Etnppl Mediates Hyperinsulinemia-Induced Insulin Resistance Through SIK1-ROS Signaling Pathway In Human Hepatocyte Cells

Research background:Insulin resistance(IR)in metabolic organs such as the liver could be induced by hyperinsulinemia.Insulin production is not regulated by the negative feedback of hypoglycemia in patients with hyperinsulinemia,resulting in excessive insulin secretion,which can lead to pancreatic cell failure,cardiovascular,cerebral,and neurological disorders,and eventually diabetes.Many metabolic disorders,such as hypertension,hyperlipidemia,hyperuricemia,and T2 DM,have IR as a common physiological hallmark.Obesity,age,and oxidative stress have all been linked to IR.Despite the fact that hyperinsulinemia is one of the major causes of IR,due to the metabolic heterogeneity shown in IR,it will be difficult to examine the causal link and hereditary factors.As a result,understanding the molecular mechanism of IR produced by hyperinsulinemia is critical.ETNPPL is a phospholipid metabolism regulator that affects fatty acid and lipid metabolism processes.Current research on ETNPPL focuses on multiple types of cancer and psychiatric disorders.ETNPPL functions as a crucial modulator in a variety of lipid metabolism pathways.However,its significance in IR control is not completely understood.Research objective:In this study,we will demonstrate the role and molecular mechanism of ETNPPL in IR hepatocyte cells induced by hyperinsulinemia in humans.Research methods:1.The HepG2-IR cell model was induced by high dose insulin.To explore the correlation between ETNPPL and HepG2-IR induced by hyperinsulinemia;2.In HepG2 cells,we overexpressed ETNPPL by using lentivirus-mediated ectopic to investigate the effects of ETNPPL perse on IR without insulin stimulation;3.Transcriptome sequencing was used to explore the downstream target genes of ETNPPL in HepG2-IR induced by hyperinsulinemia;4.To explore whether ETNPPL induces insulin resistance by promoting ROS production and inhibiting AKT activity through its downstream target genes.Research results:1.ETNPPL mediated hyperinsulinemia-induced IR in HepG2 cells;2.ETNPPL-induced IR through ROS-mediated inactivation of the PI3K/AKT pathway in HepG2 cells;3.Transcriptome sequencing showed that SIK1 was a key gene downstream of ETNPPL,which may be associated with IR induced by hyperinsulinemia;4.Hyperinsulinemia induced IR in HepG2 cells by promoting ETNPPL-SIK1 expression to expand ROS production and further inhibit PI3K/AKT signaling pathway.Research conclusion:ETNPPL mediates hyperinsulinemia-induced insulin resistance through SIK1-ROS-mediated inactivation of the PI3K/AKT pathway in human hepatocyte cells.