Regulation of Hepatic Stellate Cells by Extracellular Nucleotides

Summary

Principal Investigator: JONATHAN DRANOFF
Affiliation: Yale University
Country: USA
Abstract: DESCRIPTION (provided by applicant): Fibrogenesis, or scar formation, occurs as a response to injury in almost all organs. Liver fibrosis and subsequent cirrhosis remains a critical health problem in the United States and worldwide despite advances in therapy of chronic liver disease. Hepatic stellate cells (HSC) are the primary fibrogenic cells of the liver. Although there have been important advances in the understanding of HSC function in recent years, critical signaling mechanisms regulating HSC activity have not been completely understood. P2Y receptors are G protein coupled receptors for extracellular ATP and other nucleotides. P2Y receptors induce downstream cellular effects through inositol triphosphate (IP3)-mediated calcium signals. Recently, we reported that HSC express P2Y receptors, and that activation of these receptors induces fibrogenesis in HSC. We have now observed that HSC express IP3 receptors (IP3R) at distinct regions within HSC: the nucleus and cell extensions. This unique pattern of IP3R expression allows for distinct effects of P2Y receptor activation mediated by these two cellular compartments. We have also observed that blockade of P2Y receptors in the whole animal may prevent development of liver fibrosis, suggesting that signaling via P2Y receptors is an important mediator of liver fibrosis in disease states. Thus we propose that P2Y receptor activation induces liver fibrosis via multiple downstream effects in distinct subcellular compartments within HSC. We will test this hypothesis through the following three Specific Aims: 1. Determine the effects of P2Y receptor activation on the function of HSC in the nucleus. 2. Determine the effects of P2Y receptor activation on the function of HSC in cell extensions. 3. Identify whether blockade of P2Y receptors inhibits liver fibrosis. We believe that the results of the proposed experiments will lead to novel understanding of HSC function and may ultimately lead to the development of new pharmacologic approaches to the treatment of liver fibrosis. Public Health Relevance: Advanced liver fibrosis, leading to cirrhosis, is the most important cause of liver failure, leading to death in the absence of liver transplantation. Multiple therapeutic approaches have been proposed to prevent or reverse liver fibrosis;however, these have been stymied due to incomplete understanding of the basic mechanisms of liver fibrosis. In the proposed work, we will identify novel pathways that are important in the pathogenesis of liver fibrosis, which should in turn lead to new approaches to prevent or liver fibrosis in patients.
Funding Period: ----------------2008 - ---------------2013-
more information: NIH RePORT

Top Publications

  1. pmc Pathological changes in pulmonary circulation in carbon tetrachloride (CCl4)-induced cirrhotic mice
    Mita Das
    Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
    PLoS ONE 9:e96043. 2014
  2. pmc Advances in cholangiocyte immunobiology
    Gaurav Syal
    Division of Gastroenterology and Hepatology, Univ of Arkansas for Medical Sciences, Little Rock AR 72223, USA
    Am J Physiol Gastrointest Liver Physiol 303:G1077-86. 2012
  3. pmc Activated hepatic stellate cells upregulate transcription of ecto-5'-nucleotidase/CD73 via specific SP1 and SMAD promoter elements
    Michel Fausther
    Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
    Am J Physiol Gastrointest Liver Physiol 303:G904-14. 2012
  4. pmc Intracellular calcium signals regulate growth of hepatic stellate cells via specific effects on cell cycle progression
    Elwy M Soliman
    Yale University School of Medicine, Department of Internal Medicine, Section of Digestive Diseases and Yale Liver Center, 333 Cedar St LMP 1080, New Haven, CT 06515, USA
    Cell Calcium 45:284-92. 2009
  5. pmc Adenosine induces loss of actin stress fibers and inhibits contraction in hepatic stellate cells via Rho inhibition
    Muhammad A Sohail
    Section of Digestive Diseases, Yale University, New Haven, CT 06520 8019, USA
    Hepatology 49:185-94. 2009

Detail Information

Publications10

  1. pmc Pathological changes in pulmonary circulation in carbon tetrachloride (CCl4)-induced cirrhotic mice
    Mita Das
    Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America
    PLoS ONE 9:e96043. 2014
    ..Lack of an experimental model of portopulmonary hypertension (POPH) has been a major obstacle in understanding of pathophysiological mechanisms underlying the disease...
  2. pmc Advances in cholangiocyte immunobiology
    Gaurav Syal
    Division of Gastroenterology and Hepatology, Univ of Arkansas for Medical Sciences, Little Rock AR 72223, USA
    Am J Physiol Gastrointest Liver Physiol 303:G1077-86. 2012
    ..Finally, because cholangiocytes release mediators critical to myofibroblastic differentiation of portal fibroblasts and hepatic stellate cells, cholangiocytes may be essential in the pathogenesis of biliary cirrhosis...
  3. pmc Activated hepatic stellate cells upregulate transcription of ecto-5'-nucleotidase/CD73 via specific SP1 and SMAD promoter elements
    Michel Fausther
    Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA
    Am J Physiol Gastrointest Liver Physiol 303:G904-14. 2012
    ..The ecto-5'-nucleotidase/CD73 enzyme is a novel cellular marker of activated liver myofibroblasts in vivo and in vitro and thus represents a promising molecular target for antifibrotic therapies in liver diseases...
  4. pmc Intracellular calcium signals regulate growth of hepatic stellate cells via specific effects on cell cycle progression
    Elwy M Soliman
    Yale University School of Medicine, Department of Internal Medicine, Section of Digestive Diseases and Yale Liver Center, 333 Cedar St LMP 1080, New Haven, CT 06515, USA
    Cell Calcium 45:284-92. 2009
    ..These data provide a new logical target for pharmacological therapy directed against progression of liver fibrosis...
  5. pmc Adenosine induces loss of actin stress fibers and inhibits contraction in hepatic stellate cells via Rho inhibition
    Muhammad A Sohail
    Section of Digestive Diseases, Yale University, New Haven, CT 06520 8019, USA
    Hepatology 49:185-94. 2009
    ..We propose that adenosine is a physiological inhibitor of the Rho pathway in HSCs with functional consequences, including loss of HSC contraction...