Oleic acid activates peroxisome proliferator-activated receptor δ to compensate insulin resistance in steatotic cells.
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.
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan City, Taiwan 70101.
Hung-Tsung
HT
Wu
Wency
W
Chen
Kai-Chun
KC
Cheng
Po-Ming
PM
Ku
Ching-Hua
CH
Yeh
Juei-Tang
JT
Cheng
D000818:Animals; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D051379:Mice; D019301:Oleic Acid / Q000494:pharmacology*; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
C473034:FFAR1 protein, human; D047494:PPAR delta; D043562:Receptors, G-Protein-Coupled; D019301:Oleic Acid; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D010738:Type C Phospholipases