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Stellate Cells

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Signaling Pathways in Liver Diseases

Abstract

Hepatic stellate cells (HSC) are located in the space of Disse in close contact with hepatocytes and sinusoidal endothelial cells. In human liver, HSC are disposed along the sinusoids with a nucleus-to-nucleus distance of 40 µm, indicating that the sinusoids are equipped with HSC at certain fixed distances [1]. These observations suggest that, although the total number of HSC constitutes a small percentage of the total number of liver cells (approximately 5–8%), their spatial disposition and extension may be sufficient to cover the entire hepatic sinusoidal microcirculatory network. This cell type has received much attention in the past two decades, the reason being its potential involvement in the fibrogenic transformation of liver tissue following chronic injury. Because of their anatomical location, ultrastructural features, and similarities with pericytes regulating blood flow in other organs, HSC have been proposed to function as liver-specific pericytes. Branches of the autonomic nerve fibers coursing through the space of Disse come in contact with HSC [2], and the nerve endings containing substance P and vasoactive intestinal peptide have been demonstrated in the vicinity of HSC [3]. Other peculiar features that suggest a functional relationship between the autonomic nervous system and HSC are the expression of N-CAM, a typical central nervous system adhesion molecule detected in hepatic nerves, and the expression of glial fibrillary acidic protein (GFAP) are restricted, among liver cell types, to HSC [4]. These observations, while reinforcing a potential functional relationship between the autonomic nervous system and HSC, raise a current key issue concerning the origin of this cell type, previously considered to be of myogenic origin owing to the expression of desmin and smooth muscle α-actin (α-SMA). Along these lines, activated HSC express nestin, a class VI intermediate filament protein originally identified as a marker for neural stem cells [5]. Remark­ably, the expression of this cell marker appears to be restricted to HSC and pericytes of brain parenchyma vessels, among all organ-specific pericytes. Adding to the intriguing features of these cells, ­quiescent stellate cells also express epimorphin, a mesenchymal morphogenic protein, which is increased after partial hepatectomy, coincident with a decline in stellate cell expression of α-SMA [6].

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Referen ces

  1. Wake K (1988) Liver perivascular cells revealed by gold and silver impregnation methods and electron microscopy. In: Motta P (ed) Biopathology of the liver, an ultrastructural approach. Kluwer, Dordrecht, pp 23–26

    Google Scholar 

  2. Lafon ME, Bioulac-Sage P, LeBail N (1989) Nerves and perisinusoidal cells in human liver. In: Wisse E, Knook DL, Decker K (eds) Cells of hepatic sinusoid. Kupffer Cell Foundation, Riswijk, pp 230–234

    Google Scholar 

  3. Ueno T, Inuzuka S, Torimura T et al (1991) Distribution of substance P and vasoactive intestinal peptide in the human liver: Light and electron immunoperoxidase methods of observation. Am J Gastroenterol 138:1233–1242

    Google Scholar 

  4. Knittel T, Aurisch S, Neubauer K et al (1996) Cell-type-specific expression of neural cell adhesion molecule (N-CAM) in Ito cells of rat liver. Am J Pathol 149:449–462

    PubMed  CAS  Google Scholar 

  5. Niki T, Pekny M, Hellemans K et al (1999) Class VI intermediate filament protein nestin is induced during activation of rat hepatic stellate cells. Hepatology 29:520–527

    Article  PubMed  CAS  Google Scholar 

  6. Yoshino R, Miura K, Segawa D et al (2006) Epimorphin expression and stellate cell status in mouse liver injury. Hepatol Res 34:238–249

    Article  PubMed  CAS  Google Scholar 

  7. Blomhoff R, Wake K (1991) Perisinusoidal stellate cells of the liver: important roles in retinol metabolism and fibrosis. FASEB J 5:271–277

    PubMed  CAS  Google Scholar 

  8. Cassiman D, Roskams T (2002) Beauty is in the eye of the beholder: emerging concepts and pitfalls in hepatic stellate cell research. J Hepatol 37:527–535

    Article  PubMed  Google Scholar 

  9. Schuppan D, Ruehl M, Somasundaram R, Hahn EG (2001) Matrix as a modulator of hepatic fibrogenesis. Semin Liver Dis 21:351–372

    Article  PubMed  CAS  Google Scholar 

  10. Friedman SL, Roll FJ, Boyles J et al (1989) Maintenance of differentiated phenotype of cultured rat hepatic lipocytes by basement membrane matrix. J Biol Chem 264:10756–10762

    PubMed  CAS  Google Scholar 

  11. Gaca MD, Zhou X, Issa R et al (2003) Basement membrane-like matrix inhibits proliferation and collagen synthesis by activated rat hepatic stellate cells: evidence for matrix-­dependent deactivation of stellate cells. Matrix Biol 22:229–239

    Article  PubMed  CAS  Google Scholar 

  12. Olaso E, Ikeda K, Eng FJ et al (2001) DDR2 receptor promotes MMP-2-mediated proliferation and invasion by hepatic stellate cells. J Clin Invest 108:1369–1378

    PubMed  CAS  Google Scholar 

  13. Friedman SL, Yamasaki G, Wong L (1994) Modulation of transforming growth factor beta receptors of rat lipocytes during the hepatic wound healing response. Enhanced binding and reduced gene expression accompany cellular activation in culture and in vivo. J Biol Chem 269:10551–10558

    PubMed  CAS  Google Scholar 

  14. Wells RG (2005) The role of matrix stiffness in hepatic stellate cell activation and liver fibrosis. J Clin Gastroenterol 39:S158–S161

    Article  Google Scholar 

  15. Pinzani M, Vizzutti F, Arena U, Marra F (2008) Technology Insight: noninvasive assessment of liver fibrosis by biochemical scores and elastography. Nat Clin Pract Gastroenterol Hepatol 5:95–106

    Article  PubMed  CAS  Google Scholar 

  16. Lim YS, Lee HC, Lee HS (2007) Switch of cadherin expression from Eto N-type during the activation of rat hepatic stellate cells. Histochem Cell Biol 127:149–160

    Article  PubMed  CAS  Google Scholar 

  17. Sicklick JK, Choi SS, Bustamante M et al (2006) Evidence for epithelialmesenchymal transitions in adult liver cells. Am J Physiol Gastrointest Liver Physiol 291:G575–G583

    Article  CAS  Google Scholar 

  18. Beaussier M, Wendum D, Schiffer E et al (2007) Prominent contribution of portal mesenchymal cells to liver fibrosis in ischemic and obstructive cholestatic injuries. Lab Invest 87:292–303

    Article  PubMed  CAS  Google Scholar 

  19. Friedman SL (2000) Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem 275:2247–2250

    Article  PubMed  CAS  Google Scholar 

  20. Pinzani M (2000) Liver fibrosis. Springer Semin Immu­nopathol 21:475–490

    Article  Google Scholar 

  21. Pinzani M, Gesualdo L, Sabbah GM, Abboud HE (1989) Effects of platelet-derived growth factor and other polypeptide mitogens on DNA synthesis and growth of cultured rat liver fat-storing cells. J Clin Invest 84:1786–1793

    Article  PubMed  CAS  Google Scholar 

  22. Pinzani M, Gentilini A, Caligiuri A et al (1995) Transforming growth factor-w1 regulates platelet-derived growth factor subunit in human liver fat-storing cells. Hepatology 21: 232–239

    PubMed  CAS  Google Scholar 

  23. Pinzani M, Milani S, DeFranco R et al (1996) Endothelin 1 is overexpressed in human cirrhotic liver and exerts multiple effects on activated hepatic stellate cells. Gastroenterology 110:534–548

    Article  PubMed  CAS  Google Scholar 

  24. Pinzani M, Milani S, Grappone C et al (1994) Expression of platelet-derived growth factor in a model of acute liver injury. Hepatology 19:701–707

    Article  PubMed  CAS  Google Scholar 

  25. Pinzani M, Milani S, Herbst H et al (1996) Expression of platelet-derived growth factor and its receptors in normal human liver and during active hepatic fibrogenesis. Am J Pathol 148:785–800

    PubMed  CAS  Google Scholar 

  26. Grappone C, Pinzani M, Parola M et al (1999) Expression of platelet-derived growth factor in newly formed cholangiocytes during experimental biliary fibrosis in rats. J Hepatol 31:100–109

    Article  PubMed  CAS  Google Scholar 

  27. Kinnman N, Hultcrantz R, Barbu V, Rey C, Wendum D, Poupon R, Housset C (2000) PDGF-mediated chemoattraction of hepatic stellate cells by bile duct segments in cholestatic liver injury. Lab Invest 80:697–707

    PubMed  CAS  Google Scholar 

  28. Kinnman N, Francoz C, Barbu V, Wendum D, Rey C, Hultcrantz R, Poupon R, Housset C (2003) The myofibroblastic conversion of peribiliary fibrogenic cells distinct from hepatic stellate cells is stimulated by platelet-derived growth factor during liver fibrogenesis. Lab Invest 83:163–173

    PubMed  CAS  Google Scholar 

  29. Li X, Eriksson U (2003) Novel PDGF family members: PDGF-C and PDGF-D. Cytokine Growth Factor Rev 14:91–98

    Article  PubMed  CAS  Google Scholar 

  30. Czochra P, Klopcic B, Meyer E et al (2006) Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice. J Hepatol 45:419–428

    Article  PubMed  CAS  Google Scholar 

  31. Claesson-Welsh L (1994) Platelet-derived receptor signals. J Biol Chem 269:32023–32026

    PubMed  CAS  Google Scholar 

  32. Cohen GB, Ren R, Baltimore D (1995) Modular binding domain in signal transduction proteins. Cell 80:237–248

    Article  PubMed  CAS  Google Scholar 

  33. Pawson T (1995) Protein modules and signalling networks. Nature 373:573–580

    Article  PubMed  CAS  Google Scholar 

  34. Marshall CJ (1994) MAP kinase kinase kinase, MAP kinase kinase and MAP kinase. Curr Opin Genet Dev 4:82–89

    Article  PubMed  CAS  Google Scholar 

  35. Marshall CJ (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80:179–185

    Article  PubMed  CAS  Google Scholar 

  36. Pages G, Lenormand P, L’Allemain G et al (1993) Mitogen-activated protein kinases p42MAPK and p44MAPK are required for fibroblast proliferation. Proc Natl Acad Sci U S A 90: 8319–8323

    Article  PubMed  CAS  Google Scholar 

  37. Marra F, Pinzani M, DeFranco R et al (1995) Involvement of phoshatidylinositol 3-kinase in the activation of extracellular signal-regulated kinase by PDGF in hepatic stellate cells. FEBS Lett 376:141–145

    Article  PubMed  CAS  Google Scholar 

  38. Marra F, Ghosh Choudhury G, Abboud HE (1996) Interferon-γ-mediated activation of STAT1α regulates growth factor-induced mitogenesis. J Clin Invest 98:1218–1230

    Article  PubMed  CAS  Google Scholar 

  39. Marra F, Arrighi MC, Fazi M et al (1999) ERK activation differentially regulates PDGF’s actions in hepatic stellate cells, and is induced by in vivo liver injury. Hepatology 30:951–958

    Article  PubMed  CAS  Google Scholar 

  40. Pinzani M, Marra F, Caligiuri A et al (1996) Inhibition by pentoxifylline of extracellular signal-regulated kinase activation by platelet-derived growth factor in hepatic stellate cells. Brit J Pharmacol 11:1117–1124

    Google Scholar 

  41. Mallat A, Gallois C, Tao J et al (1998) Platelet-derived growth factor-BB and thrombin generate positive and negative signals for human hepatic stellate cell proliferation. Role of a prostaglandin/cyclic AMP pathway and cross-talk with endothelin receptors. J Biol Chem 273: 27300–27305

    Article  PubMed  CAS  Google Scholar 

  42. Failli P, De Franco RM, Caligiuri A et al (2000) Nitrova­sodilators inhibit platelet-derived growth factor-induced proliferation and migration of activated human hepatic stellate cells. Gastroenterology 119:479–492

    Article  PubMed  CAS  Google Scholar 

  43. Mallat A, Preaux AM, Serradeil-Le Gal C et al (1996) Growth inhibitory properties of endothelin-1 in activated human hepatic stellate cells: a cyclic adenosine monophosphate-mediated pathway. Inhibition of both extracellular signal-regulated kinase and c-Jun kinase and upregulation of endothelin B receptors. J Clin Invest 98:2771–2778

    Article  PubMed  CAS  Google Scholar 

  44. Wu J, Dent P, Jelinek T et al (1993) Inhibition of the EGF-activated MAP kinase signalling pathway by adenosine 3′, 5′-monophosphate. Science 262:1065–1069

    Article  PubMed  CAS  Google Scholar 

  45. Graves LM, Bornfelt KE, Raines EW et al (1993) Protein kinase A antagonizes platelet-derived growth factor-induced signalling by mitogen-activated protein kinase in human arterial smooth muscle cells. Proc Natl Acad Sci U S A 90: 10300–10304

    Article  PubMed  CAS  Google Scholar 

  46. Kawada N, Uoya M, Seki S et al (1997) Regulation by cAMP of STAT1 activation in hepatic stellate cells. Biochem Biophys Res Comm 233:464–469

    Article  PubMed  CAS  Google Scholar 

  47. Valius M, Kazlaukas A (1993) Phospholipase C-γ and phosphatidylinositol 3-kinase are the downstream mediators of the PDGF receptor’s mitogenic signal. Cell 73:321–334

    Article  PubMed  CAS  Google Scholar 

  48. Kundra V, Escobedo JA, Kazlaukas A et al (1993) Regulation of chemotaxis by platelet-derived growth factor receptor β. Nature 367:474–476

    Article  Google Scholar 

  49. Marra F, Gentilini A, Pinzani M et al (1997) Phosphatidylinositol 3-kinase is required for platelet-derived growth factor’s actions on hepatic stellate cells. Gastroenterology 112: 1297–1306

    Article  PubMed  CAS  Google Scholar 

  50. Gentilini A, Marra F, Gentilini P, Pinzani M (2000) Phosph­atidylinositol-3 kinase and extracellular signal-­regulated kinase mediate the chemotactic and mitogenic effects of insulin-like growth factor-I in human hepatic stellate cells. J Hepatol 32:227–234

    Article  PubMed  CAS  Google Scholar 

  51. Datta SR, Brunet A, Greenberg ME (1999) Cellular survival: a play in three Akts. Genes Dev 13:2905–2927

    Article  PubMed  CAS  Google Scholar 

  52. Gerard C, Rollins BJ (2001) Chemokines and disease. Nat Immunol 2:108–115

    Article  PubMed  CAS  Google Scholar 

  53. Jones SM, Kazlauskas A (2001) Growth-factor-dependent mitogenesis requires two distinct phases of signalling. Nature Cell Biol 3:165–172

    Article  PubMed  CAS  Google Scholar 

  54. Jones SM, Klinghoffer R, Prestwich GD et al (1999) PDGF induces an early and late wave of PI 3-kinase activity, and only the late wave is required for progression trough G1. Curr Biol 9:512–521

    Article  PubMed  CAS  Google Scholar 

  55. Bonacchi A, Romagnani P, Romanelli RG et al (2001) Signal transduction by the chemokine receptor CXCR3. Activation of Ras/ERK, Src and PI 3-K/Akt controls cell migration and proliferation in human vascular pericytes. J Biol Chem 276:9945–9954

    Article  PubMed  CAS  Google Scholar 

  56. Pinzani M, Knauss TC, Pierce GF et al (1991) Mitogenic signals for platelet-derived growth factor isoforms in liver fat-storing cells. Am J Physiol 260:C485–C491

    Google Scholar 

  57. Rockey DC, Chung JJ (1994) Interferon γ inhibits lipocyte activation and extracellular matrix mRNA expression during experimental liver injury: implications for treatment of hepatic fibrosis. J Investig Med 42:660–670

    PubMed  CAS  Google Scholar 

  58. Wang Z, Estacion M, Mordan LJ (1993) Ca2+ influx via T-type channels modulates PDGF-induced replication of mouse fibroblasts. Am J Physiol 26:C1239–C1246

    Google Scholar 

  59. Ma H, Matsunaga H, Li B et al (1996) Ca2+ channel activation by platelet-derived growth factor-induced tyrosine phosphorylation and Ras guanine triphosphate-binding proteins in rat glomerular mesangial cells. J Clin Invest 97: 2332–2341

    Article  PubMed  CAS  Google Scholar 

  60. Carloni V, Pinzani M, Giusti S et al (2000) Tyrosine phosphorylation of focal adhesion kinase by PDGF is dependent on Ras in human hepatic stellate cells. Hepatology 31:131–140

    Article  PubMed  CAS  Google Scholar 

  61. Rombouts K, Lottini B, Caligiuri A et al (2008) MARCKS is a downstream effector in platelet-derived growth factor-induced cell motility in activated human hepatic stellate cells. Exp Cell Res 314:1444–1454

    Article  PubMed  CAS  Google Scholar 

  62. Di Sario A, Svegliati Baroni G, Bendia E et al (1997) Characterization of ion transport mechanisms regulating intracellular pH in hepatic stellate cells. Am J Physiol 273:G39–G48

    Google Scholar 

  63. Di Sario A, Bendia E, Svegliati Baroni G et al (1999) Intracellular pathways mediating Na+/H+ exchange activation by platelet-derived growth factor in rat hepatic stellate cells. Gastroenterology 116:1155–1166

    Article  PubMed  Google Scholar 

  64. Di Sario A, Svegliati Baroni G, Bendia E et al (2001) Intracellular pH regulation and Na+/H+ exchange activity in human hepatic stellate cells: effects of platelet-derived growth factor, insulin-like growth factor 1 and insulin. J Hepatol 34:378–385

    Article  PubMed  Google Scholar 

  65. Benedetti A, Di Sario A, Casini A et al (2001) Inhibition of the Na+/H+ exchanger reduces rat hepatic stellate cell activity and liver fibrosis: an in vitro and in vivo study. Gastroenterology 120:545–556

    Article  PubMed  CAS  Google Scholar 

  66. Caligiuri A, DeFranco RMS, Romanelli RG et al (2003) Antifibrogenic effects of canrenone, an antialdosteronic drug, on human hepatic stellate cells. Gastroenterology 124:504–520

    Article  PubMed  CAS  Google Scholar 

  67. Parola M, Robino G, Marra F et al (1998) HNE interacts directly with JNK isoforms in human hepatic stellate cells. J Clin Invest 102:1942–1950

    Article  PubMed  CAS  Google Scholar 

  68. Robino G, Parola M, Marra F et al (2000) Interaction between 4-hydroxy-2, 3-alkenals and the PDGF-β receptor. Reduced tyrosine phosphorylation and downstream signaling in hepatic stellate cells. J Biol Chem 275: 40561–40567

    Article  PubMed  CAS  Google Scholar 

  69. Rovida E, Navari N, Caligiuri A et al (2008) ERK5 differentially regulates PDGF-induced proliferation and migration of hepatic stellate cells. J Hepatol 48:107–115

    Article  PubMed  CAS  Google Scholar 

  70. Fibbi G, Pucci M, Grappone C et al (1999) Functions of the fibrinolytic system in human Ito cells and its control by basic fibroblast and platelet-derived growth factor. Hepatology 29:868–878

    Article  PubMed  CAS  Google Scholar 

  71. Napoli J, Prentice D, Niinami C et al (1997) Sequential increases in the intrahepatic expression of epidermal growth factor, basic fibroblast growth factor, and transforming growth factor β in a bile duct ligated rat model of cirrhosis. Hepatology 26:624–633

    PubMed  CAS  Google Scholar 

  72. Yu C, Wang F, Jin C et al (2003) Role of fibroblast growth factor type 1 and 2 in carbon tetrachloride-induced hepatic injury and fibrogenesis. Am J Pathol 163:1653–1662

    PubMed  CAS  Google Scholar 

  73. Delrieu I (2000) The high molecular weight isoforms of basic fibroblast growth factor (FGF-2): an insight into an intracrine mechanism. FEBS Lett 468:6–10

    Article  PubMed  CAS  Google Scholar 

  74. Ankoma-Sey V, Matli M, Chang KB et al (1998) Coordinated induction of VEGF receptors in mesenchymal cell types during rat hepatic wound healing. Oncogene 17:115–121

    Article  PubMed  CAS  Google Scholar 

  75. Mashiba S, Mochida S, Ishikawa K et al (1999) Inhibition of hepatic stellate cell contraction during activation in vitro by vascular endothelial growth factor in association with upregulation of FLT tyrosine kinase receptor family, FLT-1. Biochem Biophys Res Commun 258:674–678

    Article  PubMed  CAS  Google Scholar 

  76. Takahashi M, Matsui A, Inao M et al (2003) ERK/MAPK-dependent PI3K/Akt phosphorylation through VEGFR-1 after VEGF stimulation in activated hepatic stellate cells. Hepatol Res 26:232–236

    Article  PubMed  CAS  Google Scholar 

  77. Ankoma-Sey V, Wang Y, Dai Z (2000) Hypoxic stimulation of vascular endothelial growth factor expression in activated rat hepatic stellate cells. Hepatology 31:141–148

    Article  PubMed  CAS  Google Scholar 

  78. Corpechot C, Barbu V, Wendum D, Kinnman N, Rey C, Poupon R, Housset C, Rosmorduc O (2002) Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis. Hepatology 35:1010–1021

    Article  PubMed  CAS  Google Scholar 

  79. Castilla A, Prieto J, Fausto N (1991) Transforming growth factors β1 and α in chronic liver disease. Effects of interferon alfa therapy. N Engl J Med 324:933–940

    Article  PubMed  CAS  Google Scholar 

  80. Nakatsukasa H, Nagy P, Evarts RP et al (1990) Cellular distribution of transforming growth factor-β1 and procollagen types I, III, and IV transcripts in carbon tetrachloride-induced rat liver fibrosis. J Clin Invest 85:1833–1843

    Article  PubMed  CAS  Google Scholar 

  81. George J, Roulot D, Koteliansky VE, Bissell DM (1999) In vivo inhibition of rat stellate cell activation by soluble transforming growth factor β type II receptor: a potential new therapy for hepatic fibrosis. Proc Natl Acad Sci U S A 96:12719–12724

    Article  PubMed  CAS  Google Scholar 

  82. Sanderson N, Factor V, Nagy P et al (1995) Hepatic expression of mature transforming growth factor β1 in transgenic mice results in multiple tissue lesions. Proc Natl Acad Sci U S A 92:2572–2576

    Article  PubMed  CAS  Google Scholar 

  83. Friedman SL (1999) Cytokines and fibrogenesis. Semin Liver Dis 19:129–140

    Article  PubMed  CAS  Google Scholar 

  84. Roulot D, Sevcsik AM, Coste T et al (1999) Role of transforming growth factor β type II receptor in hepatic fibrosis: studies of human chronic hepatitis C and experimental fibrosis in rats. Hepatology 29:1730–1738

    Article  PubMed  CAS  Google Scholar 

  85. Dooley S, Delvoux B, Lahme B et al (2000) Modulation of transforming growth factor β response and signaling during transdifferentiation of rat hepatic stellate cells to myofibroblasts. Hepatology 31:1094–1106

    Article  PubMed  CAS  Google Scholar 

  86. Inoue T, Thomas JH (2000) Suppressors of transforming growth factor-β pathway mutants in the Caenorhabditis elegans dauer formation pathway. Genetics 156:1035–1046

    PubMed  CAS  Google Scholar 

  87. Inagaki Y, Truter S, Ramirez F (1994) Transforming growth factor-β stimulates alpha 2(I) collagen gene expression through a cis-acting element that contains an Sp1-binding site. J Biol Chem 269:14828–14834

    PubMed  CAS  Google Scholar 

  88. Inagaki Y, Nemoto T, Nakao A et al (2001) Interaction between GC box binding factors and Smad proteins modulates cell lineage-specific alpha 2(I) collagen gene transcription. J Biol Chem 276:16573–16579

    Article  PubMed  CAS  Google Scholar 

  89. Inagaki Y, Mamura M, Kanamaru Y et al (2001) Constitutive phosphorylation and nuclear localization of Smad3 are correlated with increased collagen gene transcription in activated hepatic stellate cells. J Cell Physiol 187:117–123

    Article  PubMed  CAS  Google Scholar 

  90. Dooley S, Hamzavi J, Breitkopf K et al (2003) Smad7 prevents activation of hepatic stellate cells and liver fibrosis in rats. Gastroenterology 125:178–191

    Article  PubMed  CAS  Google Scholar 

  91. Kopp J, Preis E, Said H et al (2005) Abrogation of transforming growth factor-β signaling by SMAD7 inhibits collagen gel contraction of human dermal fibroblasts. J Biol Chem 280:21570–21576

    Article  PubMed  CAS  Google Scholar 

  92. Kopp J, Seyhan H, Muller B et al (2006) N-acetyl-l-cysteine abrogates fibrogenic properties of fibroblasts isolated from Dupuytren’s disease by blunting TGF-β signalling. J Cell Mol Med 10:157–165

    Article  PubMed  CAS  Google Scholar 

  93. Ueno H, Sakamoto T, Nakamura T et al (2000) A soluble transforming growth factor β receptor expressed in muscle prevents liver fibrogenesis and dysfunction in rats. Hum Gene Ther 11:33–42

    Article  PubMed  CAS  Google Scholar 

  94. Weng H, Mertens PR, Gressner AM, Dooley S (2007) IFN-γ abrogates profibrogenic TGF-β signaling in liver by targeting expression of inhibitory and receptor Smads. J Hepatol 46:295–303

    Article  PubMed  CAS  Google Scholar 

  95. Zeisberg M, Hanai J, Sugimoto H et al (2003) BMP-7 counteracts TGF-β1-induced epithelial- to-mesenchymal transition and reverses chronic renal injury. Nat Med 9:964–968

    Article  PubMed  CAS  Google Scholar 

  96. Liu X, Hu H, Yin JQ (2006) Therapeutic strategies against TGF-β signaling pathway in hepatic fibrosis. Liver Int 26:8–22

    Article  PubMed  Google Scholar 

  97. Reimann T, Hempel U, Krautwald S et al (1997) Trans­forming growth factor-β1 induces activation of Ras, Raf-1, MEK and MAPK in rat hepatic stellate cells. FEBS Lett 403:57–60

    Article  PubMed  CAS  Google Scholar 

  98. Davis BH, Chen AP, Beno DWA (1996) Raf and mitogen-activated protein kinase regulate stellate cell collagen gene expression. J Biol Chem 271:11039–11042

    Article  PubMed  CAS  Google Scholar 

  99. Garcia-Trevijano ER, Iraburu MJ, Fontana L et al (1999) Transforming growth factor β1 induces the expression of alpha1(I) procollagen mRNA by a hydrogen peroxide-C/EBPβ-dependent mechanism in rat hepatic stellate cells. Hepatology 29:960–970

    Article  PubMed  CAS  Google Scholar 

  100. De Bleser PJ, Xu G, Rombouts K et al (1999) Glutathione levels discriminate between oxidative stress and transforming growth factor-β signaling in activated rat hepatic stellate cells. J Biol Chem 274:33881–33887

    Article  PubMed  Google Scholar 

  101. Sugiyama M, Ichida T, Sato T et al (1998) Expression of activin A is increased in cirrhotic and fibrotic rat livers. Gastroenterology 114:550–558

    Article  PubMed  CAS  Google Scholar 

  102. Marra F, Delogu W, Petrai I et al (2004) Differential requirement of members of the MAPK family for CCL2 expression by hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 287:G18–G26

    Article  Google Scholar 

  103. Patella S, Phillips DJ, Tchongue J et al (2006) Follistatin attenuates early liver fibrosis: effects on hepatic stellate cell activation and hepatocyte apoptosis. Am J Physiol Gastrointest Liver Physiol 290:G137–G144

    Article  CAS  Google Scholar 

  104. Brigstock DR (2003) The CCN family: a new stimulus package. J Endocrinol 178:169–175

    Article  PubMed  CAS  Google Scholar 

  105. Duncan MR, Frazier KS, Abramson S et al (1999) Connective tissue growth factor mediates transforming growth factor β-induced collagen synthesis: down-regulation by cAMP. FASEB J 13:1774–1786

    PubMed  CAS  Google Scholar 

  106. Gao R, Brigstock DR (2004) Connective tissue growth factor (CCN2) induces adhesion of rat activated hepatic stellate cells by binding of its C-terminal domain to integrin αv β3 and heparan sulphate proteoglycan. J Biol Chem 279:8848–8855

    Article  PubMed  CAS  Google Scholar 

  107. Grotendorst GR (1997) Connective tissue growth factor: a mediator of TGF-β action on fibroblasts. Cytokine Growth Factor Rev 8:171–179

    Article  PubMed  CAS  Google Scholar 

  108. Igarashi A, Nashiro K, Kikuchi K et al (1996) Connective tissue growth factor gene expression in tissue sections from localized scleroderma, keloid, other fibrotic skin disorders. J Invest Dermatol 106:729–733

    Article  PubMed  CAS  Google Scholar 

  109. Ito Y, Aten J, Bende RJ et al (1998) Expression of connective tissue growth factor in human renal fibrosis. Kidney Int 53:853–861

    Article  PubMed  CAS  Google Scholar 

  110. Ozaki S, Sato Y, Yasoshima M et al (2005) Diffuse expression of heparan sulfate proteoglycan and connective tissue growth factor in fibrous septa with many mast cells relate to unresolving hepatic fibrosis of congenital hepatic fibrosis. Liver Int 25:817–828

    Article  PubMed  CAS  Google Scholar 

  111. Rachfal AW, Brigstock DR (2003) Connective tissue growth factor (CTGF/CCN2) in hepatic fibrosis. Hepatol Res 26:1–9

    Article  PubMed  CAS  Google Scholar 

  112. Shin JY, Hur W, Wang JS et al (2005) HCV core protein promotes liver fibrogenesis via up-regulation of CTGF with TGF-β1. Exp Mol Med 37:138–145

    PubMed  CAS  Google Scholar 

  113. Paradis V, Perlemuter G, Bonvoust F et al (2001) High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology 34:738–744

    Article  PubMed  CAS  Google Scholar 

  114. Paradis V, Dargere D, Bonvoust F et al (2002) Effects and regulation of connective tissue growth factor on hepatic stellate cells. Lab Invest 82:767–774

    PubMed  CAS  Google Scholar 

  115. Gressner O, Lahme B, Gressner AM et al (2007) Differential effects of TGF-β on connective tissue growth factor expression in hepatic stellate cells and hepatocytes. J Hepatol 47:699–710

    Article  PubMed  CAS  Google Scholar 

  116. Simonson MS, Dunn MJ (1991) Endothelins: a family of regulatory peptides. Hypertension 17:856–863

    PubMed  CAS  Google Scholar 

  117. Simonson MS (1993) Endothelins: multifunctional renal peptides. Physiol Rev 73:375–411

    PubMed  CAS  Google Scholar 

  118. Yanagisawa M, Masaki T (1989) Endothelin, a novel endothelium-derived peptide. Biochem Pharmacol 38: 1877–1883

    Article  PubMed  CAS  Google Scholar 

  119. Gandhi CR, Stephenson K, Olson MS (1990) Endothelin, a potent peptide agonist in the liver. J Biol Chem 265: 17432–17435

    PubMed  CAS  Google Scholar 

  120. Gandhi CR, Behal RH, Harvey SA et al (1992) Hepatic effects of endothelin. Receptor characterization and endothelin-induced signal transduction in hepatocytes. Biochem J 287:897–904

    PubMed  CAS  Google Scholar 

  121. Roden M, Vierhapper H, Liener K, Waldhausl W (1992) Endothelin-1- stimulated glucose production in vitro in the isolated perfused rat liver. Metabolism 41:290–295

    Article  PubMed  CAS  Google Scholar 

  122. Thran-Thi T-A, Kawada N, Decker K (1993) Regulation of endothelin-1 action on the perfused rat liver. FEBS Lett 318:353–357

    Article  Google Scholar 

  123. Serradeil-Le Gal C, Jouneaux C, Sanchez-Bueno A et al (1991) Endothelin action in rat liver. Receptors, free Ca2+ oscillations, and activation of glycogenolysis. J Clin Invest 87:133–138

    Article  PubMed  CAS  Google Scholar 

  124. Rieder H, Ramadori G, Meyer zum Buschenfelde KH (1991) Sinusoidal endothelial liver cells in vitro release endothelin: augmentation by transforming growth factor ß and Kupffer cell-conditioned media. Klin Wochenschr 69:387–391

    Article  PubMed  CAS  Google Scholar 

  125. Furoya S, Naruse S, Nakayama T, Nokihara K (1992) Binding of 125I- endothelin-1 to fat-storing cells in rat liver revealed by electron microscopic radioautography. Anat Embryol 185:97–100

    Article  Google Scholar 

  126. Gondo K, Ueno T, Masaharu S et al (1993) The ­endothelin-1 binding site in rat liver tissue: light- and electron-microscopic autoradiographic studies. Gastroenterology 104: 1745–1749

    PubMed  CAS  Google Scholar 

  127. Housset CN, Rockey DC, Bissel DM (1993) Endotelin receptors in rat liver: lipocytes as a contractile target for endothelin 1. Proc Natl Acad Sci U S A 90:9266–9270

    Article  PubMed  CAS  Google Scholar 

  128. Rockey DC, Fouassier L, Chung JJ et al (1998) Cellular localization of endothelin-1 and increased production in liver injury in the rat: potential for autocrine and paracrine effects on stellate cells. Hepatology 27:472–480

    Article  PubMed  CAS  Google Scholar 

  129. Shao R, Yan W, Rockey DC (1999) Regulation of ­endothelin-1 synthesis by endothelin-converting enzyme-1 during wound healing. J Biol Chem 274:3228–3234

    Article  PubMed  CAS  Google Scholar 

  130. Shao R, Shi Z, Gotwals PJ et al (2003) Cell and molecular regulation of endothelin-1 production during hepatic wound healing. Mol Biol Cell 14:2327–2341

    Article  PubMed  CAS  Google Scholar 

  131. Chi X, Anselmi K, Watkins S, Gandhi CR (2003) Prevention of cultured rat stellate cell transformation and endothelin-B receptor upregulation by retinoic. Br J Pharmacol 139: 765–774

    Article  PubMed  CAS  Google Scholar 

  132. Reinehr RM, Kubitz R, Peters-Regehr T et al (1998) Activation of rat hepatic stellate cells in culture is associated with increased sensitivity to endothelin 1. Hepatology 28:1566–1577

    Article  PubMed  CAS  Google Scholar 

  133. Wang YZ, Pouyssegur J, Dunn MJ (1994) Endothelin stimulates mitogen-activated protein kinase activity in mesangial cells through ET(A). J Am Soc Nephrol 5: 1074–1080

    PubMed  CAS  Google Scholar 

  134. Mallat A, Fouassier F, Preaux AM et al (1995) Growth inhibitory properties of endothelin-1 in human hepatic myofibroblastic Ito cells: an endothelin B receptor-­mediated pathway. J Clin Invest 96:42–49

    Article  PubMed  CAS  Google Scholar 

  135. Reinehr R, Fischer R, Haussinger D (2002) Regulation of endothelin-A receptor sensitivity by cyclic adenosine monophosphate in rat hepatic stellate cells. Hepatology 36:861–873

    PubMed  CAS  Google Scholar 

  136. Bataller R, Gines P, Nicolas JM et al (2000) Angiotensin II induces contraction and proliferation of human hepatic stellate cells. Gastroenterology 118:1149–1156

    Article  PubMed  CAS  Google Scholar 

  137. Pinzani M, Failli P, Ruocco C et al (1992) Fat-storing cells as liver-specific pericytes: spatial dynamics of ­agonist-stimulated intracellular calcium transients. J Clin Invest 90:642–646

    Article  PubMed  CAS  Google Scholar 

  138. Bataller R, Gabele E, Schoonhoven R et al (2003) Prolonged infusion of angiotensin II into normal rats induces stellate cell activation and proinflammatory events in liver. Am J Physiol Gastrointest Liver Physiol 285: G642–G651

    Google Scholar 

  139. Bataller R, Schwabe RF, Choi YH et al (2003) NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. J Clin Invest 112:1383–1394

    PubMed  CAS  Google Scholar 

  140. De Minicis S, Brenner DA (2007) NOX in liver fibrosis. Arch Biochem Biophys 462:266–272

    Article  PubMed  CAS  Google Scholar 

  141. Choi SS, Sicklick JK, Ma Q et al (2006) Sustained activation of Rac1 in hepatic stellate cells promotes liver injury and fibrosis in mice. Hepatology 44:1267–1277

    Article  PubMed  CAS  Google Scholar 

  142. Jonsson JR, Clouston AD, Ando Y et al (2001) Angiotensin-converting enzyme inhibition attenuates the progression of rat hepatic fibrosis. Gastroenterology 121:148–155

    Article  PubMed  CAS  Google Scholar 

  143. Ramalho LN, Ramalho FS, Zucoloto S et al (2002) Effect of losartan, an angiotensin II antagonist, on secondary biliary cirrhosis. Hepatogastroenterology 49:1499–1502

    PubMed  CAS  Google Scholar 

  144. Wei HS, Li DG, Lu HM, Zhan YT et al (2000) Effects of AT1 receptor antagonist, losartan, on rat hepatic fibrosis induced by CCl4. World J Gastroenterol 6:540–545

    PubMed  CAS  Google Scholar 

  145. Rimola A, Londono MC, Guevara G et al (2004) Beneficial effect of angiotensin-blocking agents on graft fibrosis in hepatitis C recurrence after liver transplantation. Transplan­tation 78:686–691

    Article  PubMed  CAS  Google Scholar 

  146. Bataller R, Nicolas JM, Gines P et al (1997) Arginine vasopressin induces contraction and stimulates growth of cultured human hepatic stellate cells. Gastroenterology 113: 615–624

    Article  PubMed  CAS  Google Scholar 

  147. Coughlin SR (2000) Thrombin signalling and protease-activated receptors. Nature 407:258–264

    Article  PubMed  CAS  Google Scholar 

  148. Marra F, Grandaliano G, Valente AJ, Abboud HE (1995) Thrombin stimulates proliferation of liver fat-storing cells and expression of monocyte chemotactic protein-1: potential role in liver injury. Hepatology 22:780–787

    PubMed  CAS  Google Scholar 

  149. Marra F, DeFranco R, Grappone C et al (1998) Expression of the thrombin receptor in human liver: up-regulation during acute and chronic injury. Hepatology 27:462–471

    Article  PubMed  CAS  Google Scholar 

  150. Pinzani M, Carloni V, Marra F et al (1994) Biosynthesis of platelet-activating factor and its 1O-acyl analogue by liver fat-storing cells. Gastroenterology 106:1301–1311

    PubMed  CAS  Google Scholar 

  151. Titos E, Claria J, Bataller R et al (2000) Hepatocyte-derived cysteinyl leukotrienes modulate vascular tone in experimental cirrhosis. Gastroenterology 119:794–805

    Article  PubMed  CAS  Google Scholar 

  152. Goulis J, Patch D, Burroughs AK (1999) Bacterial infection in the pathogenesis of variceal bleeding. Lancet 353: 139–142

    Article  PubMed  CAS  Google Scholar 

  153. Rossi D, Zlotnik A (2000) The biology of chemokines and their receptors. Annu Rev Immunol 18:217–242

    Article  PubMed  CAS  Google Scholar 

  154. Marra F (1999) Hepatic stellate cells and the regulation of liver inflammation. J Hepatol 31:1120–1130

    Article  PubMed  CAS  Google Scholar 

  155. Romagnani P, Beltrame C, Annunziato F et al (1999) Role for interactions between IP-10/Mig and CXCR3 in proliferative glomerulonephritis. J Am Soc Nephrol 10:2518–2526

    PubMed  CAS  Google Scholar 

  156. Schweickart VL, Epp A, Raport CJ, Gray PW (2000) CCR11 is a functional receptor for the monocyte chemoattractant protein family of chemokines. J Biol Chem 275: 9550–9556

    Article  PubMed  CAS  Google Scholar 

  157. Bonacchi A, Petrai I, DeFranco RMS et al (2003) The chemokine CCL21 modulates lymphocyte recruitment and fibrosis in chronic hepatitis C. Gastroenterology 125: 1060–1076

    Article  PubMed  CAS  Google Scholar 

  158. Schwabe RF, Bataller R, Brenner DA (2003) Human hepatic stellate cells express CCR5 and RANTES to induce proliferation and migration. Am J Physiol Gastrointest Liver Physiol 285:G949–G958

    Google Scholar 

  159. Ashkenazi A, Dixit VM (1998) Death receptors: signaling and modulation. Science 281:1305–1308

    Article  PubMed  CAS  Google Scholar 

  160. Ledgerwood EC, Pober JS, Bradley JR (1999) Recent advances in the molecular basis of TNF signal tranduction. Lab Invest 79:1041–1050

    PubMed  CAS  Google Scholar 

  161. Rothe J, Lesslauer W, Loetscher H et al (1993) Mice lacking the tumour necrosis factor receptor-1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria Monocytogenes. Nature 364:798–802

    Article  PubMed  CAS  Google Scholar 

  162. Knittel T, Muller L, Saile B, Ramadori G (1997) Effect of tumour necrosis factor-α on proliferation, activation and protein synthesis of rat hepatic stellate cells. J Hepatol 27:1067–1080

    Article  PubMed  CAS  Google Scholar 

  163. Armendariz-Borunda J, Katayama K, Seyer JM (1992) Transcriptional mechanisms of type I collagen gene expression are differentially regulated by interleukin-1β, tumor necrosis factor α, and transforming growth factor β in Ito cells. J Biol Chem 267:14316–14321

    PubMed  CAS  Google Scholar 

  164. Gallois C, Habib A, Tao J et al (1998) Role of NF-κB in the antiproliferative effect of endothelin-1 and tumor necrosis factor-α in human hepatic stellate cells. Involvement of cyclooxygenase-2. J Biol Chem 273:23183–23190

    Article  PubMed  CAS  Google Scholar 

  165. Hellerbrand C, Jobin C, Licato LL et al (1998) Cytokines induce NF-κB in activated but not in quiescent rat hepatic stellate cells. Am J Physiol 275:G269–G278

    Google Scholar 

  166. Efsen E, Pastacaldi S, Bonacchi A et al (2001) Agonist-specific regulation of monocyte chemoattractant protein-1 expression by cyclo-oxygenase metabolites in hepatic stellate cells. Hepatology 33:713–721

    Article  PubMed  CAS  Google Scholar 

  167. Elsharkawy AM, Wright MC, Hay RT et al (1999) Persistent activation of nuclear factor-κB in cultured rat hepatic stellate cells involves the induction of potentially novel Rel-like factors and prolonged changes in the expression of IκB family proteins. Hepatology 30:761–769

    Article  PubMed  CAS  Google Scholar 

  168. Beg A, Sha W, Bronson R et al (1995) Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-κB. Nature 376:167–170

    Article  PubMed  CAS  Google Scholar 

  169. Lang A, Schoonhoven R, Tuvia S et al (2000) Nuclear factor κB in proliferation, activation, and apoptosis in rat hepatic stellate cells. J Hepatol 33:49–58

    Article  PubMed  CAS  Google Scholar 

  170. Saile B, Matthes N, Knittel T, Ramadori G (1999) Transforming growth factor β and tumor necrosis factor α inhibit both apoptosis and proliferation of activated rat hepatic stellate cells. Hepatology 30:196–202

    Article  PubMed  CAS  Google Scholar 

  171. Reeves HL, Dack CL, Peak M et al (2000) Stress-activated protein kinases in the activation of rat hepatic stellate cells in culture. J Hepatol 32:465–472

    Article  PubMed  CAS  Google Scholar 

  172. Poulos JE, Weber JD, Bellezzo JM et al (1997) Fibronectin and cytokines increase JNK, ERK, AP-1 activity, and transin gene expression in rat hepatic stellate cells. Am J Physiol 273:G804–G811

    Google Scholar 

  173. Hernandez-Munoz I, De la Torre P, Sanchez-Alcazar JA et al (1997) Tumor necrosis factor α inhibits collagen alpha 1(I) gene expression in rat hepatic stellate cells through a G protein. Gastroenterology 113:625–640

    Article  PubMed  CAS  Google Scholar 

  174. Hernandez I, de la Torre P, Rey-Campos J et al (2000) Collagen alpha1(I) gene contains an element responsive to tumor necrosis factor-α located in the 5′ untranslated region of its first exon. DNA Cell Biol 19:341–352

    Article  PubMed  CAS  Google Scholar 

  175. Houglum K, Buck M, Kim DJ, Chojkier M (1998) TNF-α inhibits liver collagen-alpha 1(I) gene expression through a tissue-specific regulatory region. Am J Physiol 274: G840–G847

    Google Scholar 

  176. Iraburu MJ, Dominguez-Rosales JA, Fontana L et al (2000) Tumor necrosis factor α down-regulates expression of the alpha1(I) collagen gene in rat hepatic stellate cells through a p20C/EBPβ- and C/EBPδ-dependent mechanism. Hepa­tology 31:1086–1093

    Article  PubMed  CAS  Google Scholar 

  177. Galli A, Crabb D, Price D et al (2000) Peroxisome proliferator-activated receptor γ transcriptional regulation is involved in platelet-derived growth factor-induced proliferation of human hepatic stellate cells. Hepatology 31: 101–108

    Article  PubMed  CAS  Google Scholar 

  178. Marra F, Efsen E, Romanelli RG et al (2000) Ligands of peroxisome proliferator-activated receptor γ modulate profibrogenic and proinflammatory actions in hepatic stellate cells. Gastroenterology 119:466–478

    Article  PubMed  CAS  Google Scholar 

  179. Miyahara T, Schrum L, Rippe R et al (2000) Peroxisome proliferator-activated receptors and hepatic stellate cell activation. J Biol Chem 275:35715–35722

    Article  PubMed  CAS  Google Scholar 

  180. Sung CK, She H, Xiong S, Tsukamoto H (2004) Tumor necrosis factor α inhibits peroxisome proliferator-activated receptor γ activity at a post-translational level in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 286:G722–G729

    Article  Google Scholar 

  181. Saile B, Knittel T, Matthes N et al (1997) CD95/CD95L-mediated apoptosis of the hepatic stellate cell. A mechanism terminating uncontrolled hepatic stellate cell proliferation during hepatic tissue repair. Am J Pathol 151: 1265–1272

    PubMed  CAS  Google Scholar 

  182. Gong W, Pecci A, Roth S et al (1998) Transformation-dependent susceptibility of rat hepatic stellate cells to apoptosis induced by soluble Fas ligand. Hepatology 28: 492–502

    Article  PubMed  CAS  Google Scholar 

  183. Taimr P, Higuchi H, Kocova E et al (2003) Activated stellate cells express the TRAIL receptor-2/death receptor-5 and undergo TRAIL-mediated apoptosis. Hepatology 37: 87–95

    Article  PubMed  CAS  Google Scholar 

  184. Trim N, Morgan S, Evans M et al (2000) Hepatic stellate cells express the low affinity nerve growth factor receptor p75 and undergo apoptosis in response to nerve growth factor stimulation. Am J Pathol 156:1235–1243

    PubMed  CAS  Google Scholar 

  185. Cassiman D, Denef C, Desmet VJ, Roskams T (2001) Human and rat hepatic stellate cells express neurotrophins and neurotrophin receptors. Hepatology 33:148–158

    Article  PubMed  CAS  Google Scholar 

  186. Ulven SM, Natarajan V, Holven KB et al (1998) Expression of retinoic acid receptor and retinoid X receptor subtypes in rat liver cells: implications for retinoid signalling in parenchymal, endothelial, Kupffer and stellate cells. Eur J Cell Biol 77:111–116

    PubMed  CAS  Google Scholar 

  187. Friedman SL, Wei S, Blaner WS (1993) Retinol release by activated rat hepatic lipocytes: regulation by Kupffer ­cell-conditioned medium and PDGF. Am J Physiol Gas­trointest Liver Physiol 264:G947–G952

    Google Scholar 

  188. Weiner FR, Blaner WS, Czaja MJ et al (1992) Ito cell expression of a nuclear retinoic acid receptor. Hepatology 15:336–342

    Article  PubMed  CAS  Google Scholar 

  189. Vogel S, Piantedosi R, Frank J et al (2000) An immortalized rat liver stellate cell line (HSC-T6): a new cell model for the study of retinoid metabolism in vitro. J Lipid Res 41:882–893

    PubMed  CAS  Google Scholar 

  190. Wang L, Tankersley LR, Tang M et al (2002) Regulation of the murine alpha(2)(I) collagen promoter by retinoic acid and retinoid X receptors. Arch Biochem Biophys 401: 262–270

    Article  PubMed  CAS  Google Scholar 

  191. Hellemans K, Verbuyst P, Quartier E et al (2004) Differential modulation of rat hepatic stellate phenotype by natural and synthetic retinoids. Hepatology 39:97–108

    Article  PubMed  CAS  Google Scholar 

  192. Imai S, Okuno M, Moriwaki H et al (1997) 9, 13-di-cis-Retinoic acid induces the production of tPA and activation of latent TGFβ via RARα in a human liver stellate cell line, LI90. FEBS Lett 411:102–106

    Article  PubMed  CAS  Google Scholar 

  193. Evans RM, Barish GD, Wang YX (2004) PPARs and the complex journey to obesity. Nat Med 10:355–361

    Article  PubMed  CAS  Google Scholar 

  194. Galli A, Crabb D, Price D et al (2000) Peroxisome proliferator-activated receptor γ transcriptional regulation is involved in platelet-derived growth factor induced proliferation of human hepatic stellate cells. Hepatology 31:101–108

    Article  PubMed  CAS  Google Scholar 

  195. Marra F, Efsen E, Romanelli RG et al (2000) Ligands of peroxisome proliferator-activated receptor γ modulate profibrogenic and proinflammatory actions in hepatic stellate cells. Gastroenterology 119:466–478

    Article  PubMed  CAS  Google Scholar 

  196. Bruck R, Weiss S, Aeed H et al (2009) Additive inhibitory effect of experimentally induced hepatic cirrhosis by agonists of peroxisome proliferator activator receptor γ and retinoic acid receptor. Dig Dis Sci 54:292–299

    Article  PubMed  CAS  Google Scholar 

  197. Guo YT, Leng XS, Li T et al (2005) Effect of ligand of peroxisome proliferator-activated receptor γ on the biological characters of hepatic stellate cells. World J Gastroenterol 11:4735–4739

    PubMed  CAS  Google Scholar 

  198. Yavrom S, Chen L, Xiong S et al (2005) Peroxisome ­proliferator-activated receptor γ suppresses proximal alpha1(I) collagen promoter via inhibition of p300-facilitated NF-I binding to DNA in hepatic stellate cells. J Biol Chem 280:40650–40659

    Article  PubMed  CAS  Google Scholar 

  199. Cheng Y, Ping J, Xu LM (2007) Effects of curcumin on peroxisome proliferator-activated receptor γ expression and nuclear translocation/redistribution in culture-activated rat hepatic stellate cells. Chin Med J (Engl) 120:794–801

    CAS  Google Scholar 

  200. Planaguma A, Claria J, Miquel R et al (2005) The selective cyclooxygenase- 2 inhibitor SC-236 reduces liver fibrosis by mechanisms involving non-parenchymal cell apoptosis and PPARγ activation. FASEB J 19:1120–1122

    PubMed  CAS  Google Scholar 

  201. Miyahara T, Schrum L, Rippe R et al (2000) Peroxisome proliferator-activated receptors and hepatic stellate cell activation. J Biol Chem 275:35715–35722

    Article  PubMed  CAS  Google Scholar 

  202. Zhao C, Chen W, Yang L et al (2006) PPARγ agonists prevent TGFβ1/Smad3-signaling in human hepatic stellate cells. Biochem Biophys Res Commun 350:385–391

    Article  PubMed  CAS  Google Scholar 

  203. Galambos JT, Hollingsworth MA, Falek A et al (1977) The rate of synthesis of glycosaminoglycans and collagen by fibroblasts cultured from adult human liver biopsies. J Clin Invest 60:107–114

    Article  PubMed  CAS  Google Scholar 

  204. Kawaguchi K, Sakaida I, Tsuchiya M et al (2004) Pioglitazone prevents hepatic steatosis, fibrosis, enzyme altered lesions in rat liver cirrhosis induced by a choline-deficient l-amino acid-defined diet. Biochem Biophys Res Commun 315:187–195

    Article  PubMed  CAS  Google Scholar 

  205. Tomita K, Azuma T, Kitamura N et al (2004) Pioglitazone prevents alcohol-induced fatty liver in rats through up-­regulation of c-Met. Gastroenterology 126:873–885

    Article  PubMed  CAS  Google Scholar 

  206. Belfort R, Harrison SA, Brown K et al (2006) A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med 355:2297–2307

    Article  PubMed  CAS  Google Scholar 

  207. Neuschwander-Tetri BA, Brunt EM, Wehmeier KR et al (2003) Interim results of a pilot study demonstrating the early effects of the PPAR-γ ligand rosiglitazone on insulin sensitivity, aminotransferases, hepatic steatosis and body weight in patients with nonalcoholic steatohepatitis. J Hepatol 38:434–440

    Article  PubMed  CAS  Google Scholar 

  208. Promrat K, Lutchman G, Uwaifo GI et al (2004) A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology 39:188–196

    Article  PubMed  CAS  Google Scholar 

  209. Everett L, Galli A, Crabb D (2000) The role of hepatic peroxisome proliferator-activated receptors (PPARs) in health and disease. Liver 20:191–199

    Article  PubMed  CAS  Google Scholar 

  210. Lee CH, Olson P, Hevener A et al (2006) PPARδ regulates glucose metabolism and insulin sensitivity. Proc Natl Acad Sci U S A 103:3444–3449

    Article  PubMed  CAS  Google Scholar 

  211. Hellemans K, Michalik L, Dittie A et al (2003) Peroxisome proliferator-activated receptor-β signaling contributes to enhanced proliferation of hepatic stellate cells. Gastro­enterology 124:184–201

    Article  PubMed  CAS  Google Scholar 

  212. Hellemans K, Rombouts K, Quartier E et al (2003) PPARβ regulates vitamin A metabolism-related gene expression in hepatic stellate cells undergoing activation. J Lipid Res 44: 280–295

    Article  PubMed  CAS  Google Scholar 

  213. Tsukamoto H, She H, Hazra S, Cheng J, Miyahara T (2006) Anti-adipogenic regulation underlies hepatic stellate cell transdifferentiation. J Gastroenterol Hepatol 21: S102–S105

    Article  CAS  Google Scholar 

  214. Fiorucci S, Antonelli E, Rizzo G et al (2004) The nuclear receptor SHP mediates inhibition of hepatic stellate cells by FXR and protects against liver fibrosis. Gastroenterology 127:1497–1512

    Article  PubMed  CAS  Google Scholar 

  215. Stedman C, Liddle C, Coulter S et al (2006) Benefit of farnesoid X receptor inhibition in obstructive cholestasis. Proc Natl Acad Sci U S A 103:11323–11328

    Article  PubMed  CAS  Google Scholar 

  216. Fiorucci S, Rizzo G, Antonelli E et al (2005) A farnesoid X receptor-small heterodimer partner regulatory cascade modulates tissue metalloproteinase inhibitor-1 and matrix metalloprotease expression in hepatic stellate cells and promotes resolution of liver fibrosis. J Pharmacol Exp Ther 314:584–595

    Article  PubMed  CAS  Google Scholar 

  217. Haughton EL, Tucker SJ, Marek CJ et al (2006) Pregnane X receptor activators inhibit human hepatic stellate cell transdifferentiation in vitro. Gastroenterology 131:194–209

    Article  PubMed  CAS  Google Scholar 

  218. Liu QH, Li DG, Huang X et al (2004) Suppressive effects of 17β-estradiol on hepatic fibrosis in CCl4-induced rat model. World J Gastroenterol 10:1315–1320

    PubMed  CAS  Google Scholar 

  219. Shimizu I (2003) Impact of oestrogens on the progression of liver disease. Liver Int 23:63–69

    Article  PubMed  CAS  Google Scholar 

  220. Xu JW, Gong J, Chang XM et al (2002) Estrogen reduces CCL(4)-induced liver fibrosis in rats. World J Gastroenterol 8:883–887

    PubMed  CAS  Google Scholar 

  221. Yasuda M, Shimizu I, Shiba M et al (1999) Suppressive effects of estradiol on dimethylnitrosamine-induced fibrosis of the liver in rats. Hepatology 29:719–727

    Article  PubMed  CAS  Google Scholar 

  222. Bissell DM (1999) Sex and hepatic fibrosis. Hepatology 29:988–989

    Article  PubMed  CAS  Google Scholar 

  223. Di Martino V, Lebray P, Myers RP et al (2004) Progression of liver fibrosis in women infected with hepatitis C: long-term benefit of estrogen exposure. Hepatology 40:1426–1433

    Article  PubMed  CAS  Google Scholar 

  224. Wang YJ, Wang SS, Bickel M et al (1998) Two novel antifibrotics, HOE 077 and Safironil, modulate stellate cell activation in rat liver injury: differential effects in males and females. Am J Pathol 152:279–287

    PubMed  CAS  Google Scholar 

  225. Lissoos TW, Beno DW, Davis BH (1993) 1, 25-Dihydroxyvi­tamin D3 activates Raf kinase and Raf perinuclear translocation via a protein kinase C-dependent pathway. J Biol Chem 268:25132–25138

    PubMed  CAS  Google Scholar 

  226. Raddatz D, Henneken M, Armbrust T et al (1996) Sub­cellular distribution of glucocorticoid receptor in cultured rat and human liver-derived cells and cell lines: influence of dexamethasone. Hepatology 24:928–933

    Article  PubMed  CAS  Google Scholar 

  227. Wickert L, Abiaka M, Bolkenius U, Gressner AM (2004) Corticosteroids stimulate selectively transforming growth factor (TGF)-β receptor type III expression in transdifferentiating hepatic stellate cells. J Hepatol 40:69–76

    Article  PubMed  CAS  Google Scholar 

  228. Beaven SW, Tontonoz P (2006) Nuclear receptors in lipid metabolism: targeting the heart of dyslipidemia. Annu Rev Med 57:313–329

    Article  PubMed  CAS  Google Scholar 

  229. Tsukamoto H, She H, Hazra S et al (2006) Antiadipogenic regulation underlies hepatic stellate cell transdifferentiation. J Gastroenterol Hepatol 21(3):S102–S105

    Article  CAS  Google Scholar 

  230. Matsuoka M, Pham NT, Tsukamoto H (1989) Differential effects of interleukin-1α, tumor necrosis factor α, and transforming growth factor β1 on cell proliferation and collagen formation by cultured fat-storing cells. Liver 9: 71–78

    PubMed  CAS  Google Scholar 

  231. Mancini R, Benedetti A, Jezequel AM (1994) An interleukin-1 receptor antagonist decreases fibrosis induced by dimethylnitrosamine in rat liver. Virchows Arch 424:25–31

    Article  PubMed  CAS  Google Scholar 

  232. Darnell JE Jr (1997) STATs and gene regulation. Science 277:1630–1633

    Article  PubMed  CAS  Google Scholar 

  233. Mallat A, Preaux AM, Blazejewski S et al (1995) Interferon alfa and γ inhibit proliferation and collagen synthesis of human Ito cells in culture. Hepatology 21:1003–1010

    Article  PubMed  CAS  Google Scholar 

  234. Ramadori G, Knittel T, Odenthal M et al (1992) Synthesis of cellular fibronectin by rat liver fat-storing (Ito) cells: regulation by cytokines. Gastroenterology 103:1313–1321

    PubMed  CAS  Google Scholar 

  235. Rockey DC, Chung JJ (1995) Inducible nitric oxide synthase in rat hepatic lipocytes and the effect of nitric oxide on lipocyte contractility. J Clin Invest 95:1199–1206

    Article  PubMed  CAS  Google Scholar 

  236. Gressner AM, Althaus M (1990) Effects of murine recombinant interferon-γ on rat liver fat storing cell proliferation, cluster formation and proteoglycan synthesis. Biochem Pharmacol 40:1953–1962

    Article  PubMed  CAS  Google Scholar 

  237. Greenwel P, Iraburu MJ, Reyes-Romero M et al (1995) Induction of an acute phase response in rats stimulates the expression of alpha1(I) procollagen messenger ribonucleic acid in their livers. Possible role of interleukin-6. Lab Invest 72:83–91

    PubMed  CAS  Google Scholar 

  238. Levy MT, Trojanowska M, Reuben A (2000) Oncostatin M: a cytokine upregulated in human cirrhosis, increases collagen production by human hepatic stellate cells. J Hepatol 32:218–226

    Article  PubMed  CAS  Google Scholar 

  239. Wang SC, Ohata M, Schrum L et al (1998) Expression of interleukin-10 by in vitro and in vivo activated hepatic stellate cells. J Biol Chem 273:302–308

    Article  PubMed  CAS  Google Scholar 

  240. Mathurin P, Xiong S, Kharbanda KK et al (2002) IL-10 receptor and coreceptor expression in quiescent and activated hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 282:G981–G990

    Google Scholar 

  241. Dranoff JA, Ogawa M, Kruglov EA et al (2004) Expression of P2Y nucleotide receptors and ectonucleotidases in quiescent and activated rat hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 287:G417–G424

    Article  Google Scholar 

  242. Kruglov E, Correa P, Arora G et al (2007) Molecular basis for calcium signaling in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 292:G975–G982

    Article  CAS  Google Scholar 

  243. Takemura S, Kawada N, Hirohashi K et al (1994) Nucleotide receptors in hepatic stellate cells of the rat. FEBS Lett 354:53–56

    Article  PubMed  CAS  Google Scholar 

  244. Hashmi AZ, Hakim W, Kruglov EA et al (2007) Adenosine inhibits cytosolic calcium signals and chemotaxis in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 292:G395–G401

    Article  CAS  Google Scholar 

  245. Chan ES, Montesinos MC, Fernandez P et al (2006) Adenosine A(2A) receptors play a role in the pathogenesis of hepatic cirrhosis. Br J Pharmacol 148:1144–1155

    Article  PubMed  CAS  Google Scholar 

  246. Ruhl CE, Everhart JE (2005) Coffee and tea consum­ption are associated with a lower incidence of chronic liver ­disease in the United States. Gastroenterology 129: 1928–1936

    Article  PubMed  Google Scholar 

  247. Marra F (2007) Leptin and liver tissue repair: do rodent models provide the answers? J Hepatol 46:12–18

    Article  PubMed  CAS  Google Scholar 

  248. Cao Q, Mak KM, Ren C, Lieber CS (2004) Leptin stimulates tissue inhibitor of metalloproteinase-1 in human hepatic stellate cells: respective roles of the JAK/STAT and JAK-mediated H2O2-dependent MAPK pathways. J Biol Chem 279:4292–4304

    Article  PubMed  CAS  Google Scholar 

  249. Wolf AM, Wolf D, Avila MA et al (2006) Up-regulation of the anti-inflammatory adipokine adiponectin in acute liver failure in mice. J Hepatol 44:537–543

    Article  PubMed  CAS  Google Scholar 

  250. Chuang JH, Wang PW, Tai MH (2004) An adipocentric view of liver fibrosis and cirrhosis. Chang Gung Med J 27:855–868

    PubMed  Google Scholar 

  251. Ding X, Saxena NK, Lin S et al (2005) The roles of leptin and adiponectin: a novel paradigm in adipocytokine regulation of liver fibrosis and stellate cell biology. Am J Pathol 166:1655–1669

    PubMed  CAS  Google Scholar 

  252. Kamada Y, Tamura S, Kiso S et al (2003) Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin. Gastroenterology 125:1796–1807

    Article  PubMed  CAS  Google Scholar 

  253. Marra F, Aleffi S, Bertolani C et al (2005) Adipokines and liver fibrosis. Eur Rev Med Pharmacol Sci 9:279–284

    PubMed  CAS  Google Scholar 

  254. Caligiuri A, Bertolani C, Guerra CT et al (2008) Adenosine monophosphate-activated protein kinase modulates the activated phenotype of hepatic stellate cells. Hepatology 47:668–676

    Article  PubMed  CAS  Google Scholar 

  255. Steppan CM, Bailey ST, Bhat S et al (2001) The hormone resistin links obesity to diabetes. Nature 409:307–312

    Article  PubMed  CAS  Google Scholar 

  256. Savage DB, Sewter CP, Klenk ES et al (2001) Resistin/Fizz3 expression in relation to obesity and peroxisome proliferator-activated receptor-γ action in humans. Diabetes 50:2199–2202

    Article  PubMed  CAS  Google Scholar 

  257. Patel L, Buckels AC, Kinghorn IJ et al (2003) Resistin is expressed in human macrophages and directly regulated by PPAR γ activators. Biochem Biophys Res Commun 300: 472–476

    Article  PubMed  CAS  Google Scholar 

  258. Bertolani C, Sancho-Bru P, Failli P et al (2006) Resistin as an intrahepatic cytokine: overexpression during chronic injury and induction of proinflammatory actions in hepatic stellate cells. Am J Pathol 169:2042–2053

    Article  PubMed  CAS  Google Scholar 

  259. Hynes RO (2002) Integrins: bidirectional allosteric signaling machines. Cell 110:673–687

    Article  PubMed  CAS  Google Scholar 

  260. Calderwood DA, Shattil SJ, Ginsberg MH (2000) Integrin and actin filaments: reciprocal regulation of cell adhesion and signaling. J Biol Chem 277:21749–21758

    Article  CAS  Google Scholar 

  261. Carloni V, Romanelli RG, Pinzani M et al (1997) Focal adhesion kinase and phospholipase Cγ involvement in adhesion and migration of human hepatic stellate cells. Gastroenterology 112:522–531

    Article  PubMed  CAS  Google Scholar 

  262. Schaller MD, Parsons JT (1993) Focal adhesion kinase: an integrin-linked protein tyrosine kinase. Trends Cell Biol 3:258–262

    Article  PubMed  CAS  Google Scholar 

  263. Schaller MD, Otey CA, Hildebrand JD, Parsons JT (1995) Focal adhesion kinase and paxillin bind to peptides mimicking β integrin cytoplasmic domains. J Cell Biol 130: 1181–1187

    Article  PubMed  CAS  Google Scholar 

  264. Carloni V, Defranco RM, Caligiuri A et al (2002) Cell adhesion regulates platelet-derived growth factor-induced MAP kinase and PI-3 kinase activation in stellate cells. Hepatology 36:582–591

    Article  PubMed  CAS  Google Scholar 

  265. Huang S, Ingber DE (1999) The structural and mechanical complexity of cell-growth control. Nat Cell Biol 1: E131–E138

    Article  CAS  Google Scholar 

  266. Robert F, Schwabe RF, Seki E et al (2006) Toll-like receptor signaling in the liver. Gastroenterology 130:1886–1900

    Article  CAS  Google Scholar 

  267. Paik YH, Schwabe RF, Bataller R et al (2003) Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology 37:1043–1055

    Article  PubMed  CAS  Google Scholar 

  268. Brun P, Castagliuolo I, Pinzani M et al (2005) Exposure to bacterial cell wall products triggers an inflammatory phenotype in hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol 289:G571–G578

    Article  CAS  Google Scholar 

  269. Thirunavukkarasu C, Uemura T, Wang LF et al (2005) Normal rat hepatic stellate cells respond to endotoxin in LBP-independent manner to produce inhibitor(s) of DNA synthesis in hepatocytes. J Cell Physiol 204:654–665

    Article  PubMed  CAS  Google Scholar 

  270. Seki E, De Minicis S, Osterreicher CH et al (2007) TLR4 enhances TGF-β signaling and hepatic fibrosis. Nat Med 13:1324–1332

    Article  PubMed  CAS  Google Scholar 

  271. Huang H, Shiffman ML, Friedman S et al (2007) A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C. Hepatology 46: 297–306

    Article  PubMed  CAS  Google Scholar 

  272. Paik YH, Lee KS, Lee HJ et al (2006) Hepatic stellate cells primed with cytokines upregulate inflammation in response to peptidoglycan or lipoteichoic acid. Lab Invest 86: 676–686

    Article  PubMed  CAS  Google Scholar 

  273. Dolganiuc A, Oak S, Kodys K et al (2004) Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation. Gastroenterology 127:1513–1524

    Article  PubMed  CAS  Google Scholar 

  274. Bataller R, Paik YH, Lindquist JN et al (2004) Hepatitis C virus core and nonstructural proteins induce fibrogenic effects in hepatic stellate cells. Gastroenterology 126: 529–540

    Article  PubMed  CAS  Google Scholar 

  275. Watanabe A, Hashmi A, Gomes DA et al (2007) Apoptotic hepatocyte DNA inhibits hepatic stellate cell chemotaxis via toll-like receptor 9. Hepatology 46:1509–1518

    Article  PubMed  CAS  Google Scholar 

  276. Jeong WI, Park O, Radaeva S et al (2006) STAT1 inhibits liver fibrosis in mice by inhibiting stellate cell prolifera­tion and stimulating NK cell cytotoxicity. Hepatology 44: 1441–1451

    Article  PubMed  CAS  Google Scholar 

  277. Jeong WI, Park O, Gao B (2008) Abrogation of the antifibrotic effects of natural killer cells/interferon-γ contributes to alcohol acceleration of liver fibrosis. Gastroenterology 134:248–258

    Article  PubMed  CAS  Google Scholar 

  278. Julien B, Grenard P, Teixeira-Clerc F et al (2005) Antifibrogenic role of the cannabinoid receptor CB2 in the liver. Gastroenterology 128:742–755

    Article  PubMed  CAS  Google Scholar 

  279. Teixeira-Clerc F, Julien B, Grenard P et al (2006) CB1 cannabinoid receptor antagonism: a new strategy for the treatment of liver fibrosis. Nat Med 12:671–676

    Article  PubMed  CAS  Google Scholar 

  280. Siegmund SV, Uchinami H, Osawa Y et al (2005) Anandamide induces necrosis in primary hepatic stellate cells. Hepatology 41:1085–1095

    Article  PubMed  CAS  Google Scholar 

  281. Siegmund SV, Seki E, Osawa Y et al (2006) Fatty acid amide hydrolase determines anandamideinduced cell death in the liver. J Biol Chem 281:10431–10438

    Article  PubMed  CAS  Google Scholar 

  282. Siegmund SV, Qian T, de Minicis S et al (2007) The endocannabinoid 2-arachidonoyl glycerol induces death of hepatic stellate cells via mitochondrial reactive oxygen species. FASEB J 21:2798–2806

    Article  PubMed  CAS  Google Scholar 

  283. Taipale J, Beachy PA (2001) The Hedgehog and Wnt signalling pathways in cancer. Nature 411:349–354

    Article  PubMed  CAS  Google Scholar 

  284. Lees C, Howie S, Sartor RB, Satsangi J (2005) The hedgehog­ signalling pathway in the gastrointestinal tract: implications­ for development, homeostasis, disease. Gastro­enterology 129:1696–1710

    Article  PubMed  CAS  Google Scholar 

  285. Sicklick JK, Li YX, Choi SS et al (2005) Role for hedgehog signaling in hepatic stellate cell activation and viability. Lab Invest 85:1368–1380

    Article  PubMed  CAS  Google Scholar 

  286. Yang L, Wang Y, Mao H et al (2008) Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells. J Hepatol 48:98–106

    Article  PubMed  CAS  Google Scholar 

  287. Omenetti A, Yang L, Li YX et al (2007) Hedgehog-mediated mesenchymal–epithelial interactions modulate hepatic response to bile duct ligation. Lab Invest 87: 499–514

    PubMed  CAS  Google Scholar 

  288. Omenetti A, Porrello A, Jung Y et al (2008) Hedgehog signaling regulates epithelial-mesenchymal transition during biliary fibrosis in rodents and humans. J Clin Invest 118:3331–3342

    PubMed  CAS  Google Scholar 

  289. Kordes C, Sawitza I, Muller-Marbach A et al (2007) CD133(α) hepatic stellate cells are progenitor cells. Biochem Biophys Res Commun 352:410–417

    Article  PubMed  CAS  Google Scholar 

  290. Hayflick L, Moorhead PS (1961) The serial cultivation of human diploid cell strains. Exp Cell Res 25:585–621

    Article  Google Scholar 

  291. Campisi J, d’Adda di Fagagna F (2007) Cellular senescence: when bad things happen to good cells. Nat Rev Mol Cell Biol 8:729–740

    Article  PubMed  CAS  Google Scholar 

  292. Serrano M, Lin AW, McCurrach ME et al (1997) Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88:593–602

    Article  PubMed  CAS  Google Scholar 

  293. Wiemann SU, Satyanarayana A, Tsahuridu M et al (2002) Hepatocyte telomere shortening and senescence are ­general markers of human liver cirrhosis. FASEB J 16: 935–942

    Article  PubMed  CAS  Google Scholar 

  294. Krizhanovsky V, Yon M, Dickins RA et al (2008) Senes­cence of activated stellate cells limits liver fibrosis. Cell 134:657–667

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Dipartimento di Medicina Interna, Università di Firenze, Viale Morgagni, 85, 50134, Firenze, Italy

    Fabio Marra, Sara Galastri, Sara Aleffi & Massimo Pinzani

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  1. Fabio Marra
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  2. Sara Galastri
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  3. Sara Aleffi
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  4. Massimo Pinzani
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Correspondence to Fabio Marra .

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  1. Inselspital, Universität Bern, Murtenstr. 35, Bern, 3010, Switzerland

    Jean-Francois Dufour

  2. Klinik für Viszeral- und, Universitätsspital Zürich, Rämistr. 100, Zürich, 8091, Switzerland

    Pierre-Alain Clavien

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Marra, F., Galastri, S., Aleffi, S., Pinzani, M. (2010). Stellate Cells. In: Dufour, JF., Clavien, PA. (eds) Signaling Pathways in Liver Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-00150-5_3

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