Oleic acid activates peroxisome proliferator-activated receptor delta to compensate insulin resistance in steatotic cells.

摘要

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 delta (PPAR delta) improves hepatic steatosis and IR, whereas the role of PPAR delta 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 PPAR delta 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 PPAR delta. Inhibition of phospholipase C (PLC) by U73122 also reversed OA-induced PPAR delta expression. Otherwise, deletion of PPAR delta augmented the OA-induced steatosis in HepG2 cells. Furthermore, IR was developed in OA-treated HepG2 cells with PPAR delta 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 PPAR delta and PPAR delta further decreased the expression of PTEN to regulate insulin sensitivity in hepatic steatosis