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ETNPPL modulates hyperinsulinemia‐induced insulin resistance through the SIK1/ROS‐mediated inactivation of the PI3K/AKT signaling pathway in hepatocytes.
- Source :
- Journal of Cellular Physiology; May2023, Vol. 238 Issue 5, p1046-1062, 17p
- Publication Year :
- 2023
-
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. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00219541
- Volume :
- 238
- Issue :
- 5
- Database :
- Complementary Index
- Journal :
- Journal of Cellular Physiology
- Publication Type :
- Academic Journal
- Accession number :
- 163743764
- Full Text :
- https://doi.org/10.1002/jcp.30993