1519-P: Role of Cyr61 in Palmitic Acid-Induced Insulin Resistance and Inflammation in Hepatocyte

Abstract

Objective: Cysteine-rich protein 61 (Cyr61, also known as Cellular Communication Network Factor 1, CCN1) is involved in a variety of diseases, such as carcinoma, inflammation, and fibrosis. It was recently reported that Cyr61 was associated with nonalcoholic fatty liver disease. Here, we evaluated the effects of Cyr61 on hepatic inflammation and insulin resistance in HepG2 cells and examined the molecular mechanisms involved. Methods: We treated HepG2 cells with palmitic acid (PA) and then evaluated insulin signaling pathway using immunoblotting. After treatment with PA, the pro-inflammatory cytokines, including IL-6, TNF-α, and IL-1β, and Cyr61 were assessed by RT-PCR and ELISA. To investigate the effects of Cyr61 on insulin resistance and inflammation, we used Cyr61 small interfering (si) RNA and anti-Cyr61 neutralizing antibodies. The Cyr61 siRNA were transiently transfected into HepG2 cells using Lipofectamine 2000. Results: Compared to the control, PA reduced IR phosphorylation, IRS-1 (Tyr612) phosphorylation, AKT phosphorylation, and GSK-3α/β phosphorylation after insulin stimulation. PA stimulated NF-κB and JNK activation in a dose-dependent manner. PA significantly increased the expression and secretion of Cyr61 and pro-inflammatory cytokines. Interestingly, neutralization of Cyr61 reduced NF-κB and JNK signaling, which was increased by PA, and recovered insulin signaling. In addition, Cyr61-si RNA treatment reduced the mRNA expression of PA-induced IL-6, TNF-α and IL-1β, and decreased NF-κB and JNK signaling. Conclusion: Inhibition of Cyr61 recovered insulin signaling and reduced inflammation in HepG2 cells. Cyr61 may play a role in PA-induced insulin resistance and inflammation in HepG2 cells. Disclosure Y.Heo: None. D.Kim: None. H.Kim: None. N.Lee: None. K.Lee: None. S.E.Y.Choi: None. Y.Y.Kang: None. S.Han: None. J.Jeon: None. Funding National Research Foundation of Korea (2020R1F1A1074019, 2021M3H1A104892211)