Mechanism Of TRB3-COP1-SIRT1 Pathway In Hepatic Insulin Resistance Induced By Lipidtoxicity

Background and Aims:Lipotoxicity in the pathogenesis of type 2 diabetes mellitus(T2DM)has attracted more and more attention by population.Abnormal lipid metabolism associated with obesity is closely related to the onset of T2DM.Our previous studies have documented that lipotoxicity contributes to the onset and development of diabetes via insulin resistance and/or compromised function of the pancreatic β-cells.Endoplasmic reticulum stress,oxidative stress and inflammation are the possible mechanisms of insulin resistance induced by lipotoxicity.The activation of NF-ΚB/MIF inflammatory signaling pathway may be a mechanism of lipoxicity-induced islet β cell dysfunction and apotpsis.However,the underlying molecular mechanisms associating lipotoxicity with insulin resistance remain to be fully elucidated.Studies have shown that TRB3 contributes to insulin resistance in individuals with susceptibility to type 2 DM,by interfering with Akt activation during fasting.In this study,we explored the role of TRB3-COP1-SIRT1 in lipotoxicity leading to insulin resistance in hepatocytes.Methods and Materials: High-fat diet(HFD)-fed mice and hepG2 cells stimulated with palmitate and were utilized as models of lipid metabolism disorders.We analyzed the interactions of SIRT1 and COP1 with each other and with TRB3 using co-immunoprecipitation,western blotting.SIRT1 ubiquitination was also explored.Results: Animal and cell experiments showed that lipotoxicity induced SIRT1 down-regulation at the protein level without altering the mRNA level,whereas,lipotoxicity led to up-regulation of TRB3 and COP1 at both the gene and protein levels.Mechanistic analysis indicated that COP1 functioned as an E3 ub-ligase of SIRT1,responsible for its proteasomal degradation under lipotoxic conditions.TRB3 recruited COP1 to SIRT1 to promote its ubiquitination.Conclusions: Our data indicated for the first time that TRB3-COP1-SIRT1 pathway played an important role in lipotoxicity leading to insulin resistance in hepatocytes,and suggested that COP1 and TRB3 could be potential therapeutic choices for the treatment of diabetes mellitus,with lipotoxicity being the important pathomechanism.