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Article Dans Une Revue American journal of physiology. Gastrointestinal and liver physiology Année : 2018

Cholesterol-enriched membrane microdomains are needed for insulin signaling and proliferation in hepatic cells.

Castro Fonseca Matheus De
  • Fonction : Auteur
Andressa Franca
  • Fonction : Auteur
Machado Florentino Rodrigo
  • Fonction : Auteur
Cristelli Fonseca Roberta
  • Fonction : Auteur
Carlos Melo Antonio
  • Fonction : Auteur
Vieira Vidigal Paula Teixeira
  • Fonction : Auteur
G Oliveira Andre
  • Fonction : Auteur
H Nathanson Michael
  • Fonction : Auteur
Fatima Leite M
  • Fonction : Auteur

Résumé

Hepatocyte proliferation during liver regeneration is a well-coordinated process regulated by the activation of several growth factor receptors, including the insulin receptor (IR). The IR can be localized in part to cholesterol-enriched membrane microdomains, but the role of such domains in insulin-mediated events in hepatocytes is not known. We investigated whether partitioning of IRs into cholesterol-enriched membrane rafts is important for the mitogenic effects of insulin in the hepatic cells. IR and lipid rafts were labeled in HepG2 cells and primary rat hepatocytes. Membrane cholesterol was depleted in vitro with metyl-β-cyclodextrin (MβCD) and in vivo with lovastatin. Insulin-induced calcium (Ca2+) signals studies were examined in HepG2 cells and in freshly isolated rat hepatocytes as well as in whole liver in vivo by intravital confocal imaging. Liver regeneration was studied by 70% partial hepatectomy (PH), and hepatocyte proliferation was assessed by PCNA staining. A subpopulation of IR was found in membrane microdomains enriched in cholesterol. Depletion of cholesterol from plasma membrane resulted in redistribution of the IR along the cells, which was associated with impaired insulin-induced nuclear Ca2+ signals, a signaling event that regulates hepatocyte proliferation. Cholesterol depletion also led to ERK1/2 hyper-phosphorylation. Lovastatin administration to rats decreased hepatic cholesterol content, disrupted lipid rafts and decreased insulin-induced Ca2+ signaling in hepatocytes, and delayed liver regeneration after PH. Therefore, membrane cholesterol content and lipid rafts integrity showed to be important for the proliferative effects of insulin in hepatic cells.

Dates et versions

hal-04318088 , version 1 (01-12-2023)

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Citer

Castro Fonseca Matheus De, Andressa Franca, Machado Florentino Rodrigo, Cristelli Fonseca Roberta, Carlos Melo Antonio, et al.. Cholesterol-enriched membrane microdomains are needed for insulin signaling and proliferation in hepatic cells.. American journal of physiology. Gastrointestinal and liver physiology, 2018, American journal of physiology. Gastrointestinal and liver physiology, 315, pp.G80-G94. ⟨10.1152/ajpgi.00008.2018⟩. ⟨hal-04318088⟩

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