“Let my liver rather heat with wine” - a review of hepatic fibrosis pathophysiology and emerging therapeutics

References

• Moffat J. Pre-1801 imprint collection (Library of Congress), Joseph Meredith Toner Collection (Library of Congress). In: The Prognostics and Prorrhetics of Hippocrates. London: Printed by T. Bensley for C. Elliot, T. Kay, and Co., opposite Somerset-House, in the Strand; 1788.
   Google Scholar
• Galen MMT. Galen on the Usefulness of the Parts of the Body. Peri Chreias Moriōn [romanized Form] De Usu Partium. Ithaca, N.Y.: Cornell University Press; 1968.
   Google Scholar
• Ross WD. The Works of Aristotle Translated into English. Oxford: Clarendon Press; 1928.
   Google Scholar
• Avicenna GOC. A Treatise on the Canon of Medicine of Avicenna, Incorporating A Translation of the First Book. New York: AMS Press; 1973.
   Google Scholar
• Brown J. A remarkable account of a liver, appearing glandulous to the eye; communicated by Mr. John Brown, Chirurgeon of St. Thomas’s Hospitall in Southwark; in a letter to one of the Secretarys of the Royal Society. Philos Trans R Soc London. 1685;15(178):1266–1268. doi:10.1098/rstl.1685.0087
   Google Scholar
• Laennec RTH, Forbes J, Fisher JD, Andral G, Harvard Medical S. A Treatise on the Diseases of the Chest, and on Mediate Auscultation. New York: Samuel S. and William Wood; 1838.
   Google Scholar
• Osler W. The Principles and Practice of Medicine, Designed for the Use of Practitioners and Students of Medicine. New York: D. Appleton and Company; 1901.
   Google Scholar
• Sherlock S. Diseases of the Liver and Biliary System. Oxford: Blackwell Scientific Publications; 1958.
   Google Scholar
• Walker JG, Doniach D, Roitt IM, Sherlock S. Serological tests in diagnosis of primary biliary cirrhosis. Lancet. 1965;1(7390):827–831. doi:10.1016/s0140-6736(65)91372-314263538
   PubMed Web of Science ®Google Scholar
• Rehm J, Samokhvalov AV, Shield KD. Global burden of alcoholic liver diseases. J Hepatol. 2013;59(1):160–168. doi:10.1016/j.jhep.2013.03.00723511777
   PubMed Web of Science ®Google Scholar
• Grant BF, Chou SP, Saha TD, et al. Prevalence of 12-month alcohol use, high-risk drinking, and DSM-IV alcohol use disorder in the United States, 2001–2002 to 2012–2013: results from the National Epidemiologic Survey on Alcohol and Related Conditions. JAMA Psychiatry. 2017;74(9):911–923. doi:10.1001/jamapsychiatry.2017.216128793133
   PubMed Web of Science ®Google Scholar
• Sarpel D, Baichoo E, Dieterich DT. Chronic hepatitis B and C infection in the United States: a review of current guidelines, disease burden and cost effectiveness of screening. Expert Rev Anti Infect Ther. 2016;14(5):511–521. doi:10.1586/14787210.2016.117406627043049
   PubMed Web of Science ®Google Scholar
• Gish RG, Cohen CA, Block JM, et al. Data supporting updating estimates of the prevalence of chronic hepatitis B and C in the United States. Hepatology. 2015;62(5):1339–1341. doi:10.1002/hep.2802626239816
   PubMed Web of Science ®Google Scholar
• Edlin BR, Eckhardt BJ, Shu MA, Holmberg SD, Swan T. Toward a more accurate estimate of the prevalence of hepatitis C in the United States. Hepatology. 2015;62(5):1353–1363. doi:10.1002/hep.2797826171595
   PubMed Web of Science ®Google Scholar
• Udompap P, Mannalithara A, Heo NY, Kim D, Kim WR. Increasing prevalence of cirrhosis among U.S. adults aware or unaware of their chronic hepatitis C virus infection. J Hepatol. 2016;64(5):1027–1032. doi:10.1016/j.jhep.2016.01.00926809112
   PubMed Web of Science ®Google Scholar
• Vernon G, Baranova A, Younossi ZM. Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther. 2011;34(3):274–285. doi:10.1111/j.1365-2036.2011.04724.x21623852
   PubMed Web of Science ®Google Scholar
• Lazo M, Hernaez R, Eberhardt MS, et al. Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988–1994. Am J Epidemiol. 2013;178(1):38–45. doi:10.1093/aje/kws44823703888
   PubMed Web of Science ®Google Scholar
• Sayiner M, Koenig A, Henry L, Younossi ZM. Epidemiology of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis in the United States and the rest of the world. Clin Liver Dis. 2016;20(2):205–214. doi:10.1016/j.cld.2015.10.00127063264
   PubMed Web of Science ®Google Scholar
• Colp C, Pappas J, Moran D, Lieberman J. Variants of α 1-antitrypsin in Puerto Rican children with asthma. Chest. 1993;103(3):812–815. doi:10.1378/chest.103.3.8128449073
   PubMed Web of Science ®Google Scholar
• Silverman EK, Miletich JP, Pierce JA, et al. α-1-antitrypsin deficiency. High prevalence in the St. Louis area determined by direct population screening. Am Rev Respir Dis. 1989;140(4):961–966. doi:10.1164/ajrccm/140.4.9612679271
   PubMed Web of Science ®Google Scholar
• O’Brien ML, Buist NR, Murphey WH. Neonatal screening for α1-antitrypsin deficiency. J Pediatr. 1978;92(6):1006–1010. doi:10.1016/s0022-3476(78)80388-6307054
   PubMed Web of Science ®Google Scholar
• Distante S, Robson KJ, Graham-Campbell J, Arnaiz-Villena A, Brissot P, Worwood M. The origin and spread of the HFE-C282Y haemochromatosis mutation. Hum Genet. 2004;115(4):269–279. doi:10.1007/s00439-004-1152-415290237
   PubMed Web of Science ®Google Scholar
• Allen KJ, Gurrin LC, Constantine CC, et al. Iron-overload-related disease in HFE hereditary hemochromatosis. N Engl J Med. 2008;358(3):221–230. doi:10.1056/NEJMoa07328618199861
   PubMed Web of Science ®Google Scholar
• McLaren GD, Gordeuk VR. Hereditary hemochromatosis: insights from the Hemochromatosis and Iron Overload Screening (HEIRS) Study. Hematology Am Soc Hematol Educ Program. 2009;195–206. doi:10.1182/asheducation-2009.1.19520008199
   PubMedGoogle Scholar
• Roberts EA, Schilsky ML. Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008;47(6):2089–2111. doi:10.1002/hep.2226118506894
   PubMed Web of Science ®Google Scholar
• Boonstra K, Beuers U, Ponsioen CY. Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol. 2012;56(5):1181–1188. doi:10.1016/j.jhep.2011.10.02522245904
   PubMed Web of Science ®Google Scholar
• Fallatah HI, Akbar HO. Autoimmune hepatitis as a unique form of an autoimmune liver disease: immunological aspects and clinical overview. Autoimmune Dis. 2012;2012:312817.23304455
   PubMedGoogle Scholar
• Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the global burden of disease study 2010. Lancet. 2012;380(9859):2095–2128. doi:10.1016/S0140-6736(12)61728-023245604
   PubMed Web of Science ®Google Scholar
• National Center for Health Statistics. Health, United States, 2016: With Chartbook on Long-term Trends in Health. DHHS Pub No. (PHS) 2017-1232. Hyattsville, MD.
   Google Scholar
• Hoyert DL, Xu J. Deaths: preliminary data for 2011. Natl Vital Stat Rep. 2012;61(6):1–51.
   PubMedGoogle Scholar
• Mellinger JL, Shedden K, Winder GS, et al. The high burden of alcoholic cirrhosis in privately insured persons in the United States. Hepatology. 2018;68(3):872–882. doi:10.1002/hep.2988729579356
   PubMed Web of Science ®Google Scholar
• Ge PS, Runyon BA. Treatment of patients with cirrhosis. N Engl J Med. 2016;375(21):2104–2105. doi:10.1056/NEJMc161233428121086
   PubMed Web of Science ®Google Scholar
• Pant C, Olyaee M, Gilroy R, et al. Emergency department visits related to cirrhosis: a retrospective study of the nationwide emergency department sample 2006 to 2011. Medicine (Baltimore). 2015;94(1):e308. doi:10.1097/MD.000000000000087425569646
   PubMed Web of Science ®Google Scholar
• National Center for Health Statistics, Center for Disease Control and Prevention, United States Census Bureau. United States National Hospital Discharge Survey: 2007 Summary. Hyattsville, MD: National Health Statistics Reports No. 29.
   Google Scholar
• Barritt AS, Jiang Y, Schmidt M, Hayashi PH, Bataller R. Charges for alcoholic cirrhosis exceed all other etiologies of cirrhosis combined: a national and state inpatient survey analysis. Dig Dis Sci. 2019;64(6):1460–1469. doi:10.1007/s10620-019-5471-730673984
   PubMed Web of Science ®Google Scholar
• Bajaj JS, Wade JB, Gibson DP, et al. The multi-dimensional burden of cirrhosis and hepatic encephalopathy on patients and caregivers. Am J Gastroenterol. 2011;106(9):1646–1653. doi:10.1038/ajg.2011.15721556040
   PubMed Web of Science ®Google Scholar
• Thiele M, Askgaard G, Timm HB, Hamberg O, Gluud LL. Predictors of health-related quality of life in outpatients with cirrhosis: results from a prospective cohort. Hepat Res Treat. 2013;2013:479639.24490061
   PubMedGoogle Scholar
• Chin JL, Pavlides M, Moolla A, Ryan JD. Non-invasive markers of liver fibrosis: adjuncts or alternatives to liver biopsy? Front Pharmacol. 2016;7:159. doi:10.3389/fphar.2016.0032327378924
   PubMed Web of Science ®Google Scholar
• Kamath PS, Wiesner RH, Malinchoc M, et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33(2):464–470. doi:10.1053/jhep.2001.2217211172350
   PubMed Web of Science ®Google Scholar
• Child CG, Turcotte JG. Surgery and portal hypertension. Major Probl Clin Surg. 1964;1:1–85.4950264
   PubMedGoogle Scholar
• Coll M, Perea L, Boon R, et al. Generation of hepatic stellate cells from human pluripotent stem cells enables in vitro modeling of liver fibrosis. Cell Stem Cell. 2018;23(1):101–113. doi:10.1016/j.stem.2018.05.02730049452
   PubMed Web of Science ®Google Scholar
• Leite SB, Roosens T, El Taghdouini A, et al. Novel human hepatic organoid model enables testing of drug-induced liver fibrosis in vitro. Biomaterials. 2016;78:1–10. doi:10.1016/j.biomaterials.2015.11.02626618472
   PubMed Web of Science ®Google Scholar
• Rodés J. Textbook of Hepatology: From Basic Science to Clinical Practice. 3rd ed. Malden, MA: Blackwell; 2007.
   Google Scholar
• Schuppan D, Afdhal NH. Liver cirrhosis. Lancet. 2008;371(9615):838–851. doi:10.1016/S0140-6736(08)60383-918328931
   PubMed Web of Science ®Google Scholar
• Gracia-Sancho J, Marrone G, Fernández-Iglesias A. Hepatic microcirculation and mechanisms of portal hypertension. Nat Rev Gastroenterol Hepatol. 2019;16(4):221–234. doi:10.1038/s41575-018-0097-330568278
   PubMed Web of Science ®Google Scholar
• Ginès P, Solà E, Angeli P, Wong F, Nadim MK, Kamath PS. Hepatorenal syndrome. Nat Rev Dis Primers. 2018;4(1):23. doi:10.1038/s41572-018-0022-730213943
   PubMed Web of Science ®Google Scholar
• Rodríguez-Roisin R, Krowka MJ. Hepatopulmonary syndrome–a liver-induced lung vascular disorder. N Engl J Med. 2008;358(22):2378–2387. doi:10.1056/NEJMra070718518509123
   PubMed Web of Science ®Google Scholar
• Porres-Aguilar M, Mukherjee D. Portopulmonary hypertension: an update. Respirology. 2015;20(2):235–242. doi:10.1111/resp.1245525523363
   PubMed Web of Science ®Google Scholar
• Garcia-Tsao G, Bosch J. Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med. 2010;362(9):823–832. doi:10.1056/NEJMra090151220200386
   PubMed Web of Science ®Google Scholar
• Wijdicks EF. Hepatic Encephalopathy. N Engl J Med. 2016;375(17):1660–1670. doi:10.1056/NEJMra160056127783916
   PubMed Web of Science ®Google Scholar
• Bedossa P, Poynard T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR cooperative study group. Hepatology. 1996;24(2):289–293. doi:10.1002/hep.5102402018690394
   PubMed Web of Science ®Google Scholar
• Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology. 1994;19(6):1513–1520.8188183
   PubMed Web of Science ®Google Scholar
• Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol. 1995;19(12):1409–1417.7503362
   PubMed Web of Science ®Google Scholar
• Ishak K, Baptista A, Bianchi L, et al. Histological grading and staging of chronic hepatitis. J Hepatol. 1995;22(6):696–699. doi:10.1016/0168-8278(95)80226-67560864
   PubMed Web of Science ®Google Scholar
• Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology. 1981;1(5):431–435.7308988
   PubMed Web of Science ®Google Scholar
• Poordad FF. FIBROSpect II: a potential noninvasive test to assess hepatic fibrosis. Expert Rev Mol Diagn. 2004;4(5):593–597. doi:10.1586/14737159.4.5.59315347253
   PubMed Web of Science ®Google Scholar
• Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38(2):518–526. doi:10.1053/jhep.2003.5034612883497
   PubMed Web of Science ®Google Scholar
• Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43(6):1317–1325. doi:10.1002/hep.2117816729309
   PubMed Web of Science ®Google Scholar
• Koda M, Matunaga Y, Kawakami M, Kishimoto Y, Suou T, Murawaki Y. FibroIndex, a practical index for predicting significant fibrosis in patients with chronic hepatitis C. Hepatology. 2007;45(2):297–306. doi:10.1002/hep.2152017256741
   PubMed Web of Science ®Google Scholar
• Forns X, Ampurdanès S, Llovet JM, et al. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Hepatology. 2002;36(4 Pt 1):986–992. doi:10.1053/jhep.2002.3612812297848
   PubMed Web of Science ®Google Scholar
• Adams LA, Bulsara M, Rossi E, et al. Hepascore: an accurate validated predictor of liver fibrosis in chronic hepatitis C infection. Clin Chem. 2005;51(10):1867–1873. doi:10.1373/clinchem.2005.04838916055434
   PubMed Web of Science ®Google Scholar
• Poynard T, Imbert-Bismut F, Munteanu M, et al. Overview of the diagnostic value of biochemical markers of liver fibrosis (FibroTest, HCV FibroSure) and necrosis (ActiTest) in patients with chronic hepatitis C. Comp Hepatol. 2004;3(1):8. doi:10.1186/1476-5926-3-815387887
   PubMedGoogle Scholar
• Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest. 2003;112(12):1776–1784. doi:10.1172/JCI2053014679171
   PubMed Web of Science ®Google Scholar
• Mutsaers SE, Birnie K, Lansley S, Herrick SE, Lim CB, Prêle CM. Mesothelial cells in tissue repair and fibrosis. Front Pharmacol. 2015;6:113. doi:10.3389/fphar.2015.0011326106328
   PubMed Web of Science ®Google Scholar
• Lua I, Li Y, Pappoe LS, Asahina K. Myofibroblastic conversion and regeneration of mesothelial cells in peritoneal and liver fibrosis. Am J Pathol. 2015;185(12):3258–3273. doi:10.1016/j.ajpath.2015.08.00926598235
   PubMed Web of Science ®Google Scholar
• Mederacke I, Hsu CC, Troeger JS, et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat Commun. 2013;4:2823. doi:10.1038/ncomms382324264436
   PubMed Web of Science ®Google Scholar
• Iwaisako K, Jiang C, Zhang M, et al. Origin of myofibroblasts in the fibrotic liver in mice. Proc Natl Acad Sci USA. 2014;111(32):E3297–E3305. doi:10.1073/pnas.140006211125074909
   PubMed Web of Science ®Google Scholar
• Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev. 2008;88(1):125–172.18195085
   PubMed Web of Science ®Google Scholar
• D’Ambrosio DN, Walewski JL, Clugston RD, Berk PD, Rippe RA, Blaner WS. Distinct populations of hepatic stellate cells in the mouse liver have different capacities for retinoid and lipid storage. PLoS One. 2011;6(9):e24993. doi:10.1371/journal.pone.002499321949825
   PubMed Web of Science ®Google Scholar
• Friedman SL. Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem. 2000;275(4):2247–2250. doi:10.1074/jbc.275.4.224710644669
   PubMed Web of Science ®Google Scholar
• Mihm S. Danger-associated molecular patterns (DAMPs): molecular triggers for sterile inflammation in the liver. Int J Mol Sci. 2018;19:10. doi:10.3390/ijms19103104
   Web of Science ®Google Scholar
• Wree A, Eguchi A, McGeough MD, et al. NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice. Hepatology. 2014;59(3):898–910. doi:10.1002/hep.2659223813842
   PubMed Web of Science ®Google Scholar
• McHedlidze T, Waldner M, Zopf S, et al. Interleukin-33-dependent innate lymphoid cells mediate hepatic fibrosis. Immunity. 2013;39(2):357–371. doi:10.1016/j.immuni.2013.07.01823954132
   PubMed Web of Science ®Google Scholar
• Canbay A, Taimr P, Torok N, Higuchi H, Friedman S, Gores GJ. Apoptotic body engulfment by a human stellate cell line is profibrogenic. Lab Invest. 2003;83(5):655–663.12746475
   PubMed Web of Science ®Google Scholar
• Zhan SS, Jiang JX, Wu J, et al. Phagocytosis of apoptotic bodies by hepatic stellate cells induces NADPH oxidase and is associated with liver fibrosis in vivo. Hepatology. 2006;43(3):435–443. doi:10.1002/hep.2109316496318
   PubMed Web of Science ®Google Scholar
• Tacke F, Zimmermann HW. Macrophage heterogeneity in liver injury and fibrosis. J Hepatol. 2014;60(5):1090–1096. doi:10.1016/j.jhep.2013.12.02524412603
   PubMed Web of Science ®Google Scholar
• Fallowfield JA, Mizuno M, Kendall TJ, et al. Scar-associated macrophages are a major source of hepatic matrix metalloproteinase-13 and facilitate the resolution of murine hepatic fibrosis. J Immunol. 2007;178(8):5288–5295. doi:10.4049/jimmunol.178.8.528817404313
   PubMed Web of Science ®Google Scholar
• Pellicoro A, Aucott RL, Ramachandran P, et al. Elastin accumulation is regulated at the level of degradation by macrophage metalloelastase (MMP-12) during experimental liver fibrosis. Hepatology. 2012;55(6):1965–1975. doi:10.1002/hep.2556722223197
   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 U S A. 2012;109(46):E3186–E3195. doi:10.1073/pnas.111996410923100531
   PubMed Web of Science ®Google Scholar
• Aoyama T, Inokuchi S, Brenner DA, Seki E. CX3CL1-CX3CR1 interaction prevents carbon tetrachloride-induced liver inflammation and fibrosis in mice. Hepatology. 2010;52(4):1390–1400. doi:10.1002/hep.2379520683935
   PubMed Web of Science ®Google Scholar
• Schuppan D, Ruehl M, Somasundaram R, Hahn EG. Matrix as a modulator of hepatic fibrogenesis. Semin Liver Dis. 2001;21(3):351–372. doi:10.1055/s-2001-1755611586465
   PubMed Web of Science ®Google Scholar
• Olaso E, Ikeda K, Eng FJ, et al. DDR2 receptor promotes MMP-2-mediated proliferation and invasion by hepatic stellate cells. J Clin Invest. 2001;108(9):1369–1378. doi:10.1172/JCI1237311696582
   PubMed Web of Science ®Google Scholar
• Wells RG. The role of matrix stiffness in regulating cell behavior. Hepatology. 2008;47(4):1394–1400. doi:10.1002/hep.2219318307210
   PubMed Web of Science ®Google Scholar
• Henderson NC, Arnold TD, Katamura Y, et al. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med. 2013;19(12):1617–1624. doi:10.1038/nm.328224216753
   PubMed Web of Science ®Google Scholar
• Ikeda K, Wang LH, Torres R, et al. Discoidin domain receptor 2 interacts with Src and Shc following its activation by type I collagen. J Biol Chem. 2002;277(21):19206–19212. doi:10.1074/jbc.M20107820011884411
   PubMed Web of Science ®Google Scholar
• Friedman SL, Sheppard D, Duffield JS, Violette S. Therapy for fibrotic diseases: nearing the starting line. Sci Transl Med. 2013;5(167):167sr161. doi:10.1126/scitranslmed.3004700
   Web of Science ®Google Scholar
• Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol. 2014;15(12):786–801. doi:10.1038/nrm390425415508
   PubMed Web of Science ®Google Scholar
• Kurokawa T, Zheng YW, Ohkohchi N. Novel functions of platelets in the liver. J Gastroenterol Hepatol. 2016;31(4):745–751. doi:10.1111/jgh.1324426632220
   PubMed Web of Science ®Google Scholar
• Nowatari T, Murata S, Fukunaga K, Ohkohchi N. Role of platelets in chronic liver disease and acute liver injury. Hepatol Res. 2014;44(2):165–172. doi:10.1111/hepr.1220523841688
   PubMed Web of Science ®Google Scholar
• Jeong WI, Park O, Suh YG, et al. Suppression of innate immunity (natural killer cell/interferon-γ) in the advanced stages of liver fibrosis in mice. Hepatology. 2011;53(4):1342–1351. doi:10.1002/hep.2419021480338
   PubMed Web of Science ®Google Scholar
• Glässner A, Eisenhardt M, Krämer B, et al. NK cells from HCV-infected patients effectively induce apoptosis of activated primary human hepatic stellate cells in a TRAIL-, FasL- and NKG2D-dependent manner. Lab Invest. 2012;92(7):967–977. doi:10.1038/labinvest.2012.5422449797
   PubMed Web of Science ®Google Scholar
• Krizhanovsky V, Yon M, Dickins RA, et al. Senescence of activated stellate cells limits liver fibrosis. Cell. 2008;134(4):657–667. doi:10.1016/j.cell.2008.06.04918724938
   PubMed Web of Science ®Google Scholar
• Deleve LD, Wang X, Guo Y. Sinusoidal endothelial cells prevent rat stellate cell activation and promote reversion to quiescence. Hepatology. 2008;48(3):920–930. doi:10.1002/hep.2235118613151
   PubMed Web of Science ®Google Scholar
• Ding BS, Cao Z, Lis R, et al. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature. 2014;505(7481):97–102. doi:10.1038/nature1268124256728
   PubMed Web of Science ®Google Scholar
• Thapa M, Chinnadurai R, Velazquez VM, et al. Liver fibrosis occurs through dysregulation of MyD88-dependent innate B-cell activity. Hepatology. 2015;61(6):2067–2079. doi:10.1002/hep.2776125711908
   PubMed Web of Science ®Google Scholar
• Novobrantseva TI, Majeau GR, Amatucci A, et al. Attenuated liver fibrosis in the absence of B cells. J Clin Invest. 2005;115(11):3072–3082. doi:10.1172/JCI2479816276416
   PubMed Web of Science ®Google Scholar
• Shi M, Zhu J, Wang R, et al. Latent TGF-β structure and activation. Nature. 2011;474(7351):343–349. doi:10.1038/nature1015221677751
   PubMed Web of Science ®Google Scholar
• Dooley S, Ten Dijke P. TGF-β in progression of liver disease. Cell Tissue Res. 2012;347(1):245–256. doi:10.1007/s00441-011-1246-y22006249
   PubMed Web of Science ®Google Scholar
• Kocabayoglu P, Lade A, Lee YA, et al. β-PDGF receptor expressed by hepatic stellate cells regulates fibrosis in murine liver injury, but not carcinogenesis. J Hepatol. 2015;63(1):141–147. doi:10.1016/j.jhep.2015.01.03625678385
   PubMed Web of Science ®Google Scholar
• Czochra P, Klopcic B, Meyer E, et al. Liver fibrosis induced by hepatic overexpression of PDGF-B in transgenic mice. J Hepatol. 2006;45(3):419–428. doi:10.1016/j.jhep.2006.04.01016842882
   PubMed Web of Science ®Google Scholar
• Hao C, Xie Y, Peng M, et al. Inhibition of connective tissue growth factor suppresses hepatic stellate cell activation in vitro and prevents liver fibrosis in vivo. Clin Exp Med. 2014;14(2):141–150. doi:10.1007/s10238-013-0229-623456538
   PubMed Web of Science ®Google Scholar
• Fuchs BC, Hoshida Y, Fujii T, et al. Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma. Hepatology. 2014;59(4):1577–1590. doi:10.1002/hep.2689824677197
   PubMed Web of Science ®Google Scholar
• Lanaya H, Natarajan A, Komposch K, et al. EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation. Nat Cell Biol. 2014;16(10):972–977. doi:10.1038/ncb303125173978
   PubMed Web of Science ®Google Scholar
• Chung SI, Moon H, Ju HL, et al. Hepatic expression of Sonic Hedgehog induces liver fibrosis and promotes hepatocarcinogenesis in a transgenic mouse model. J Hepatol. 2016;64(3):618–627. doi:10.1016/j.jhep.2015.10.00726471504
   PubMed Web of Science ®Google Scholar
• Chen Y, Choi SS, Michelotti GA, et al. Hedgehog controls hepatic stellate cell fate by regulating metabolism. Gastroenterology. 2012;143(5):1319–1329. doi:10.1053/j.gastro.2012.07.11522885334
   PubMed Web of Science ®Google Scholar
• El-Agroudy NN, El-Naga RN, El-Razeq RA, El-Demerdash E. Forskolin, a hedgehog signalling inhibitor, attenuates carbon tetrachloride-induced liver fibrosis in rats. Br J Pharmacol. 2016;173(22):3248–3260. doi:10.1111/bph.1361127590029
   PubMed Web of Science ®Google Scholar
• Pratap A, Singh S, Mundra V, et al. Attenuation of early liver fibrosis by pharmacological inhibition of smoothened receptor signaling. J Drug Target. 2012;20(9):770–782. doi:10.3109/1061186X.2012.71990022994359
   PubMed Web of Science ®Google Scholar
• Mallat A, Teixeira-Clerc F, Lotersztajn S. Cannabinoid signaling and liver therapeutics. J Hepatol. 2013;59(4):891–896. doi:10.1016/j.jhep.2013.03.03223567085
   PubMed Web of Science ®Google Scholar
• Guillot A, Hamdaoui N, Bizy A, et al. Cannabinoid receptor 2 counteracts interleukin-17-induced immune and fibrogenic responses in mouse liver. Hepatology. 2014;59(1):296–306. doi:10.1002/hep.2659823813495
   PubMed Web of Science ®Google Scholar
• Gross B, Pawlak M, Lefebvre P, Staels B. PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD. Nat Rev Endocrinol. 2017;13(1):36–49. doi:10.1038/nrendo.2016.13527636730
   PubMed Web of Science ®Google Scholar
• Zhang F, Kong D, Chen L, et al. Peroxisome proliferator-activated receptor-γ interrupts angiogenic signal transduction by transrepression of platelet-derived growth factor-β receptor in hepatic stellate cells. J Cell Sci. 2014;127(Pt 2):305–314. doi:10.1242/jcs.12830624259663
   PubMed Web of Science ®Google Scholar
• Qian J, Niu M, Zhai X, Zhou Q, Zhou Y. β-Catenin pathway is required for TGF-β1 inhibition of PPARγ expression in cultured hepatic stellate cells. Pharmacol Res. 2012;66(3):219–225. doi:10.1016/j.phrs.2012.06.00322706027
   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):1675–1685. doi:10.1056/NEJMoa090792920427778
   PubMed Web of Science ®Google Scholar
• Ratziu V, Harrison SA, Francque S, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-α and -δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150(5):1147–1159. doi:10.1053/j.gastro.2016.01.03826874076
   PubMed Web of Science ®Google Scholar
• Rotman Y, Sanyal AJ. Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease. Gut. 2017;66(1):180–190. doi:10.1136/gutjnl-2016-31243127646933
   PubMed Web of Science ®Google Scholar
• Neuschwander-Tetri BA, Loomba R, Sanyal AJ, et al. Farnesoid X nuclear receptor ligand obeticholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): a multicentre, randomised, placebo-controlled trial. Lancet. 2015;385(9972):956–965. doi:10.1016/S0140-6736(14)61933-425468160
   PubMed Web of Science ®Google Scholar
• Ding N, RT Y, Subramaniam N, et al. A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell. 2013;153(3):601–613. doi:10.1016/j.cell.2013.03.02823622244
   PubMed Web of Science ®Google Scholar
• Hellemans K, Grinko I, Rombouts K, Schuppan D, Geerts A. All-trans and 9-cis retinoic acid alter rat hepatic stellate cell phenotype differentially. Gut. 1999;45(1):134–142. doi:10.1136/gut.45.1.13410369717
   PubMed Web of Science ®Google Scholar
• Duran A, Hernandez ED, Reina-Campos M, et al. p62/SQSTM1 by binding to vitamin D receptor inhibits hepatic stellate cell activity, fibrosis, and liver cancer. Cancer Cell. 2016;30(4):595–609. doi:10.1016/j.ccell.2016.09.00427728806
   PubMed Web of Science ®Google Scholar
• Beaven SW, Wroblewski K, Wang J, et al. Liver X receptor signaling is a determinant of stellate cell activation and susceptibility to fibrotic liver disease. Gastroenterology. 2011;140(3):1052–1062. doi:10.1053/j.gastro.2010.11.05321134374
   PubMed Web of Science ®Google Scholar
• Li T, Eheim AL, Klein S, et al. Novel role of nuclear receptor Rev-erbα in hepatic stellate cell activation: potential therapeutic target for liver injury. Hepatology. 2014;59(6):2383–2396. doi:10.1002/hep.2704924497272
   PubMed Web of Science ®Google Scholar
• Okuno M, Moriwaki H, Imai S, et al. Retinoids exacerbate rat liver fibrosis by inducing the activation of latent TGF-β in liver stellate cells. Hepatology. 1997;26(4):913–921. doi:10.1053/jhep.1997.v26.pm00093283139328313
   PubMed Web of Science ®Google Scholar
• Hardy T, Mann DA. Epigenetics in liver disease: from biology to therapeutics. Gut. 2016;65(11):1895–1905. doi:10.1136/gutjnl-2015-31129227624887
   PubMed Web of Science ®Google Scholar
• Mann J, Chu DC, Maxwell A, et al. MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology. 2010;138(2):705–714. doi:10.1053/j.gastro.2009.10.002
   Web of Science ®Google Scholar
• Mann J, Oakley F, Akiboye F, Elsharkawy A, Thorne AW, Mann DA. Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis. Cell Death Differ. 2007;14(2):275–285. doi:10.1038/sj.cdd.440197916763620
   PubMed Web of Science ®Google Scholar
• El Taghdouini A, Sørensen AL, Reiner AH, et al. Genome-wide analysis of DNA methylation and gene expression patterns in purified, uncultured human liver cells and activated hepatic stellate cells. Oncotarget. 2015;6(29):26729–26745. doi:10.18632/oncotarget.492526353929
   PubMed Web of Science ®Google Scholar
• Bian EB, Huang C, Ma TT, et al. DNMT1-mediated PTEN hypermethylation confers hepatic stellate cell activation and liver fibrogenesis in rats. Toxicol Appl Pharmacol. 2012;264(1):13–22. doi:10.1016/j.taap.2012.06.02222841775
   PubMed Web of Science ®Google Scholar
• Zeybel M, Hardy T, Wong YK, et al. Multigenerational epigenetic adaptation of the hepatic wound-healing response. Nat Med. 2012;18(9):1369–1377. doi:10.1038/nm.289322941276
   PubMed Web of Science ®Google Scholar
• Kitano M, Bloomston PM. Hepatic stellate cells and microRNAs in pathogenesis of liver fibrosis. J Clin Med. 2016;5:3. doi:10.3390/jcm5030038
   Web of Science ®Google Scholar
• Yu F, Lu Z, Huang K, et al. MicroRNA-17-5p-activated Wnt/β-catenin pathway contributes to the progression of liver fibrosis. Oncotarget. 2016;7(1):81–93. doi:10.18632/oncotarget.644726637809
   PubMedGoogle Scholar
• Coll M, El Taghdouini A, Perea L, et al. Integrative miRNA and gene expression profiling analysis of human quiescent hepatic stellate cells. Sci Rep. 2015;5:11549. doi:10.1038/srep1154926096707
   PubMed Web of Science ®Google Scholar
• Hyun J, Wang S, Kim J, et al. MicroRNA-378 limits activation of hepatic stellate cells and liver fibrosis by suppressing Gli3 expression. Nat Commun. 2016;7:10993. doi:10.1038/ncomms1099327001906
   PubMed Web of Science ®Google Scholar
• Sun X, He Y, Ma TT, Huang C, Zhang L, Li J. Participation of miR-200a in TGF-β1-mediated hepatic stellate cell activation. Mol Cell Biochem. 2014;388(1–2):11–23. doi:10.1007/s11010-013-1895-024242045
   PubMed Web of Science ®Google Scholar
• Yang JJ, Tao H, Hu W, et al. MicroRNA-200a controls Nrf2 activation by target Keap1 in hepatic stellate cell proliferation and fibrosis. Cell Signal. 2014;26(11):2381–2389. doi:10.1016/j.cellsig.2014.07.01625049078
   PubMed Web of Science ®Google Scholar
• Yang JJ, Tao H, Liu LP, Hu W, Deng ZY, Li J. miR-200a controls hepatic stellate cell activation and fibrosis via SIRT1/Notch1 signal pathway. Inflamm Res. 2017;66(4):341–352. doi:10.1007/s00011-016-1020-428025657
   PubMed Web of Science ®Google Scholar
• Page A, Paoli PP, Hill SJ, et al. Alcohol directly stimulates epigenetic modifications in hepatic stellate cells. J Hepatol. 2015;62(2):388–397. doi:10.1016/j.jhep.2014.09.03325457206
   PubMed Web of Science ®Google Scholar
• Hernández-Gea V, Hilscher M, Rozenfeld R, et al. Endoplasmic reticulum stress induces fibrogenic activity in hepatic stellate cells through autophagy. J Hepatol. 2013;59(1):98–104. doi:10.1016/j.jhep.2013.02.01623485523
   PubMed Web of Science ®Google Scholar
• Thoen LF, Guimarães EL, Dollé L, et al. A role for autophagy during hepatic stellate cell activation. J Hepatol. 2011;55(6):1353–1360. doi:10.1016/j.jhep.2011.07.01021803012
   PubMed Web of Science ®Google Scholar
• Hernández-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):938–946. doi:10.1053/j.gastro.2011.12.04422240484
   PubMed Web of Science ®Google Scholar
• Koo JH, Lee HJ, Kim W, Kim SG. Endoplasmic reticulum stress in hepatic stellate cells promotes liver fibrosis via PERK-mediated degradation of HNRNPA1 and up-regulation of SMAD2. Gastroenterology. 2016;150(1):181–193. doi:10.1053/j.gastro.2015.09.03926435271
   PubMed Web of Science ®Google Scholar
• Kim RS, Hasegawa D, Goossens N, et al. The XBP1 arm of the unfolded protein response induces fibrogenic activity in hepatic stellate cells through autophagy. Sci Rep. 2016;6:39342.27996033
   PubMed Web of Science ®Google Scholar
• Heindryckx F, Binet F, Ponticos M, et al. Endoplasmic reticulum stress enhances fibrosis through IRE1α-mediated degradation of miR-150 and XBP-1 splicing. EMBO Mol Med. 2016;8(7):729–744. doi:10.15252/emmm.20150592527226027
   PubMed Web of Science ®Google Scholar
• Kawasaki K, Ushioda R, Ito S, Ikeda K, Masago Y, Nagata K. Deletion of the collagen-specific molecular chaperone Hsp47 causes endoplasmic reticulum stress-mediated apoptosis of hepatic stellate cells. J Biol Chem. 2015;290(6):3639–3646. doi:10.1074/jbc.M114.59213925525267
   PubMed Web of Science ®Google Scholar
• Yi HS, Lee YS, Byun JS, et al. Alcohol dehydrogenase III exacerbates liver fibrosis by enhancing stellate cell activation and suppressing natural killer cells in mice. Hepatology. 2014;60(3):1044–1053. doi:10.1002/hep.2713724668648
   PubMed Web of Science ®Google Scholar
• Wilson CL, Murphy LB, Leslie J, et al. Ubiquitin C-terminal hydrolase 1: a novel functional marker for liver myofibroblasts and a therapeutic target in chronic liver disease. J Hepatol. 2015;63(6):1421–1428. doi:10.1016/j.jhep.2015.07.03426264933
   PubMed Web of Science ®Google Scholar
• Meng F, Wang K, Aoyama T, et al. Interleukin-17 signaling in inflammatory, Kupffer cells, and hepatic stellate cells exacerbates liver fibrosis in mice. Gastroenterology. 2012;143(3):765–776.doi:10.1053/j.gastro.2012.05.04922687286
   PubMed Web of Science ®Google Scholar
• Chiu YS, Wei CC, Lin YJ, Hsu YH, Chang MS. IL-20 and IL-20R1 antibodies protect against liver fibrosis. Hepatology. 2014;60(3):1003–1014. doi:10.1002/hep.2718924763901
   PubMed Web of Science ®Google Scholar
• Jiao J, Ooka K, Fey H, et al. Interleukin-15 receptor α on hepatic stellate cells regulates hepatic fibrogenesis in mice. J Hepatol. 2016;65(2):344–353. doi:10.1016/j.jhep.2016.04.02027154062
   PubMed Web of Science ®Google Scholar
• Kong X, Feng D, Wang H, et al. Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. Hepatology. 2012;56(3):1150–1159. doi:10.1002/hep.2574422473749
   PubMed Web of Science ®Google Scholar
• Pellicoro A, Ramachandran P, Iredale JP, Fallowfield JA. Liver fibrosis and repair: immune regulation of wound healing in a solid organ. Nat Rev Immunol. 2014;14(3):181–194. doi:10.1038/nri362324566915
   PubMed Web of Science ®Google Scholar
• Kendall TJ, Hennedige S, Aucott RL, et al. p75 Neurotrophin receptor signaling regulates hepatic myofibroblast proliferation and apoptosis in recovery from rodent liver fibrosis. Hepatology. 2009;49(3):901–910. doi:10.1002/hep.2270119072833
   PubMed Web of Science ®Google Scholar
• Oh Y, Park O, Swierczewska M, et al. Systemic PEGylated TRAIL treatment ameliorates liver cirrhosis in rats by eliminating activated hepatic stellate cells. Hepatology. 2016;64(1):209–223. doi:10.1002/hep.2843226710118
   PubMed Web of Science ®Google Scholar
• Fink SL, Cookson BT. Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect Immun. 2005;73(4):1907–1916. doi:10.1128/IAI.73.4.1907-1916.200515784530
   PubMed Web of Science ®Google Scholar
• Lee YA, Wallace MC, Friedman SL. Pathobiology of liver fibrosis: a translational success story. Gut. 2015;64(5):830–841. doi:10.1136/gutjnl-2014-30684225681399
   PubMed Web of Science ®Google Scholar
• Karin M, Lin A. NF-κB at the crossroads of life and death. Nat Immunol. 2002;3(3):221–227. doi:10.1038/ni0302-22111875461
   PubMed Web of Science ®Google Scholar
• Kucharczak J, Simmons MJ, Fan Y, Gélinas C. To be, or not to be: NF-κB is the answer–role of Rel/NF-κB in the regulation of apoptosis. Oncogene. 2003;22(56):8961–8982. doi:10.1038/sj.onc.120723014663476
   PubMed Web of Science ®Google Scholar
• Pradere JP, Kluwe J, De Minicis S, et al. Hepatic macrophages but not dendritic cells contribute to liver fibrosis by promoting the survival of activated hepatic stellate cells in mice. Hepatology. 2013;58(4):1461–1473. doi:10.1002/hep.2642923553591
   PubMed Web of Science ®Google Scholar
• Anan A, Baskin-Bey ES, Bronk SF, Werneburg NW, Shah VH, Gores GJ. Proteasome inhibition induces hepatic stellate cell apoptosis. Hepatology. 2006;43(2):335–344. doi:10.1002/hep.2103616440346
   PubMed Web of Science ®Google Scholar
• Murphy FR, Issa R, Zhou X, et al. Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver fibrosis. J Biol Chem. 2002;277(13):11069–11076. doi:10.1074/jbc.M11149020011796725
   PubMed Web of Science ®Google Scholar
• Shaker ME, Ghani A, Shiha GE, Ibrahim TM, Mehal WZ. Nilotinib induces apoptosis and autophagic cell death of activated hepatic stellate cells via inhibition of histone deacetylases. Biochim Biophys Acta. 2013;1833(8):1992–2003. doi:10.1016/j.bbamcr.2013.02.03323499874
   PubMed Web of Science ®Google Scholar
• Dhanasekaran DN, Reddy EP. JNK signaling in apoptosis. Oncogene. 2008;27(48):6245–6251. doi:10.1038/onc.2008.30118931691
   PubMed Web of Science ®Google Scholar
• Hao H, Zhang D, Shi J, et al. Sorafenib induces autophagic cell death and apoptosis in hepatic stellate cell through the JNK and Akt signaling pathways. Anticancer Drugs. 2016;27(3):192–203. doi:10.1097/CAD.000000000000031626629768
   PubMed Web of Science ®Google Scholar
• Muñoz-Espín D, Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol. 2014;15(7):482–496. doi:10.1038/nrm382324954210
   PubMed Web of Science ®Google Scholar
• Chicas A, Wang X, Zhang C, et al. Dissecting the unique role of the retinoblastoma tumor suppressor during cellular senescence. Cancer Cell. 2010;17(4):376–387. doi:10.1016/j.ccr.2010.01.02320385362
   PubMed Web of Science ®Google Scholar
• Sun P, Yoshizuka N, New L, et al. PRAK is essential for ras-induced senescence and tumor suppression. Cell. 2007;128(2):295–308. doi:10.1016/j.cell.2006.11.05017254968
   PubMed Web of Science ®Google Scholar
• Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997;88(5):593–602. doi:10.1016/s0092-8674(00)81902-99054499
   PubMed Web of Science ®Google Scholar
• Alimonti A, Nardella C, Chen Z, et al. A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. J Clin Invest. 2010;120(3):681–693. doi:10.1172/JCI4053520197621
   PubMed Web of Science ®Google Scholar
• Schnabl B, Purbeck CA, Choi YH, Hagedorn CH, Brenner D. Replicative senescence of activated human hepatic stellate cells is accompanied by a pronounced inflammatory but less fibrogenic phenotype. Hepatology. 2003;37(3):653–664. doi:10.1053/jhep.2003.5009712601363
   PubMed Web of Science ®Google Scholar
• Evan GI, d’Adda Di Fagagna F. Cellular senescence: hot or what? Curr Opin Genet Dev. 2009;19(1):25–31. doi:10.1016/j.gde.2008.11.00919181515
   PubMed Web of Science ®Google Scholar
• Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013;75:685–705. doi:10.1146/annurev-physiol-030212-18365323140366
   PubMed Web of Science ®Google Scholar
• Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99–118.20078217
   PubMed Web of Science ®Google Scholar
• Kuilman T, Peeper DS. Senescence-messaging secretome: SMS-ing cellular stress. Nat Rev Cancer. 2009;9(2):81–94. doi:10.1038/nrc256019132009
   PubMed Web of Science ®Google Scholar
• Acosta JC, O’Loghlen A, Banito A, et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell. 2008;133(6):1006–1018. doi:10.1016/j.cell.2008.03.03818555777
   PubMed Web of Science ®Google Scholar
• Kuilman T, Michaloglou C, Vredeveld LC, et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell. 2008;133(6):1019–1031. doi:10.1016/j.cell.2008.03.03918555778
   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 U S A. 2012;109(24):9448–9453. doi:10.1073/pnas.120184010922566629
   PubMed Web of Science ®Google Scholar
• Troeger JS, Mederacke I, Gwak GY, et al. Deactivation of hepatic stellate cells during liver fibrosis resolution in mice. Gastroenterology. 2012;143(4):1073–1083.doi:10.1053/j.gastro.2012.06.03622750464
   PubMed Web of Science ®Google Scholar
• Huang P, Zhang L, Gao Y, et al. Direct reprogramming of human fibroblasts to functional and expandable hepatocytes. Cell Stem Cell. 2014;14(3):370–384. doi:10.1016/j.stem.2014.01.00324582927
   PubMed Web of Science ®Google Scholar
• Song G, Pacher M, Balakrishnan A, et al. Direct reprogramming of hepatic myofibroblasts into hepatocytes in vivo attenuates liver fibrosis. Cell Stem Cell. 2016;18(6):797–808. doi:10.1016/j.stem.2016.01.01026923201
   PubMed Web of Science ®Google Scholar
• Chang ML, Yeh CT, Chang PY, Chen JC. Comparison of murine cirrhosis models induced by hepatotoxin administration and common bile duct ligation. World J Gastroenterol. 2005;11(27):4167–4172. doi:10.3748/wjg.v11.i27.416716015684
   PubMed Web of Science ®Google Scholar
• van Zonneveld M, Zondervan PE, Cakaloglu Y, et al. Peg-interferon improves liver histology in patients with HBeAg-positive chronic hepatitis B: no additional benefit of combination with lamivudine. Liver Int. 2006;26(4):399–405. doi:10.1111/j.1478-3231.2006.01257.x16629642
   PubMed Web of Science ®Google Scholar
• Xu B, Lin L, Xu G, et al. Long-term lamivudine treatment achieves regression of advanced liver fibrosis/cirrhosis in patients with chronic hepatitis B. J Gastroenterol Hepatol. 2015;30(2):372–378. doi:10.1111/jgh.1271825167956
   PubMed Web of Science ®Google Scholar
• Dienstag JL, Goldin RD, Heathcote EJ, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology. 2003;124(1):105–117. doi:10.1053/gast.2003.5001312512035
   PubMed Web of Science ®Google Scholar
• Marcellin P, Gane E, Buti M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study. Lancet. 2013;381(9865):468–475. doi:10.1016/S0140-6736(12)61425-123234725
   PubMed Web of Science ®Google Scholar
• Buti M, Fung S, Gane E, et al. Long-term clinical outcomes in cirrhotic chronic hepatitis B patients treated with tenofovir disoproxil fumarate for up to 5 years. Hepatol Int. 2015;9(2):243–250. doi:10.1007/s12072-015-9614-425788199
   PubMed Web of Science ®Google Scholar
• Tsai NC, Marcellin P, Buti M, et al. Viral suppression and cirrhosis regression with tenofovir disoproxil fumarate in Asians with chronic hepatitis B. Dig Dis Sci. 2015;60(1):260–268. doi:10.1007/s10620-014-3336-725179493
   PubMed Web of Science ®Google Scholar
• Chang TT, Liaw YF, Wu SS, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology. 2010;52(3):886–893. doi:10.1002/hep.2378520683932
   PubMed Web of Science ®Google Scholar
• Schiff ER, Lee SS, Chao YC, et al. Long-term treatment with entecavir induces reversal of advanced fibrosis or cirrhosis in patients with chronic hepatitis B. Clin Gastroenterol Hepatol. 2011;9(3):274–276. doi:10.1016/j.cgh.2010.11.04021145419
   PubMed Web of Science ®Google Scholar
• Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B for up to 5 years. Gastroenterology. 2006;131(6):1743–1751. doi:10.1053/j.gastro.2006.09.02017087951
   PubMed Web of Science ®Google Scholar
• Hou JL, Xu D, Shi G, et al. Long-term telbivudine treatment results in resolution of liver inflammation and fibrosis in patients with chronic hepatitis B. Adv Ther. 2015;32(8):727–741. doi:10.1007/s12325-015-0232-226329749
   PubMed Web of Science ®Google Scholar
• Lok AS, Everhart JE, Chung RT, et al. Evolution of hepatic steatosis in patients with advanced hepatitis C: results from the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial. Hepatology. 2009;49(6):1828–1837. doi:10.1002/hep.2286519291787
   PubMed Web of Science ®Google Scholar
• Chen CJ, Yang HI, Iloeje UH, Group R-HS. Hepatitis B virus DNA levels and outcomes in chronic hepatitis B. Hepatology. 2009;49(5 Suppl):S72–S84. doi:10.1002/hep.2288419399801
   PubMed Web of Science ®Google Scholar
• George SL, Bacon BR, Brunt EM, Mihindukulasuriya KL, Hoffmann J, Di Bisceglie AM. Clinical, virologic, histologic, and biochemical outcomes after successful HCV therapy: a 5-year follow-up of 150 patients. Hepatology. 2009;49(3):729–738. doi:10.1002/hep.2269419072828
   PubMed Web of Science ®Google Scholar
• Bachofner JA, Valli PV, Kröger A, et al. Direct antiviral agent treatment of chronic hepatitis C results in rapid regression of transient elastography and fibrosis markers fibrosis-4 score and aspartate aminotransferase-platelet ratio index. Liver Int. 2017;37(3):369–376. doi:10.1111/liv.1325627678216
   PubMed Web of Science ®Google Scholar
• Enomoto M, Ikura Y, Tamori A, et al. Short-term histological evaluations after achieving a sustained virologic response to direct-acting antiviral treatment for chronic hepatitis C. United Eur Gastroenterol J. 2018;6(9):1391–1400. doi:10.1177/2050640618791053
   Web of Science ®Google Scholar
• Lledó GM, Carrasco I, Benítez-Gutiérrez LM, et al. Regression of liver fibrosis after curing chronic hepatitis C with oral antivirals in patients with and without HIV coinfection. AIDS. 2018;32(16):2347–2352. doi:10.1097/QAD.000000000000196630096074
   PubMed Web of Science ®Google Scholar
• Colmenero J, Bataller R, Sancho-Bru P, et al. Effects of losartan on hepatic expression of nonphagocytic NADPH oxidase and fibrogenic genes in patients with chronic hepatitis C. Am J Physiol Gastrointest Liver Physiol. 2009;297(4):G726–G734. doi:10.1152/ajpgi.00162.200919628656
   PubMed Web of Science ®Google Scholar
• McHutchison J, Goodman Z, Patel K, et al. Farglitazar lacks antifibrotic activity in patients with chronic hepatitis C infection. Gastroenterology. 2010;138(4):1365–1373. doi:10.1053/j.gastro.2009.12.003
   Web of Science ®Google Scholar
• Verrill C, Markham H, Templeton A, Carr NJ, Sheron N. Alcohol-related cirrhosis–early abstinence is a key factor in prognosis, even in the most severe cases. Addiction. 2009;104(5):768–774. doi:10.1111/j.1360-0443.2009.02521.x19344445
   PubMed Web of Science ®Google Scholar
• Kim MY, Cho MY, Baik SK, et al. Beneficial effects of candesartan, an angiotensin-blocking agent, on compensated alcoholic liver fibrosis - a randomized open-label controlled study. Liver Int. 2012;32(6):977–987. doi:10.1111/j.1478-3231.2012.02774.x22364262
   PubMed Web of Science ®Google Scholar
• Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology. 2002;36(3):525–531. doi:10.1053/jhep.2002.3608812198643
   PubMed Web of Science ®Google Scholar
• Poupon RE, Poupon R, Balkau B. Ursodiol for the long-term treatment of primary biliary cirrhosis. The UDCA-PBC study group. N Engl J Med. 1994;330(19):1342–1347. doi:10.1056/NEJM1994051233019038152446
   PubMed Web of Science ®Google Scholar
• Corpechot C, Carrat F, Bonnand AM, Poupon RE, Poupon R. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology. 2000;32(6):1196–1199. doi:10.1053/jhep.2000.2024011093724
   PubMed Web of Science ®Google Scholar
• Czaja AJ, Carpenter HA. Decreased fibrosis during corticosteroid therapy of autoimmune hepatitis. J Hepatol. 2004;40(4):646–652. doi:10.1016/j.jhep.2004.01.00915030981
   PubMed Web of Science ®Google Scholar
• Mohamadnejad M, Malekzadeh R, Nasseri-Moghaddam S, et al. Impact of immunosuppressive treatment on liver fibrosis in autoimmune hepatitis. Dig Dis Sci. 2005;50(3):547–551. doi:10.1007/s10620-005-2472-515810640
   PubMed Web of Science ®Google Scholar
• Falize L, Guillygomarc’h A, Perrin M, et al. Reversibility of hepatic fibrosis in treated genetic hemochromatosis: a study of 36 cases. Hepatology. 2006;44(2):472–477. doi:10.1002/hep.2126016871557
   PubMed Web of Science ®Google Scholar
• Brunt EM, Kleiner DE, Wilson LA, Belt P, Neuschwander-Tetri BA; (CRN) NCRN. Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology. 2011;53(3):810–820. doi:10.1002/hep.2412721319198
   PubMed Web of Science ®Google Scholar
• Promrat K, Kleiner DE, Niemeier HM, et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51(1):121–129. doi:10.1002/hep.2327619827166
   PubMed Web of Science ®Google Scholar
• Aithal GP, Thomas JA, Kaye PV, et al. Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology. 2008;135(4):1176–1184. doi:10.1053/j.gastro.2008.06.04718718471
   PubMed Web of Science ®Google Scholar
• Ratziu V, Charlotte F, Bernhardt C, et al. Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology. 2010;51(2):445–453. doi:10.1002/hep.2327019877169
   PubMed Web of Science ®Google Scholar
• Zein CO, Yerian LM, Gogate P, et al. Pentoxifylline improves nonalcoholic steatohepatitis: a randomized placebo-controlled trial. Hepatology. 2011;54(5):1610–1619. doi:10.1002/hep.2454421748765
   PubMed Web of Science ®Google Scholar
• Gorina E, Richeldi L, Raghu G, et al. PRAISE, a randomized, placebo-controlled, double-blind Phase 2 clinical trial of pamrevlumab (FG-3019) in IPF patients. Eur Respir J. 2017;50(suppl61):OA3400. doi:10.1183/13993003.00711-2017
   Web of Science ®Google Scholar
• Harrison SA, Abdelmalek MF, Caldwell S, et al. Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis. Gastroenterology. 2018;155(4):1140–1153. doi:10.1053/j.gastro.2018.07.00629990488
   PubMed Web of Science ®Google Scholar
• Patsenker E, Popov Y, Stickel F, Jonczyk A, Goodman SL, Schuppan D. Inhibition of integrin αvβ6 on cholangiocytes blocks transforming growth factor-β activation and retards biliary fibrosis progression. Gastroenterology. 2008;135(2):660–670. doi:10.1053/j.gastro.2008.04.00918538673
   PubMed Web of Science ®Google Scholar
• Friedman SL, Ratziu V, Harrison SA, et al. A randomized, placebo-controlled trial of cenicriviroc for treatment of nonalcoholic steatohepatitis with fibrosis. Hepatology. 2018;67(5):1754–1767. doi:10.1002/hep.2947728833331
   PubMed Web of Science ®Google Scholar
• Frenette CT, Morelli G, Shiffman ML, et al. Emricasan improves liver function in patients with cirrhosis and high Model for End-Stage Liver Disease scores compared with placebo. Clin Gastroenterol Hepatol. 2019;17(4):774–783. doi:10.1016/j.cgh.2018.06.01229913280
   PubMed Web of Science ®Google Scholar
• Loomba R, Lawitz E, Mantry PS, et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology. 2018;67(2):549–559. doi:10.1002/hep.29514.28892558
   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. doi:10.1111/liv.1221823782511
   PubMed Web of Science ®Google Scholar
• Zhang Z, Lin H, Shi M, et al. Human umbilical cord mesenchymal stem cells improve liver function and ascites in decompensated liver cirrhosis patients. J Gastroenterol Hepatol. 2012;27(Suppl 2):112–120. doi:10.1111/j.1440-1746.2011.07024.x22320928
   PubMed Web of Science ®Google Scholar
• Shi M, Zhang Z, Xu R, et al. Human mesenchymal stem cell transfusion is safe and improves liver function in acute-on-chronic liver failure patients. Stem Cells Transl Med. 2012;1(10):725–731. doi:10.5966/sctm.2012-003423197664
   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. doi:10.1111/jgh.1202923855301
   PubMed Web of Science ®Google Scholar
• Mohamadnejad M, Alimoghaddam K, Mohyeddin-Bonab M, et al. Phase 1 trial of autologous bone marrow mesenchymal stem cell transplantation in patients with decompensated liver cirrhosis. Arch Iran Med. 2007;10(4):459–466.17903050
   PubMed Web of Science ®Google Scholar
• Kharaziha P, Hellström PM, Noorinayer B, et al. Improvement of liver function in liver cirrhosis patients after autologous mesenchymal stem cell injection: a phase I-II clinical trial. Eur J Gastroenterol Hepatol. 2009;21(10):1199–1205. doi:10.1097/MEG.0b013e32832a1f6c19455046
   PubMed Web of Science ®Google Scholar
• Peng L, Xie DY, Lin BL, et al. Autologous bone marrow mesenchymal stem cell transplantation in liver failure patients caused by hepatitis B: short-term and long-term outcomes. Hepatology. 2011;54(3):820–828. doi:10.1002/hep.2443421608000
   PubMed Web of Science ®Google Scholar
• El-Ansary M, Abdel-Aziz I, Mogawer S, et al. Phase II trial: undifferentiated versus differentiated autologous mesenchymal stem cells transplantation in Egyptian patients with HCV induced liver cirrhosis. Stem Cell Rev. 2012;8(3):972–981. doi:10.1007/s12015-011-9322-y
   PubMed Web of Science ®Google Scholar
• Amin MA, Sabry D, Rashed LA, et al. Short-term evaluation of autologous transplantation of bone marrow-derived mesenchymal stem cells in patients with cirrhosis: Egyptian study. Clin Transplant. 2013;27(4):607–612. doi:10.1111/ctr.1217923923970
   PubMed Web of Science ®Google Scholar
• Fellouse FA, Wiesmann C, Sidhu SS. Synthetic antibodies from a four-amino-acid code: a dominant role for tyrosine in antigen recognition. Proc Natl Acad Sci U S A. 2004;101(34):12467–12472. doi:10.1073/pnas.040178610115306681
   PubMed Web of Science ®Google Scholar
• Kuai J, Mosyak L, Brooks J, et al. Characterization of binding mode of action of a blocking anti-platelet-derived growth factor (PDGF)-B monoclonal antibody, MOR8457, reveals conformational flexibility and avidity needed for PDGF-BB to bind PDGF receptor-β. Biochemistry. 2015;54(10):1918–1929. doi:10.1021/bi501542525707433
   PubMed Web of Science ®Google Scholar
• Huang HW, Mohan SK, Yu C. The NMR solution structure of human epidermal growth factor (hEGF) at physiological pH and its interactions with suramin. Biochem Biophys Res Commun. 2010;402(4):705–710. doi:10.1016/j.bbrc.2010.10.08921029725
   PubMed Web of Science ®Google Scholar
• Hua C, Zhu Y, Xu W, et al. Characterization by high-resolution crystal structure analysis of a triple-helix region of human collagen type III with potent cell adhesion activity. Biochem Biophys Res Commun. 2019;508(4):1018–1023. doi:10.1016/j.bbrc.2018.12.01830545625
   PubMed Web of Science ®Google Scholar
• Elkins PA, Ho YS, Smith WW, et al. Structure of the C-terminally truncated human ProMMP9, a gelatin-binding matrix metalloproteinase. Acta Crystallogr D Biol Crystallogr. 2002;58(Pt 7):1182–1192. doi:10.1107/s090744490200784912077439
   PubMedGoogle Scholar
• Rose AS, Bradley AR, Valasatava Y, Duarte JM, Prlic A, Rose PW. NGL viewer: web-based molecular graphics for large complexes. Bioinformatics. 2018;34(21):3755–3758. doi:10.1093/bioinformatics/bty41929850778
   PubMed Web of Science ®Google Scholar
• Hart PJ, Deep S, Taylor AB, Shu Z, Hinck CS, Hinck AP. Crystal structure of the human TβR2 ectodomain–TGF-β3 complex. Nat Struct Biol. 2002;9(3):203–208. doi:10.1038/nsb76611850637
   PubMedGoogle Scholar
• Ogunjimi AA, Zeqiraj E, Ceccarelli DF, Sicheri F, Wrana JL, David L. Structural basis for specificity of TGFβ family receptor small molecule inhibitors. Cell Signal. 2012;24(2):476–483. doi:10.1016/j.cellsig.2011.09.02721983015
   PubMed Web of Science ®Google Scholar
• Tebben AJ, Ruzanov M, Gao M, et al. Crystal structures of apo and inhibitor-bound TGFβR2 kinase domain: insights into TGFβR isoform selectivity. Acta Crystallogr D Struct Biol. 2016;72(Pt 5):658–674. doi:10.1107/S205979831600362427139629
   PubMedGoogle Scholar
• Wang Q, Liu F, Qi S, et al. Discovery of 4-((N-(2-(dimethylamino)ethyl)acrylamido)methyl)-N-(4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)phenyl)benzamide (CHMFL-PDGFR-159) as a highly selective type II PDGFRα kinase inhibitor for PDGFRα driving chronic eosinophilic leukemia. Eur J Med Chem. 2018;150:366–384. doi:10.1016/j.ejmech.2018.03.00329544149
   PubMed Web of Science ®Google Scholar
• Peng P, Chen H, Zhu Y, et al. Structure-based design of 1-heteroaryl-1,3-propanediamine derivatives as a novel series of CC-chemokine receptor 5 antagonists. J Med Chem. 2018;61(21):9621–9636. doi:10.1021/acs.jmedchem.8b0107730234300
   PubMed Web of Science ®Google Scholar
• Liu S, Song X, Chrunyk BA, et al. Crystal structures of interleukin 17A and its complex with IL-17 receptor A. Nat Commun. 2013;4:1888. doi:10.1038/ncomms288023695682
   PubMed Web of Science ®Google Scholar
• Su L, Wang Y, Wang J, et al. Structural basis of TLR2/TLR1 activation by the synthetic agonist diprovocim. J Med Chem. 2019;62(6):2938–2949. doi:10.1021/acs.jmedchem.8b0158330829478
   PubMed Web of Science ®Google Scholar
• Mineev KS, Goncharuk SA, Arseniev AS. Toll-like receptor 3 transmembrane domain is able to perform various homotypic interactions: an NMR structural study. FEBS Lett. 2014;588(21):3802–3807. doi:10.1016/j.febslet.2014.08.03125217833
   PubMed Web of Science ®Google Scholar
• Nyman T, Stenmark P, Flodin S, Johansson I, Hammarström M, Nordlund P. The crystal structure of the human toll-like receptor 10 cytoplasmic domain reveals a putative signaling dimer. J Biol Chem. 2008;283(18):11861–11865. doi:10.1074/jbc.C80000120018332149
   PubMed Web of Science ®Google Scholar
• Casimiro-Garcia A, Bigge CF, Davis JA, et al. Effects of modifications of the linker in a series of phenylpropanoic acid derivatives: synthesis, evaluation as PPARα/γ dual agonists, and X-ray crystallographic studies. Bioorg Med Chem. 2008;16(9):4883–4907. doi:10.1016/j.bmc.2008.03.04318394907
   PubMed Web of Science ®Google Scholar
• Chandra V, Huang P, Hamuro Y, et al. Structure of the intact PPAR-γ-RXR- nuclear receptor complex on DNA. Nature. 2008;456(7220):350–356. doi:10.1038/nature0741319043829
   PubMed Web of Science ®Google Scholar