis.
非酒精性脂肪性肝病常与 2 型糖尿病相关；然而，最近的研究对这一观点提出了挑战，因为肝脂肪变性并不总是与胰岛素抵抗（IR）相关。已知油酸（OA）可诱导肝脂肪变性而不伴有胰岛素敏感性降低；然而，其机制尚不清楚。先前的研究表明，过氧化物酶体增殖物激活受体 δ（PPARδ）的激活可改善肝脂肪变性和 IR，而 OA 对胰岛素敏感性的改善作用是否与 PPARδ 有关尚不清楚。在此，我们通过用 OA 孵育 HepG2 细胞来诱导脂肪变性，OA 通过钙依赖性途径显著增加了 PPARδ 的表达。OA 还诱导了 G 蛋白偶联受体 40（GPR40）的表达，通过小干扰 RNA 转染敲除 GPR40 可部分逆转 OA 对 PPARδ 的作用。PLC 的抑制剂 U73122 也逆转了 OA 诱导的 PPARδ 表达。相反，PPARδ 的缺失增强了 OA 诱导的 HepG2 细胞脂肪变性。此外，在 PPARδ 缺失的 OA 处理的 HepG2 细胞中发生了 IR，而胰岛素相关信号和胰岛素刺激的糖原合成通过磷酸酶和张力蛋白同源物（PTEN）表达的增加而减少。总之，OA 通过激活 GPR40-PLC-钙途径来增加 PPARδ 的表达，而 PPARδ 进一步降低了 PTEN 的表达，从而调节肝脂肪变性中的胰岛素敏感性。
