Early to Phase II drugs currently under investigation for the treatment of liver fibrosis

Bibliography

• Schuppan D, Afdhal NH. Liver cirrhosis. Lancet 2008;371(9615):838-51
   PubMed Web of Science ®Google Scholar
• Hernandez-Gea V, Friedman SL. Pathogenesis of liver fibrosis. Annu Rev Pathol 2011;6:425-56
   PubMed Web of Science ®Google Scholar
• Kim WR, Brown RSJr, Terrault NA, et al. Burden of liver disease in the United States: summary of a workshop. Hepatology 2002;36(1):227-42
   PubMed Web of Science ®Google Scholar
• Manos MM, Leyden WA, Murphy RC, et al. Limitations of conventionally derived chronic liver disease mortality rates: results of a comprehensive assessment. Hepatology 2008;47(4):1150-7
   PubMed Web of Science ®Google Scholar
• Lim YS, Kim WR. The global impact of hepatic fibrosis and end-stage liver disease. Clin Liver Dis 2008;12(4):733-46, vii
   PubMed Web of Science ®Google Scholar
• Ratib S, West J, Crooks CJ, et al. Diagnosis of liver cirrhosis in England, a cohort study, 1998-2009: a comparison with cancer. Am J Gastroenterol 2014;109(2):190-8
   PubMed Web of Science ®Google Scholar
• Asrani SK, Larson JJ, Yawn B, et al. Underestimation of liver-related mortality in the United States. Gastroenterology 2013;145(2):375-82; e1-2
   PubMed Web of Science ®Google Scholar
• Blachier M, Leleu H, Peck-Radosavljevic M, et al. The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol 2013;58(3):593-608
   PubMed Web of Science ®Google Scholar
• Kerr WC, Fillmore KM, Marvy P. Beverage-specific alcohol consumption and cirrhosis mortality in a group of English-speaking beer-drinking countries. Addiction 2000;95(3):339-46
   PubMed Web of Science ®Google Scholar
• Cheung O, Sanyal AJ. Recent advances in nonalcoholic fatty liver disease. Curr Opin Gastroenterol 2009;25(3):230-7
   PubMed Web of Science ®Google Scholar
• Williams CD, Stengel J, Asike MI, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 2011;140(1):124-31
   PubMed Web of Science ®Google Scholar
• Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004;40(6):1387-95
   PubMed Web of Science ®Google Scholar
• Chitturi S, Wong VW, Farrell G. Nonalcoholic fatty liver in Asia: firmly entrenched and rapidly gaining ground. J Gastroenterol Hepatol 2011;26(Suppl 1):163-72
   PubMedGoogle Scholar
• Farrell GC, Wong VW, Chitturi S. NAFLD in Asia – as common and important as in the West. Nat Rev Gastroenterol Hepatol 2013;10(5):307-18
   PubMed Web of Science ®Google Scholar
• Friedman SL. Evolving challenges in hepatic fibrosis. Nat Rev Gastroenterol Hepatol 2010;7(8):425-36
   PubMed Web of Science ®Google Scholar
• Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology 2008;134(6):1655-69
   PubMed Web of Science ®Google Scholar
• Jiao J, Friedman SL, Aloman C. Hepatic fibrosis. Curr Opin Gastroenterol 2009;25(3):223-9
   PubMed Web of Science ®Google Scholar
• Parola M, Pinzani M. Hepatic wound repair. Fibrogenesis Tissue Repair 2009;2(1):4
   PubMedGoogle Scholar
• Forbes SJ, Parola M. Liver fibrogenic cells. Best Pract Res Clin Gastroenterol 2011;25(2):207-17
   PubMed Web of Science ®Google Scholar
• Cassiman D, Libbrecht L, Desmet V, et al. Hepatic stellate cell/myofibroblast subpopulations in fibrotic human and rat livers. J Hepatol 2002;36(2):200-9
   PubMed Web of Science ®Google Scholar
• Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 2008;88(1):125-72
   PubMed Web of Science ®Google Scholar
• Wells RG. The portal fibroblast: not just a poor man’s stellate cell. Gastroenterology 2014;147(1):41-7
   PubMed Web of Science ®Google Scholar
• Zeisberg M, Yang C, Martino M, et al. Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem 2007;282(32):23337-47
   PubMed Web of Science ®Google Scholar
• Miyata E, Masuya M, Yoshida S, et al. Hematopoietic origin of hepatic stellate cells in the adult liver. Blood 2008;111(4):2427-35
   PubMed Web of Science ®Google Scholar
• Russo FP, Alison MR, Bigger BW, et al. The bone marrow functionally contributes to liver fibrosis. Gastroenterology 2006;130(6):1807-21
   PubMed Web of Science ®Google Scholar
• Forbes SJ, Russo FP, Rey V, et al. A significant proportion of myofibroblasts are of bone marrow origin in human liver fibrosis. Gastroenterology 2004;126(4):955-63
   PubMed Web of Science ®Google Scholar
• Schuppan D, Ruehl M, Somasundaram R, et al. Matrix as a modulator of hepatic fibrogenesis. Semin Liver Dis 2001;21(3):351-72
   PubMed Web of Science ®Google Scholar
• Schaffner F, Poper H. Capillarization of hepatic sinusoids in man. Gastroenterology 1963;44:239-42
   PubMed Web of Science ®Google Scholar
• Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005;115(2):209-18
   PubMed Web of Science ®Google Scholar
• Seki E, Schwabe RF. Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology 2014. 10.1002/hep.27332
   Web of Science ®Google Scholar
• Muddu AK, Guha IN, Elsharkawy AM, et al. Resolving fibrosis in the diseased liver: translating the scientific promise to the clinic. Int J Biochem Cell Biol 2007;39(4):695-714
   PubMed Web of Science ®Google Scholar
• Gressner AM, Weiskirchen R, Breitkopf K, et al. Roles of TGF-beta in hepatic fibrosis. Front Biosci 2002;7:d793-807
   PubMed Web of Science ®Google Scholar
• Bissell DM, Roulot D, George J. Transforming growth factor beta and the liver. Hepatology 2001;34(5):859-67
   PubMed Web of Science ®Google Scholar
• Inagaki Y, Okazaki I. Emerging insights into transforming growth factor beta Smad signal in hepatic fibrogenesis. Gut 2007;56(2):284-92
   PubMed Web of Science ®Google Scholar
• Miura K, Kodama Y, Inokuchi S, et al. Toll-like receptor 9 promotes steatohepatitis by induction of interleukin-1beta in mice. Gastroenterology 2010;139(1):323-34; e7
   PubMed Web of Science ®Google Scholar
• Gieling RG, Wallace K, Han YP. Interleukin-1 participates in the progression from liver injury to fibrosis. Am J Physiol Gastrointest Liver Physiol 2009;296(6):G1324-31
   PubMed Web of Science ®Google Scholar
• Petrasek J, Bala S, Csak T, et al. IL-1 receptor antagonist ameliorates inflammasome-dependent alcoholic steatohepatitis in mice. J Clin Invest 2012;122(10):3476-89
   PubMed Web of Science ®Google Scholar
• Osawa Y, Hoshi M, Yasuda I, et al. Tumor necrosis factor-alpha promotes cholestasis-induced liver fibrosis in the mouse through tissue inhibitor of metalloproteinase-1 production in hepatic stellate cells. PLoS One 2013;8(6):e65251
   PubMedGoogle Scholar
• Tomita K, Tamiya G, Ando S, et al. Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Gut 2006;55(3):415-24
   PubMed Web of Science ®Google Scholar
• Tan Z, Qian X, Jiang R, et al. IL-17A plays a critical role in the pathogenesis of liver fibrosis through hepatic stellate cell activation. J Immunol 2013;191(4):1835-44
   PubMed Web of Science ®Google Scholar
• Kronenberger B, Rudloff I, Bachmann M, et al. Interleukin-22 predicts severity and death in advanced liver cirrhosis: a prospective cohort study. BMC Med 2012;10:102
   PubMed Web of Science ®Google Scholar
• Ehling J, Bartneck M, Wei X, et al. CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis. Gut 2014;63(12):1960-71
   PubMed Web of Science ®Google Scholar
• Baeck C, Wei X, Bartneck M, et al. Pharmacological inhibition of the chemokine C-C motif chemokine ligand 2 (monocyte chemoattractant protein 1) accelerates liver fibrosis regression by suppressing Ly-6C(+) macrophage infiltration in mice. Hepatology 2014;59(3):1060-72
   PubMed Web of Science ®Google Scholar
• Berres ML, Koenen RR, Rueland A, et al. Antagonism of the chemokine Ccl5 ameliorates experimental liver fibrosis in mice. J Clin Invest 2010;120(11):4129-40
   PubMed Web of Science ®Google Scholar
• Katsounas A, Schlaak JF, Lempicki RA. CCL5: a double-edged sword in host defense against the hepatitis C virus. Int Rev Immunol 2011;30(5-6):366-78
   PubMed Web of Science ®Google Scholar
• Vespasiani-Gentilucci U, Carotti S, Perrone G, et al. Hepatic toll-like receptor 4 expression is associated with portal inflammation and fibrosis in patients with NAFLD. Liver Int 2014. 10.1111/liv.12531
   Web of Science ®Google Scholar
• Benias PC, Gopal K, Bodenheimer HJr, et al. Hepatic expression of toll-like receptors 3, 4, and 9 in primary biliary cirrhosis and chronic hepatitis C. Clin Res Hepatol Gastroenterol 2012;36(5):448-54
   PubMed Web of Science ®Google Scholar
• Roh YS, Park S, Kim JW, et al. Toll-like receptor 7-mediated type I interferon signaling prevents cholestasis- and hepatotoxin-induced liver fibrosis. Hepatology 2014;60(1):237-49
   PubMed Web of Science ®Google Scholar
• Howell J, Sawhney R, Skinner N, et al. Toll-like receptor 3 and 7/8 function is impaired in hepatitis C rapid fibrosis progression post-liver transplantation. Am J Transplant 2013;13(4):943-53
   PubMed Web of Science ®Google Scholar
• Moon HJ, Finney J, Ronnebaum T, et al. Human lysyl oxidase-like 2. Bioorg Chem 2014;57:231-41
   PubMed Web of Science ®Google Scholar
• Perepelyuk M, Terajima M, Wang AY, et al. Hepatic stellate cells and portal fibroblasts are the major cellular sources of collagens and lysyl oxidases in normal liver and early after injury. Am J Physiol Gastrointest Liver Physiol 2013;304(6):G605-14
   PubMed Web of Science ®Google Scholar
• Vadasz Z, Kessler O, Akiri G, et al. Abnormal deposition of collagen around hepatocytes in Wilson’s disease is associated with hepatocyte specific expression of lysyl oxidase and lysyl oxidase like protein-2. J Hepatol 2005;43(3):499-507
   PubMed Web of Science ®Google Scholar
• Barry-Hamilton V, Spangler R, Marshall D, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nat Med 2010;16(9):1009-17
   PubMed Web of Science ®Google Scholar
• Zhang Y, Ghazwani M, Li J, et al. MiR-29b inhibits collagen maturation in hepatic stellate cells through down-regulating the expression of HSP47 and lysyl oxidase. Biochem Biophys Res Commun 2014;446(4):940-4
   PubMed Web of Science ®Google Scholar
• Kisseleva T, Cong M, Paik Y, et al. Myofibroblasts revert to an inactive phenotype during regression of liver fibrosis. Proc Natl Acad Sci USA 2012;109(24):9448-53
   PubMed Web of Science ®Google Scholar
• Liu X, Xu J, Brenner DA, et al. Reversibility of liver fibrosis and inactivation of fibrogenic myofibroblasts. Curr Pathobiol Rep 2013;1(3):209-14
   Google Scholar
• Xie G, Karaca G, Swiderska-Syn M, et al. Cross-talk between Notch and Hedgehog regulates hepatic stellate cell fate in mice. Hepatology 2013;58(5):1801-13
   PubMed Web of Science ®Google Scholar
• Borkham-Kamphorst E, Schaffrath C, Van de Leur E, et al. The anti-fibrotic effects of CCN1/CYR61 in primary portal myofibroblasts are mediated through induction of reactive oxygen species resulting in cellular senescence, apoptosis and attenuated TGF-beta signaling. Biochim Biophys Acta 2014;1843(5):902-14
   PubMed Web of Science ®Google Scholar
• Kim KH, Chen CC, Monzon RI, et al. Matricellular protein CCN1 promotes regression of liver fibrosis through induction of cellular senescence in hepatic myofibroblasts. Mol Cell Biol 2013;33(10):2078-90
   PubMed Web of Science ®Google Scholar
• Klein S, Klosel J, Schierwagen R, et al. Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates hepatic fibrosis in rats. Lab Invest 2012;92(10):1440-50
   PubMed Web of Science ®Google Scholar
• Tacke F, Zimmermann HW. Macrophage heterogeneity in liver injury and fibrosis. J Hepatol 2014;60(5):1090-6
   PubMed Web of Science ®Google Scholar
• Ramachandran P, Pellicoro A, Vernon MA, et al. Differential Ly-6C expression identifies the recruited macrophage phenotype, which orchestrates the regression of murine liver fibrosis. Proc Natl Acad Sci USA 2012;109(46):E3186-95
   PubMed Web of Science ®Google Scholar
• Bataller R, Paik YH, Lindquist JN, et al. Hepatitis C virus core and nonstructural proteins induce fibrogenic effects in hepatic stellate cells. Gastroenterology 2004;126(2):529-40
   PubMed Web of Science ®Google Scholar
• Crabb DW, Matsumoto M, Chang D, et al. Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology. Proc Nutr Soc 2004;63(1):49-63
   PubMed Web of Science ®Google Scholar
• Mello T, Ceni E, Surrenti C, et al. Alcohol induced hepatic fibrosis: role of acetaldehyde. Mol Aspects Med 2008;29(1-2):17-21
   PubMed Web of Science ®Google Scholar
• Fujii H, Kawada N. Fibrogenesis in alcoholic liver disease. World J Gastroenterol 2014;20(25):8048-54
   PubMed Web of Science ®Google Scholar
• Schuppan D, Schattenberg JM. Non-alcoholic steatohepatitis: pathogenesis and novel therapeutic approaches. J Gastroenterol Hepatol 2013;28(Suppl 1):68-76
   PubMed Web of Science ®Google Scholar
• Schnabl B, Brenner DA. Interactions between the intestinal microbiome and liver diseases. Gastroenterology 2014;146(6):1513-24
   PubMed Web of Science ®Google Scholar
• Brenner DA, Seki E, Taura K, et al. Non-alcoholic steatohepatitis-induced fibrosis: toll-like receptors, reactive oxygen species and Jun N-terminal kinase. Hepatol Res 2011;41(7):683-6
   PubMed Web of Science ®Google Scholar
• Basaranoglu M, Basaranoglu G, Sabuncu T, et al. Fructose as a key player in the development of fatty liver disease. World J Gastroenterol 2013;19(8):1166-72
   PubMed Web of Science ®Google Scholar
• Lim JS, Mietus-Snyder M, Valente A, et al. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol 2010;7(5):251-64
   PubMed Web of Science ®Google Scholar
• Adkins Y, Schie IW, Fedor D, et al. A novel mouse model of nonalcoholic steatohepatitis with significant insulin resistance. Lab Invest 2013;93(12):1313-22
   PubMed Web of Science ®Google Scholar
• Puri P, Mirshahi F, Cheung O, et al. Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease. Gastroenterology 2008;134(2):568-76
   PubMed Web of Science ®Google Scholar
• Lee JS, Zheng Z, Mendez R, et al. Pharmacologic ER stress induces non-alcoholic steatohepatitis in an animal model. Toxicol Lett 2012;211(1):29-38
   PubMed Web of Science ®Google Scholar
• Lake AD, Novak P, Hardwick RN, et al. The adaptive endoplasmic reticulum stress response to lipotoxicity in progressive human nonalcoholic fatty liver disease. Toxicol Sci 2014;137(1):26-35
   PubMed Web of Science ®Google Scholar
• Meakin PJ, Chowdhry S, Sharma RS, et al. Susceptibility of Nrf2-null mice to steatohepatitis and cirrhosis upon consumption of a high-fat diet is associated with oxidative stress, perturbation of the unfolded protein response, and disturbance in the expression of metabolic enzymes, but not with insulin resistance. Mol Cell Biol 2014;34(17):3305-20
   PubMed Web of Science ®Google Scholar
• Gracia-Sancho J, Guixe-Muntet S, Hide D, et al. Modulation of autophagy for the treatment of liver diseases. Expert Opin Investig Drugs 2014;23(7):965-77
   PubMed Web of Science ®Google Scholar
• Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. N Engl J Med 2013;368(7):651-62
   PubMed Web of Science ®Google Scholar
• Ravikumar B, Sarkar S, Davies JE, et al. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev 2010;90(4):1383-435
   PubMed Web of Science ®Google Scholar
• Czaja MJ, Ding WX, Donohue TMJr, et al. Functions of autophagy in normal and diseased liver. Autophagy 2013;9(8):1131-58
   PubMed Web of Science ®Google Scholar
• Ni HM, Woolbright BL, Williams J, et al. Nrf2 promotes the development of fibrosis and tumorigenesis in mice with defective hepatic autophagy. J Hepatol 2014;61(3):617-25
   PubMed Web of Science ®Google Scholar
• Wang J, Kang R, Huang H, et al. Hepatitis C virus core protein activates autophagy through EIF2AK3 and ATF6 UPR pathway-mediated MAP1LC3B and ATG12 expression. Autophagy 2014;10(5):766-84
   PubMed Web of Science ®Google Scholar
• Shinohara Y, Imajo K, Yoneda M, et al. Unfolded protein response pathways regulate Hepatitis C virus replication via modulation of autophagy. Biochem Biophys Res Commun 2013;432(2):326-32
   PubMed Web of Science ®Google Scholar
• Huang H, Kang R, Wang J, et al. Hepatitis C virus inhibits AKT-tuberous sclerosis complex (TSC), the mechanistic target of rapamycin (MTOR) pathway, through endoplasmic reticulum stress to induce autophagy. Autophagy 2013;9(2):175-95
   PubMed Web of Science ®Google Scholar
• Shrivastava S, Bhanja Chowdhury J, Steele R, et al. Hepatitis C virus upregulates Beclin1 for induction of autophagy and activates mTOR signaling. J Virol 2012;86(16):8705-12
   PubMed Web of Science ®Google Scholar
• Zhang HT, Chen GG, Hu BG, et al. Hepatitis B virus x protein induces autophagy via activating death-associated protein kinase. J Viral Hepat 2014;21(9):642-9
   PubMed Web of Science ®Google Scholar
• Tian Y, Sir D, Kuo CF, et al. Autophagy required for hepatitis B virus replication in transgenic mice. J Virol 2011;85(24):13453-6
   PubMed Web of Science ®Google Scholar
• Sir D, Tian Y, Chen WL, et al. The early autophagic pathway is activated by hepatitis B virus and required for viral DNA replication. Proc Natl Acad Sci USA 2010;107(9):4383-8
   PubMed Web of Science ®Google Scholar
• Churin Y, Roderfeld M, Stiefel J, et al. Pathological impact of hepatitis B virus surface proteins on the liver is associated with the host genetic background. PLoS One 2014;9(3):e90608
   PubMedGoogle Scholar
• Singh R, Kaushik S, Wang Y, et al. Autophagy regulates lipid metabolism. Nature 2009;458(7242):1131-5
   PubMed Web of Science ®Google Scholar
• Hernandez-Gea V, Ghiassi-Nejad Z, Rozenfeld R, et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues. Gastroenterology 2012;142(4):938-46
   PubMed Web of Science ®Google Scholar
• Thoen LF, Guimaraes EL, Dolle L, et al. A role for autophagy during hepatic stellate cell activation. J Hepatol 2011;55(6):1353-60
   PubMed Web of Science ®Google Scholar
• Stankov MV, Panayotova-Dimitrova D, Leverkus M, et al. Autophagy inhibition due to thymidine analogues as novel mechanism leading to hepatocyte dysfunction and lipid accumulation. AIDS 2012;26(16):1995-2006
   PubMed Web of Science ®Google Scholar
• Farrell GC, van Rooyen D, Gan L, et al. NASH is an inflammatory disorder: pathogenic, prognostic and therapeutic implications. Gut Liver 2012;6(2):149-71
   PubMed Web of Science ®Google Scholar
• Amir M, Czaja MJ. Autophagy in nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol 2011;5(2):159-66
   PubMed Web of Science ®Google Scholar
• Kwanten WJ, Martinet W, Michielsen PP, et al. Role of autophagy in the pathophysiology of nonalcoholic fatty liver disease: a controversial issue. World J Gastroenterol 2014;20(23):7325-38
   PubMed Web of Science ®Google Scholar
• Gonzalez-Rodriguez A, Mayoral R, Agra N, et al. Impaired autophagic flux is associated with increased endoplasmic reticulum stress during the development of NAFLD. Cell Death Dis 2014;5:e1179
   PubMed Web of Science ®Google Scholar
• Fukuo Y, Yamashina S, Sonoue H, et al. Abnormality of autophagic function and cathepsin expression in the liver from patients with non-alcoholic fatty liver disease. Hepatol Res 2014;44(9):1026-36
   PubMed Web of Science ®Google Scholar
• Sinha RA, Farah BL, Singh BK, et al. Caffeine stimulates hepatic lipid metabolism by the autophagy-lysosomal pathway in mice. Hepatology 2014;59(4):1366-80
   PubMed Web of Science ®Google Scholar
• Lin CW, Zhang H, Li M, et al. Pharmacological promotion of autophagy alleviates steatosis and injury in alcoholic and non-alcoholic fatty liver conditions in mice. J Hepatol 2013;58(5):993-9
   PubMed Web of Science ®Google Scholar
• Hidvegi T, Ewing M, Hale P, et al. An autophagy-enhancing drug promotes degradation of mutant alpha1-antitrypsin Z and reduces hepatic fibrosis. Science 2010;329(5988):229-32
   PubMed Web of Science ®Google Scholar
• Puls F, Goldschmidt I, Bantel H, et al. Autophagy-enhancing drug carbamazepine diminishes hepatocellular death in fibrinogen storage disease. J Hepatol 2013;59(3):626-30
   PubMed Web of Science ®Google Scholar
• He W, Wang B, Yang J, et al. Chloroquine improved carbon tetrachloride-induced liver fibrosis through its inhibition of the activation of hepatic stellate cells: role of autophagy. Biol Pharm Bull 2014;37(9):1505-9
   PubMed Web of Science ®Google Scholar
• Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. Lancet 2014;383(9930):1749-61
   PubMed Web of Science ®Google Scholar
• Ellis EL, Mann DA. Clinical evidence for the regression of liver fibrosis. J Hepatol 2012;56(5):1171-80
   PubMed Web of Science ®Google Scholar
• Issa R, Zhou X, Constandinou CM, et al. Spontaneous recovery from micronodular cirrhosis: evidence for incomplete resolution associated with matrix cross-linking. Gastroenterology 2004;126(7):1795-808
   PubMed Web of Science ®Google Scholar
• Schuppan D, Pinzani M. Anti-fibrotic therapy: lost in translation? J Hepatol 2012;56(Suppl 1):S66-74
   PubMedGoogle Scholar
• Friedman SL, Sheppard D, Duffield JS, et al. Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med 2013;5(167):167sr1
   PubMed Web of Science ®Google Scholar
• Kisseleva T, Brenner DA. Anti-fibrogenic strategies and the regression of fibrosis. Best Pract Res Clin Gastroenterol 2011;25(2):305-17
   PubMed Web of Science ®Google Scholar
• Popov Y, Schuppan D. Targeting liver fibrosis: strategies for development and validation of antifibrotic therapies. Hepatology 2009;50(4):1294-306
   PubMed Web of Science ®Google Scholar
• Popov Y, Patsenker E, Fickert P, et al. Mdr2 (Abcb4)-/- mice spontaneously develop severe biliary fibrosis via massive dysregulation of pro- and antifibrogenic genes. J Hepatol 2005;43(6):1045-54
   PubMed Web of Science ®Google Scholar
• Kampschulte M, Stockl C, Langheinrich AC, et al. Western diet in ApoE-LDLR double-deficient mouse model of atherosclerosis leads to hepatic steatosis, fibrosis, and tumorigenesis. Lab Invest 2014;94(11):1273-82
   PubMed Web of Science ®Google Scholar
• Sugiyama M, Tanaka Y, Kurbanov F, et al. Direct cytopathic effects of particular hepatitis B virus genotypes in severe combined immunodeficiency transgenic with urokinase-type plasminogen activator mouse with human hepatocytes. Gastroenterology 2009;136(2):652-62; e3
   PubMed Web of Science ®Google Scholar
• Washburn ML, Bility MT, Zhang L, et al. A humanized mouse model to study hepatitis C virus infection, immune response, and liver disease. Gastroenterology 2011;140(4):1334-44
   PubMed Web of Science ®Google Scholar
• Robinet E, Baumert TF. A first step towards a mouse model for hepatitis C virus infection containing a human immune system. J Hepatol 2011;55(3):718-20
   PubMed Web of Science ®Google Scholar
• Bility MT, Zhang L, Washburn ML, et al. Generation of a humanized mouse model with both human immune system and liver cells to model hepatitis C virus infection and liver immunopathogenesis. Nat Protoc 2012;7(9):1608-17
   PubMed Web of Science ®Google Scholar
• Bility MT, Cheng L, Zhang Z, et al. Hepatitis B virus infection and immunopathogenesis in a humanized mouse model: induction of human-specific liver fibrosis and M2-like macrophages. PLoS Pathog 2014;10(3):e1004032
   PubMed Web of Science ®Google Scholar
• Traber PG, Zomer E. Therapy of experimental NASH and fibrosis with galectin inhibitors. PLoS One 2013;8(12):e83481
   PubMed Web of Science ®Google Scholar
• Traber PG, Chou H, Zomer E, et al. Regression of fibrosis and reversal of cirrhosis in rats by galectin inhibitors in thioacetamide-induced liver disease. PLoS One 2013;8(10):e75361
   PubMed Web of Science ®Google Scholar
• Yoshida T, Adachi E, Nigi H, et al. Changes of sinusoidal basement membrane collagens in early hepatic fibrosis induced with CCl4 in cynomolgus monkeys. Pathology 1999;31(1):29-35
   PubMed Web of Science ®Google Scholar
• Ding K, Liu MR, Li J, et al. Establishment of a liver fibrosis model in cynomolgus monkeys. Exp Toxicol Pathol 2014;66(5-6):257-61
   PubMed Web of Science ®Google Scholar
• Zhang JJ, Meng XK, Dong C, et al. Development of a new animal model of liver cirrhosis in swine. Eur Surg Res 2009;42(1):35-9
   PubMed Web of Science ®Google Scholar
• Li H, Chen TW, Zhang XM, et al. Liver lobe volumes and the ratios of liver lobe volumes to spleen volume on magnetic resonance imaging for staging liver fibrosis in a minipig model. PLoS One 2013;8(11):e79681
   PubMedGoogle Scholar
• Chen XL, Chen TW, Li ZL, et al. Spleen size measured on enhanced MRI for quantitatively staging liver fibrosis in minipigs. J Magn Reson Imaging 2013;38(3):540-7
   PubMed Web of Science ®Google Scholar
• Li H, Chen TW, Chen XL, et al. Magnetic resonance-based total liver volume and magnetic resonance-diffusion weighted imaging for staging liver fibrosis in mini-pigs. World J Gastroenterol 2012;18(48):7225-33
   PubMed Web of Science ®Google Scholar
• Lee L, Alloosh M, Saxena R, et al. Nutritional model of steatohepatitis and metabolic syndrome in the Ossabaw miniature swine. Hepatology 2009;50(1):56-67
   PubMed Web of Science ®Google Scholar
• van de Bovenkamp M, Groothuis GM, Draaisma AL, et al. Precision-cut liver slices as a new model to study toxicity-induced hepatic stellate cell activation in a physiologic milieu. Toxicol Sci 2005;85(1):632-8
   PubMed Web of Science ®Google Scholar
• Clouzeau-Girard H, Guyot C, Combe C, et al. Effects of bile acids on biliary epithelial cell proliferation and portal fibroblast activation using rat liver slices. Lab Invest 2006;86(3):275-85
   PubMed Web of Science ®Google Scholar
• Guyot C, Combe C, Clouzeau-Girard H, et al. Specific activation of the different fibrogenic cells in rat cultured liver slices mimicking in vivo situations. Virchows Arch 2007;450(5):503-12
   PubMed Web of Science ®Google Scholar
• Guyot C, Lepreux S, Combe C, et al. Fibrogenic cell phenotype modifications during remodelling of normal and pathological human liver in cultured slices. Liver Int 2010;30(10):1529-40
   PubMed Web of Science ®Google Scholar
• Westra IM, Oosterhuis D, Groothuis GM, et al. The effect of antifibrotic drugs in rat precision-cut fibrotic liver slices. PLoS One 2014;9(4):e95462
   PubMed Web of Science ®Google Scholar
• Moran-Salvador E, Titos E, Rius B, et al. Cell-specific PPARgamma deficiency establishes anti-inflammatory and anti-fibrogenic properties for this nuclear receptor in non-parenchymal liver cells. J Hepatol 2013;59(5):1045-53
   PubMed Web of Science ®Google Scholar
• Gonzalo T, Beljaars L, van de Bovenkamp M, et al. Local inhibition of liver fibrosis by specific delivery of a platelet-derived growth factor kinase inhibitor to hepatic stellate cells. J Pharmacol Exp Ther 2007;321(3):856-65
   PubMed Web of Science ®Google Scholar
• Regev A, Berho M, Jeffers LJ, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002;97(10):2614-18
   PubMed Web of Science ®Google Scholar
• Zhou K, Lu LG. Assessment of fibrosis in chronic liver diseases. J Dig Dis 2009;10(1):7-14
   PubMed Web of Science ®Google Scholar
• Kim BK, Fung J, Yuen MF, et al. Clinical application of liver stiffness measurement using transient elastography in chronic liver disease from longitudinal perspectives. World J Gastroenterol 2013;19(12):1890-900
   PubMed Web of Science ®Google Scholar
• Castera L, Vilgrain V, Angulo P. Noninvasive evaluation of NAFLD. Nat Rev Gastroenterol Hepatol 2013;10(11):666-75
   PubMed Web of Science ®Google Scholar
• Fuchs BC, Wang H, Yang Y, et al. Molecular MRI of collagen to diagnose and stage liver fibrosis. J Hepatol 2013;59(5):992-8
   PubMed Web of Science ®Google Scholar
• Polasek M, Fuchs BC, Uppal R, et al. Molecular MR imaging of liver fibrosis: a feasibility study using rat and mouse models. J Hepatol 2012;57(3):549-55
   PubMed Web of Science ®Google Scholar
• Castera L. Invasive and non-invasive methods for the assessment of fibrosis and disease progression in chronic liver disease. Best Pract Res Clin Gastroenterol 2011;25(2):291-303
   PubMed Web of Science ®Google Scholar
• Sebastiani G, Gkouvatsos K, Plebani M. Non-invasive assessment of liver fibrosis: it is time for laboratory medicine. Clin Chem Lab Med 2011;49(1):13-32
   PubMed Web of Science ®Google Scholar
• Barascuk N, Veidal SS, Larsen L, et al. A novel assay for extracellular matrix remodeling associated with liver fibrosis: an enzyme-linked immunosorbent assay (ELISA) for a MMP-9 proteolytically revealed neo-epitope of type III collagen. Clin Biochem 2010;43(10-11):899-904
   PubMed Web of Science ®Google Scholar
• Veidal SS, Vassiliadis E, Barascuk N, et al. Matrix metalloproteinase-9-mediated type III collagen degradation as a novel serological biochemical marker for liver fibrogenesis. Liver Int 2010;30(9):1293-304
   PubMed Web of Science ®Google Scholar
• Veidal SS, Karsdal MA, Vassiliadis E, et al. MMP mediated degradation of type VI collagen is highly associated with liver fibrosis--identification and validation of a novel biochemical marker assay. PLoS One 2011;6(9):e24753
   PubMed Web of Science ®Google Scholar
• Nielsen MJ, Veidal SS, Karsdal MA, et al. Plasma Pro-C3 (N-terminal type III collagen propeptide) predicts fibrosis progression in patients with chronic hepatitis C. Liver Int 2014. 10.1111/liv.12700
   PubMed Web of Science ®Google Scholar
• Rosenberg WM, Voelker M, Thiel R, et al. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology 2004;127(6):1704-13
   PubMed Web of Science ®Google Scholar
• Xie Q, Zhou X, Huang P, et al. The performance of enhanced liver fibrosis (ELF) test for the staging of liver fibrosis: a meta-analysis. PLoS One 2014;9(4):e92772
   PubMedGoogle Scholar
• Poynard T, Zoulim F, Ratziu V, et al. Longitudinal assessment of histology surrogate markers (FibroTest-ActiTest) during lamivudine therapy in patients with chronic hepatitis B infection. Am J Gastroenterol 2005;100(9):1970-80
   PubMed Web of Science ®Google Scholar
• Parkes J, Roderick P, Harris S, et al. Enhanced liver fibrosis test can predict clinical outcomes in patients with chronic liver disease. Gut 2010;59(9):1245-51
   PubMed Web of Science ®Google Scholar
• Ripoll C, Groszmann R, Garcia-Tsao G, et al. Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis. Gastroenterology 2007;133(2):481-8
   PubMed Web of Science ®Google Scholar
• Nielsen K, Clemmesen JO, Vassiliadis E, et al. Liver collagen in cirrhosis correlates with portal hypertension and liver dysfunction. APMIS 2014;122(12):1213-22
   PubMed Web of Science ®Google Scholar
• Kumar M, Kumar A, Hissar S, et al. Hepatic venous pressure gradient as a predictor of fibrosis in chronic liver disease because of hepatitis B virus. Liver Int 2008;28(5):690-8
   PubMed Web of Science ®Google Scholar
• Schuppan D, Kim YO. Evolving therapies for liver fibrosis. J Clin Invest 2013;123(5):1887-901
   PubMed Web of Science ®Google Scholar
• Real LM, Caruz A, Rivero-Juarez A, et al. A polymorphism linked to RRAS, SCAF1, IRF3 and BCL2L12 genes is associated with cirrhosis in hepatitis C virus carriers. Liver Int 2014;34(4):558-66
   PubMed Web of Science ®Google Scholar
• Inamine T, Higa S, Noguchi F, et al. Association of genes involved in bile acid synthesis with the progression of primary biliary cirrhosis in Japanese patients. J Gastroenterol 2013;48(10):1160-70
   PubMed Web of Science ®Google Scholar
• Guo J, Hong F, Loke J, et al. A DDX5 S480A polymorphism is associated with increased transcription of fibrogenic genes in hepatic stellate cells. J Biol Chem 2010;285(8):5428-37
   PubMed Web of Science ®Google Scholar
• Sanyal AJ, McCullough AJ, Friedman SL, et al. Trial designs and endpoints for liver disease secondary to nonalcoholic fatty liver disease (NAFLD). AASLD/FDA Workshop; FDA White Oak Campus, Silver Spring, Maryland, USA; 2013
   Google Scholar
• Sanyal AJ, Brunt EM, Kleiner DE, et al. Endpoints and clinical trial design for nonalcoholic steatohepatitis. Hepatology 2011;54(1):344-53
   PubMedGoogle Scholar
• Silveira MG, Brunt EM, Heathcote J, et al. American Association for the Study of Liver Diseases endpoints conference: design and endpoints for clinical trials in primary biliary cirrhosis. Hepatology 2010;52(1):349-59
   PubMed Web of Science ®Google Scholar
• McHutchison J, Poynard T, Afdhal N. Fibrosis as an end point for clinical trials in liver disease: a report of the international fibrosis group. Clin Gastroenterol Hepatol 2006;4(10):1214-20
   PubMed Web of Science ®Google Scholar
• Wang L, Li J, Liu H, et al. Pilot study of umbilical cord-derived mesenchymal stem cell transfusion in patients with primary biliary cirrhosis. J Gastroenterol Hepatol 2013;28(Suppl 1):85-92
   PubMed Web of Science ®Google Scholar
• Jang YO, Kim YJ, Baik SK, et al. Histological improvement following administration of autologous bone marrow-derived mesenchymal stem cells for alcoholic cirrhosis: a pilot study. Liver Int 2014;34(1):33-41
   PubMed Web of Science ®Google Scholar
• Mohamadnejad M, Alimoghaddam K, Bagheri M, et al. Randomized placebo-controlled trial of mesenchymal stem cell transplantation in decompensated cirrhosis. Liver Int 2013;33(10):1490-6
   PubMed Web of Science ®Google Scholar
• Volarevic V, Nurkovic J, Arsenijevic N, et al. Concise review: therapeutic potential of mesenchymal stem cells for the treatment of acute liver failure and cirrhosis. Stem Cells 2014;32(11):2818-23
   PubMed Web of Science ®Google Scholar
• Neverova N, Teerlink JR. Serelaxin: a potential new drug for the treatment of acute heart failure. Expert Opin Investig Drugs 2014;23(7):1017-26
   PubMed Web of Science ®Google Scholar
• Canbay A, Feldstein A, Baskin-Bey E, et al. The caspase inhibitor IDN-6556 attenuates hepatic injury and fibrosis in the bile duct ligated mouse. J Pharmacol Exp Ther 2004;308(3):1191-6
   PubMed Web of Science ®Google Scholar
• Barreyro FJ, Holod S, Finocchietto PV, et al. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int 2014. 10.1111/liv.12570
   PubMed Web of Science ®Google Scholar
• Pockros PJ, Schiff ER, Shiffman ML, et al. Oral IDN-6556, an antiapoptotic caspase inhibitor, may lower aminotransferase activity in patients with chronic hepatitis C. Hepatology 2007;46(2):324-9
   PubMed Web of Science ®Google Scholar
• Wang Q, Usinger W, Nichols B, et al. Cooperative interaction of CTGF and TGF-beta in animal models of fibrotic disease. Fibrogenesis Tissue Repair 2011;4(1):4
   PubMedGoogle Scholar
• Donepudi AC, Aleksunes LM, Driscoll MV, et al. The traditional ayurvedic medicine, Eugenia jambolana (Jamun fruit), decreases liver inflammation, injury and fibrosis during cholestasis. Liver Int 2012;32(4):560-73
   PubMed Web of Science ®Google Scholar
• Choi JH, Hwang YP, Choi CY, et al. Anti-fibrotic effects of the anthocyanins isolated from the purple-fleshed sweet potato on hepatic fibrosis induced by dimethylnitrosamine administration in rats. Food Chem Toxicol 2010;48(11):3137-43
   PubMed Web of Science ®Google Scholar
• Bendia E, Benedetti A, Baroni GS, et al. Effect of cyanidin 3-O-beta-glucopyranoside on hepatic stellate cell proliferation and collagen synthesis induced by oxidative stress. Dig Liver Dis 2005;37(5):342-8
   PubMedGoogle Scholar
• Poudyal H, Panchal S, Brown L. Comparison of purple carrot juice and beta-carotene in a high-carbohydrate, high-fat diet-fed rat model of the metabolic syndrome. Br J Nutr 2010;104(9):1322-32
   PubMed Web of Science ®Google Scholar
• Hoofnagle JH, Van Natta ML, Kleiner DE, et al. Vitamin E and changes in serum alanine aminotransferase levels in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2013;38(2):134-43
   PubMed Web of Science ®Google Scholar
• Clemmesen JO, Giraldi A, Ott P, et al. Sildenafil does not influence hepatic venous pressure gradient in patients with cirrhosis. World J Gastroenterol 2008;14(40):6208-12
   PubMed Web of Science ®Google Scholar
• Olaywi M, Bhatia T, Anand S, et al. Novel anti-diabetic agents in non-alcoholic fatty liver disease: a mini-review. Hepatobiliary Pancreat Dis Int 2013;12(6):584-8
   PubMed Web of Science ®Google Scholar
• Foster T, Budoff MJ, Saab S, et al. Atorvastatin and antioxidants for the treatment of nonalcoholic fatty liver disease: the St Francis Heart Study randomized clinical trial. Am J Gastroenterol 2011;106(1):71-7
   PubMed Web of Science ®Google Scholar
• Sanyal AJ, Chalasani N, Kowdley KV, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362(18):1675-85
   PubMed Web of Science ®Google Scholar
• Park H, Shima T, Yamaguchi K, et al. Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease. J Gastroenterol 2011;46(1):101-7
   PubMed Web of Science ®Google Scholar
• Mudaliar S, Henry RR, Sanyal AJ, et al. Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease. Gastroenterology 2013;145(3):574-82; e1
   PubMed Web of Science ®Google Scholar
• Fiorucci S, Distrutti E, Ricci P, et al. Targeting FXR in cholestasis: hype or hope. Expert Opin Ther Targets 2014;18:1449-59
   PubMed Web of Science ®Google Scholar
• Verbeke L, Farre R, Trebicka J, et al. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology 2014;59(6):2286-98
   PubMed Web of Science ®Google Scholar
• Xaubet A, Serrano-Mollar A, Ancochea J. Pirfenidone for the treatment of idiopathic pulmonary fibrosis. Expert Opin Pharmacother 2014;15(2):275-81
   PubMed Web of Science ®Google Scholar
• Woodcock HV, Maher TM. The treatment of idiopathic pulmonary fibrosis. F1000Prime Rep 2014;6:16
   Google Scholar
• FDA. Approval based on a surrogate endpoint or on an effect on a clinical endpoint other than survival or irreversible morbidity. 21CFR314510 2014. Available from: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.510
   Google Scholar
• Kim YH, Hwang JH, Kim KS, et al. NAD(P)H:quinone oxidoreductase 1 activation reduces blood pressure through regulation of endothelial nitric oxide synthase acetylation in spontaneously hypertensive rats. Am J Hypertens 2015;28(1):50-7
   PubMed Web of Science ®Google Scholar
• Domitrovic R, Jakovac H. Antifibrotic activity of anthocyanidin delphinidin in carbon tetrachloride-induced hepatotoxicity in mice. Toxicology 2010;272(1-3):1-10
   PubMed Web of Science ®Google Scholar
• Kaji K, Yoshiji H, Ikenaka Y, et al. Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats. J Gastroenterol 2014;49(3):481-91
   PubMed Web of Science ®Google Scholar
• Tanaka H, Yang GX, Iwakoshi N, et al. Anti-CD40 ligand monoclonal antibody delays the progression of murine autoimmune cholangitis. Clin Exp Immunol 2013;174(3):364-71
   PubMed Web of Science ®Google Scholar
• Lipson KE, Wong C, Teng Y, et al. CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis. Fibrogenesis Tissue Repair 2012;5(Suppl 1 Proceedings of Fibroproliferative disorders: from biochemical analysis to targeted therapiesPetro E Petrides and David Brenner):S24
   PubMedGoogle Scholar
• Argo CK, Patrie JT, Lackner C, et al. Effects of N-3 fish oil on metabolic and histological parameters in NASH: a double-blind, randomized, placebo-controlled trial. J Hepatol 2015;62(1):190-7
   PubMed Web of Science ®Google Scholar
• Fan JG, Cao HX. Role of diet and nutritional management in non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2013;28(Suppl 4):81-7
   PubMed Web of Science ®Google Scholar
• Machado MV, Coutinho J, Carepa F, et al. How adiponectin, leptin, and ghrelin orchestrate together and correlate with the severity of nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2012;24(10):1166-72
   PubMed Web of Science ®Google Scholar
• Luo J, Ko B, Elliott M, et al. A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci Transl Med 2014;6(247):247ra100
   PubMed Web of Science ®Google Scholar
• Jalan R, Wright G, Davies NA, et al. L-Ornithine phenylacetate (OP): a novel treatment for hyperammonemia and hepatic encephalopathy. Med Hypotheses 2007;69(5):1064-9
   PubMed Web of Science ®Google Scholar
• Boettcher E, Csako G, Pucino F, et al. Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment Pharmacol Ther 2012;35(1):66-75
   PubMed Web of Science ®Google Scholar
• Lenz HJ, Kahn M. Safely targeting cancer stem cells via selective catenin coactivator antagonism. Cancer Sci 2014;105(9):1087-92
   PubMed Web of Science ®Google Scholar
• Scott LJ. Rifaximin: a review of its use in reducing recurrence of overt hepatic encephalopathy episodes. Drugs 2014;74(18):2153-60
   PubMed Web of Science ®Google Scholar
• Han YP, Kong M, Zheng S, et al. Vitamin D in liver diseases: from mechanisms to clinical trials. J Gastroenterol Hepatol 2013;28(Suppl 1):49-55
   PubMedGoogle Scholar