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Am J Physiol Gastrointest Liver Physiol. 2018 Jul 1;315(1):G80-G94. doi: 10.1152/ajpgi.00008.2018. Epub 2018 Feb 22.

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

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Brazilian Biosciences National Laboratory, Brazilian Center for Research in Energy and Materials , Campinas, Sao Paulo , Brazil.
Department of Physiology and Biophysics, Federal University of Minas Gerais , Belo Horizonte, Minas Gerais , Brazil.
Department of Molecular Medicine, Federal University of Minas Gerais , Belo Horizonte , Brazil.
Center for Gastrointestinal Biology, Federal University of Minas Gerais , Belo Horizonte, Minas Gerais , Brazil.
Department of Pathological Anatomy and Forensic Medicine, Federal University of Minas Gerais , Belo Horizonte , Brazil.
Lille Inflammation Research International Center-UMR995, INSERM, University of Lille , Lille , France.
Section of Digestive Diseases, Department of Internal Medicine, Yale University , New Haven, Connecticut.


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. NEW & NOTEWORTHY One of insulin's actions is to stimulate liver regeneration. Here we show that a subpopulation of insulin receptors is in a specialized cholesterol-enriched region of the cell membrane and this subfraction is important for insulin's proliferative effects.


calcium signaling; hepatocytes; insulin signaling; lipid rafts; liver regeneration

[Available on 2019-07-01]

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