Hepatic PTEN Signaling Regulates Systemic Metabolic Homeostasis through Hepatokines-Mediated Liver-to-Peripheral Organs Crosstalk - Université de Lille Accéder directement au contenu
Article Dans Une Revue International Journal of Molecular Sciences Année : 2022

Hepatic PTEN Signaling Regulates Systemic Metabolic Homeostasis through Hepatokines-Mediated Liver-to-Peripheral Organs Crosstalk

Flavien Berthou
  • Fonction : Auteur
Daniel Abegg
  • Fonction : Auteur
Margot Fournier
  • Fonction : Auteur
Christine Maeder
  • Fonction : Auteur
Dobrochna Dolicka
  • Fonction : Auteur
Marta C. de Sousa
  • Fonction : Auteur
Alexander Adibekian
  • Fonction : Auteur
Michelangelo Foti
  • Fonction : Auteur

Résumé

Liver-derived circulating factors deeply affect the metabolism of distal organs. Herein, we took advantage of the hepatocyte-specific PTEN knockout mice (LPTENKO), a model of hepatic steatosis associated with increased muscle insulin sensitivity and decreased adiposity, to identify potential secreted hepatic factors improving metabolic homeostasis. Our results indicated that protein factors, rather than specific metabolites, released by PTEN-deficient hepatocytes trigger an improved muscle insulin sensitivity and a decreased adiposity in LPTENKO. In this regard, a proteomic analysis of conditioned media from PTEN-deficient primary hepatocytes identified seven hepatokines whose expression/secretion was deregulated. Distinct expression patterns of these hepatokines were observed in hepatic tissues from human/mouse with NAFLD. The expression of specific factors was regulated by the PTEN/PI3K, PPAR or AMPK signaling pathways and/or modulated by classical antidiabetic drugs. Finally, loss-of-function studies identified FGF21 and the triad AHSG, ANGPTL4 and LECT2 as key regulators of insulin sensitivity in muscle cells and in adipocytes biogenesis, respectively. These data indicate that hepatic PTEN deficiency and steatosis alter the expression/secretion of hepatokines regulating insulin sensitivity in muscles and the lipid metabolism in adipose tissue. These hepatokines could represent potential therapeutic targets to treat obesity and insulin resistance.
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hal-04520586 , version 1 (25-03-2024)

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Flavien Berthou, Cyril Sobolewski, Daniel Abegg, Margot Fournier, Christine Maeder, et al.. Hepatic PTEN Signaling Regulates Systemic Metabolic Homeostasis through Hepatokines-Mediated Liver-to-Peripheral Organs Crosstalk. International Journal of Molecular Sciences, 2022, International Journal of Molecular Sciences, 23, pp.39-59. ⟨10.3390/ijms23073959⟩. ⟨hal-04520586⟩

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