2. Academic Validation
  3. ETNPPL modulates hyperinsulinemia-induced insulin resistance through the SIK1/ROS-mediated inactivation of the PI3K/AKT signaling pathway in hepatocytes

ETNPPL modulates hyperinsulinemia-induced insulin resistance through the SIK1/ROS-mediated inactivation of the PI3K/AKT signaling pathway in hepatocytes

  • J Cell Physiol. 2023 Mar 16. doi: 10.1002/jcp.30993.
Xueyi Chen 1,  Ping Liu 2,  Wei Zhang 2,  Xiaofang Li 3,  Caihua Wang 1,  Feifei Han 2,  Wenxuan Liu 1,  Yaoyao Huang 1,  Man Li 2,  Yujia Li 2,  Xiaomin Sun 2,  Xiaobin Fan 4,  Wenqing Li 1,  Yuyan Xiong 1 5,  Lu Qian 1 2 5
Affiliations

Affiliations

  • 1 Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Shaanxi, Xi'an, China.
  • 2 Department of Endocrinology, Xi'an No. 3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Shaanxi, Xi'an, P.R. China.
  • 3 Department of Gastroenterology, Xi'an No. 3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Shaanxi, Xi'an, P.R. China.
  • 4 Department of Obstetrics and Gynecology, Xi'an No. 3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Shaanxi, Xi'an, P.R. China.
  • 5 Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No. 3 Hospital, The Affiliated Hospital of Northwest University, Northwest University, Shaanxi, Xi'an, China.
PMID: 36924049 DOI: 10.1002/jcp.30993
Abstract

Hyperinsulinemia is a critical risk factor for the pathogenesis of Insulin resistance (IR) in metabolic tissues, including the liver. Ethanolamine phosphate phospholyase (ETNPPL), a newly discovered metabolic Enzyme that converts phosphoethanolamine (PEA) to ammonia, inorganic phosphate, and acetaldehyde, is abundantly expressed in liver tissue. Whether it plays a role in the regulation of hyperinsulinemia-induced IR in hepatocytes remains elusive. Here, we established an in vitro hyperinsulinemia-induced IR model in the HepG2 human liver Cancer cell line and primary mouse hepatocyte via a high dose of Insulin treatment. Next, we overexpressed ETNPPL by using lentivirus-mediated ectopic to investigate the effects of ETNPPL per se on IR without Insulin stimulation. To explore the underlying mechanism of ETNPPL mediating hyperinsulinemia-induced IR in HepG2, we performed genome-wide transcriptional analysis using RNA sequencing (RNA-seq) to identify the downstream target gene of ETNPPL. The results showed that ETNPPL expression levels in both mRNA and protein were significantly upregulated in hyperinsulinemia-induced IR in HepG2 and primary mouse hepatocytes. Upon silencing ETNPPL, hyperinsulinemia-induced IR was ameliorated. Under normal conditions without IR in hepatocytes, overexpressing ETNPPL promotes IR, Reactive Oxygen Species (ROS) generation, and Akt inactivation. Transcriptome analysis revealed that salt-inducible kinase 1 (SIK1) is markedly downregulated in the ETNPPL knockdown HepG2 cells. Moreover, disrupting SIK1 prevents ETNPPL-induced ROS accumulation, damage to the PI3K/Akt pathway and IR. Our study reveals that ETNPPL mediates hyperinsulinemia-induced IR through the SIK1/ROS-mediated inactivation of the PI3K/Akt signaling pathway in hepatocyte cells. Targeting ETNPPL may present a potential strategy for hyperinsulinemia-associated metabolic disorders such as type 2 diabetes.

Keywords

ETNPPL; PI3K/AKT; ROS; hyperinsulinemia; insulin resistance; salt-inducible kinase.

Figures
Products