The insulin receptor translocates to the nucleus to regulate cell proliferation in liver

Amaya, Maria Jimena; Oliveira, André G.; Guimarães, Erika S.; Casteluber, Marisa C. F.; Carvalho, Sandhra M.; Andrade, Lídia M.; Pinto, Mauro Cunha Xavier; Mennone, Albert; Oliveira, Cleida A.; Resende, Rodrigo R.; Menezes, Gustavo B.; Nathanson, Michael H.; Leite, M. Fátima

doi:10.1002/hep.26609

Cited by 60 publications

(86 citation statements)

References 39 publications

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“…The mechanisms responsible for platelet uptake and translocation to the nucleus remain unknown but may resemble translocation of plasma membrane proteins such as epidermal growth factor receptors, the insulin receptor, and the HGF receptor cMet to the nucleus of the hepatocyte. [37][38][39] In conclusion, our combined results demonstrate that platelets stimulate hepatocyte proliferation in a mechanism that is, at least in part, dependent on platelet internalization by hepatocytes followed by transfer of RNA stored in the anucleate platelet. Although in vivo confirmation of this mechanism is required, these studies provide fundamentally new insights in the stimulatory effects of platelets on liver regeneration.…”

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confidence: 57%

Horizontal RNA transfer mediates platelet-induced hepatocyte proliferation

Kirschbaum¹,

Karimian²,

Adelmeijer³

et al. 2015

Blood

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Key Points• Platelets stimulate proliferation of HepG2 cells, which requires uptake of platelets by the HepG2 cell.• Platelets stimulate HepG2 cell proliferation in part by transfer of RNA from the anucleate platelet to the nucleated HepG2 cell.Liver regeneration is stimulated by blood platelets, but the molecular mechanisms involved are largely unexplored. Although platelets are anucleate, they do contain coding or regulatory RNAs that can be functional within the platelet or, after transfer, in other cell types. Here, we show that platelets and platelet-like particles (PLPs) derived from the megakaryoblastic cell line MEG-01 stimulate proliferation of HepG2 cells. Platelets or PLPs were internalized within 1 hour by HepG2 cells and accumulated in the perinuclear region of the hepatocyte. Platelet internalization also occurred following a partial hepatectomy in mice. Annexin A5 blocked platelet internalization and HepG2 proliferation. We labeled total RNA of MEG-01 cells by incorporation of 5-ethynyluridine (EU) and added EU-labeled PLPs to HepG2 cells. PLP-derived RNA was detected in the cytoplasm of the HepG2 cell. We next generated PLPs containing green fluorescent protein (GFP)-tagged actin messenger RNA. PLPs did not synthesize GFP, but in coculture with HepG2 cells, significant GFP protein synthesis was demonstrated. RNA-degrading enzymes partly blocked the stimulating effect of platelets on hepatocyte proliferation. Thus, platelets stimulate hepatocyte proliferation via a mechanism that is dependent on platelet internalization by hepatocytes followed by functional transfer of RNA stored in the anucleate platelet. This mechanism may contribute to platelet-mediated liver regeneration. (Blood. 2015;126(6):798-806) IntroductionBlood platelets have essential roles in hemostasis and thrombosis, inflammation, host defense, and wound healing. [1][2][3][4] Emerging evidence from recent in vitro and in vivo studies suggests that platelets have a pivotal role in liver regeneration. [5][6][7][8] In experimental animal models in which platelets were depleted or functionally impaired, liver regeneration after a partial liver resection was substantially delayed. 6 Conversely, following a partial liver resection in animals with a drug-induced thrombocytosis, liver regeneration was accelerated. 9,10 In a clinical study, we showed that a low platelet count is an independent predictor of delayed postoperative liver function recovery following a partial liver resection, suggesting that platelets stimulate liver regeneration also in humans. 11The molecular mechanisms of platelet-mediated stimulation of liver regeneration are largely unexplored. Platelets contain 2 distinct types of storage organelles: a granules and dense granules. The a granules contain, among many proteins, a number of growth factors that have an established role in liver regeneration (platelet-derived growth factor [PDGF], hepatocyte growth factor [HGF], insulin-like growth factor [IGF], and vascular endothelial growth factor [VEGF]). 8,12 In addition...

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mentioning

confidence: 57%

Horizontal RNA transfer mediates platelet-induced hepatocyte proliferation

Kirschbaum¹,

Karimian²,

Adelmeijer³

et al. 2015

Blood

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“…Good glycolytic activity and glycemic control in the perioperative period will help to ensure adequate liver regeneration [92,93] .…”

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confidence: 99%

Systemic hemodynamics in advanced cirrhosis: Concerns during perioperative period of liver transplantation

Hori

Ogura

Onishi

et al. 2016

WJH

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Advanced liver cirrhosis is usually accompanied by portal hypertension. Long-term portal hypertension results in various vascular alterations. The systemic hemodynamic state in patients with cirrhosis is termed a hyperdynamic state. This peculiar hemodynamic state is characterized by an expanded blood volume, high cardiac output, and low total peripheral resistance. Vascular alterations do not disappear even long after liver transplantation (LT), and recipients with cirrhosis exhibit a persistent systemic hyperdynamic state even after LT. Stability of optimal systemic hemodynamics is indispensable for adequate portal venous flow (PVF) and successful LT, and reliable parameters for optimal systemic hemodynamics and adequate PVF are required. Even a subtle disorder in systemic hemodynamics is precisely indicated by the balance between cardiac output and blood volume. The indocyanine green (ICG) kinetics reflect the patient's functional hepatocytes and effective PVF, and PVF is a major determinant of the ICG elimination Hori T et al . Peculiar hemodynamics in advanced cirrhosis constant (k ICG) in the well-preserved allograft. The k ICG value is useful to set the optimal PVF during living-donor LT and to evaluate adequate PVF after LT. Perioperative management has a large influence on the postoperative course and outcome; therefore, key points and unexpected pitfalls for intensive management are herein summarized. Transplant physicians should fully understand the peculiar systemic hemodynamic behavior in LT recipients with cirrhosis and recognize the critical importance of PVF after LT.

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“…Despite the hypoglycemic (and subsequent hypo-insulinemic) response by mice to PH, nuclear trafficking of the insulin receptor to hepatocellular nuclei in early regenerating liver was recently demonstrated and implicated as pro-regenerative [33]. Nevertheless, the specific mechanisms linking nuclear insulin signaling to liver regeneration require further characterization.…”

Section: Insulin Receptormentioning

confidence: 95%

Elucidating Metabolic and Epigenetic Mechanisms that Regulate Liver Regeneration

Huang

Rudnick

2015

Curr Pathobiol Rep

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The regenerative capability of the liver is essential for recovery from all hepatic injuries. Although long studied, the signals that regulate such regeneration require further elucidation if knowledge about regenerative mechanisms is to be translated into improved clinical therapy. Alterations in metabolism have been the focus of recent experimental investigations as a possible source of essential signals that control liver regeneration. Although the specific mechanisms linking metabolism and regeneration remain unknown, specific growth factors, secondary messengers, and transcription factors have been suggested by published analyses. Epigenetic mechanisms are also emerging as potential intermediaries between hepatic insufficiency-induced changes in metabolism and regenerative hepatocellular proliferation. This article reviews the recent literature relevant to these considerations, with particular emphasis on contemporary data that link metabolic and epigenetic signals to the regulation of liver regulation. The relevance of metabolic-epigenetic regulation of experimental hepatic regeneration with respect to human liver diseases is also briefly considered.

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The insulin receptor translocates to the nucleus to regulate cell proliferation in liver

Cited by 60 publications

References 39 publications

Horizontal RNA transfer mediates platelet-induced hepatocyte proliferation

Horizontal RNA transfer mediates platelet-induced hepatocyte proliferation

Systemic hemodynamics in advanced cirrhosis: Concerns during perioperative period of liver transplantation

Elucidating Metabolic and Epigenetic Mechanisms that Regulate Liver Regeneration

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