ETNPPL modulates hyperinsulinemia-induced insulin resistance through the SIK1/ROS-mediated inactivation of the PI3K/AKT signaling pathway in hepatocytes.
Animals
Humans
Mice
Diabetes Mellitus, Type 2
/ metabolism
Hepatocytes
/ metabolism
Hyperinsulinism
/ genetics
Insulin
/ metabolism
Insulin Resistance
/ genetics
Phosphatidylinositol 3-Kinases
/ metabolism
Protein Serine-Threonine Kinases
/ metabolism
Proto-Oncogene Proteins c-akt
/ genetics
Reactive Oxygen Species
/ metabolism
Signal Transduction
ETNPPL
PI3K/AKT
ROS
hyperinsulinemia
insulin resistance
salt-inducible kinase
Journal
Journal of cellular physiology
ISSN: 1097-4652
Titre abrégé: J Cell Physiol
Pays: United States
ID NLM: 0050222
Informations de publication
Date de publication:
05 2023
05 2023
Historique:
revised:
16
02
2023
received:
23
11
2022
accepted:
27
02
2023
medline:
18
5
2023
pubmed:
17
3
2023
entrez:
16
3
2023
Statut:
ppublish
Résumé
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.
Substances chimiques
Insulin
0
Phosphatidylinositol 3-Kinases
EC 2.7.1.-
phosphorylethanolamine
78A2BX7AEU
Protein Serine-Threonine Kinases
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Reactive Oxygen Species
0
SIK1 protein, human
EC 2.7.11.1
Sik1 protein, mouse
EC 2.7.11.1
Alanine-glyoxylate transaminase
EC 2.6.1.44
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1046-1062Informations de copyright
© 2023 Wiley Periodicals LLC.
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