New drugs for NAFLD: lessons from basic models to the clinic

  • Katharina C. Reimer
  • Alexander Wree
  • Christoph Roderburg
  • Frank TackeEmail author
Review Article


The term nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of increasingly harmful conditions ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) to liver fibrosis and end-stage cirrhosis. NAFLD is the currently most common form of chronic liver disease in both adults and children worldwide. As NAFLD evolves as a global pandemic alongside the still growing prevalence of metabolic syndrome, obesity, and diabetes, it is inevitable to develop effective counterstrategies. Over the last decades, great effort has been dedicated to the understanding of the pathogenesis of NAFLD. This includes the development of an array of models for NAFLD, ranging from advanced in vitro (primary cells, 3D cultures, biochip, spheroids, organoids) to in vivo rodent models (particularly in mice). Based on these approaches novel therapies have been proposed and subsequently evaluated for patients with advanced forms of NAFLD, in particular those with NASH and liver fibrosis or cirrhosis. In this review, we delineate the current understanding of disease pathophysiology and depict how novel therapeutic strategies aim to exploit these different mechanisms to ameliorate, treat, or stop progression of NASH. We also discuss obstacles and chances along the way from basic models to promising clinical treatment options.

Graphical abstract


NAFLD NASH Fatty liver Fibrosis Animal models Clinical trials Endpoints 



This work was funded by German Research Foundation (WR173/3-1, TA434/3-1, SFB/TRR57 and CRC1382 to AW and FT) and German Cancer Aid (Deutsche Krebshilfe 70113000 to AW).

Compliance with ethical standards

Conflict of interest

Dr. Tacke’s group has received research funding from Allergan, Inventiva, Bristol Myers Squibb, and Galapagos. The other authors state no conflict of interest.

Research involving human and animals participants

This article is a review of the literature and does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Brunt EM, Neuschwander-Tetri BA, Oliver D, Wehmeier KR, Bacon BR. Nonalcoholic steatohepatitis: histologic features and clinical correlations with 30 blinded biopsy specimens. Hum Pathol. 2004;35(9):1070–82 (Epub 2004/09/).CrossRefGoogle Scholar
  2. 2.
    Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, et al. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology. 2005;129(1):113–21 (Epub 2005/07/14).CrossRefGoogle Scholar
  3. 3.
    Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116(6):1413–9 (Epub 1999/05/29).CrossRefGoogle Scholar
  4. 4.
    Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology (Baltimore, Md). 2016;64(1):73–84. 2015/12/29).CrossRefGoogle Scholar
  5. 5.
    Wong MCS, Huang JLW, George J, Huang J, Leung C, Eslam M, et al. The changing epidemiology of liver diseases in the Asia–Pacific region. Nat Rev Gastroenterol Hepatol. 2019;16(1):57–73. 2018/08/31).CrossRefPubMedGoogle Scholar
  6. 6.
    Bedossa P. Pathology of non-alcoholic fatty liver disease. Liver Int. 2017;37(Suppl 1):85–9. 2017/01/05).CrossRefPubMedGoogle Scholar
  7. 7.
    Ekstedt M, Hagstrom H, Nasr P, Fredrikson M, Stal P, Kechagias S, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology (Baltimore, Md). 2015;61(5):1547–54. 2014/08/16).CrossRefGoogle Scholar
  8. 8.
    Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z, et al. Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: systematic review and meta-analysis. Hepatology (Baltimore, Md). 2017;65(5):1557–65. 2017/01/29).CrossRefGoogle Scholar
  9. 9.
    Vilar-Gomez E, Calzadilla-Bertot L, Wai-Sun Wong V, Castellanos M, Aller-de la Fuente R, Metwally M, et al. Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study. Gastroenterology. 2018;155(2):443-57 e17. Scholar
  10. 10.
    Noureddin M, Vipani A, Bresee C, Todo T, Kim IK, Alkhouri N, et al. NASH leading cause of liver transplant in women: updated analysis of indications for liver transplant and ethnic and gender variances. Am J Gastroenterol. 2018;113(11):1649–59. 2018/06/09).CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64(6):1388–402. doi: 10.1016/j.jhep.2015.11.004.Google Scholar
  12. 12.
    Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology (Baltimore, Md). 2010;52(5):1836–46. 2010/11/03).CrossRefGoogle Scholar
  13. 13.
    Bechmann LP, Hannivoort RA, Gerken G, Hotamisligil GS, Trauner M, Canbay A. The interaction of hepatic lipid and glucose metabolism in liver diseases. J Hepatol. 2012;56(4):952–64. 2011/12/17).CrossRefPubMedGoogle Scholar
  14. 14.
    Wree A, Kahraman A, Gerken G, Canbay A. Obesity affects the liver - the link between adipocytes and hepatocytes. Digestion. 2011;83(1–2):124–33. 2010/11/03).CrossRefPubMedGoogle Scholar
  15. 15.
    Tacke F, Weiskirchen R. An update on the recent advances in antifibrotic therapy. Expert Rev Gastroenterol Hepatol. 2018;12(11):1143–52. 2018/09/29).CrossRefPubMedGoogle Scholar
  16. 16.
    Eguchi A, Wree A, Feldstein AE. Biomarkers of liver cell death. J Hepatol. 2014;60(5):1063–74. 2014/01/15).CrossRefPubMedGoogle Scholar
  17. 17.
    Luedde T, Kaplowitz N, Schwabe RF. Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology. 2014;147(4):765-83.e4. 2014/07/22).CrossRefGoogle Scholar
  18. 18.
    Schwabe RF, Luedde T. Apoptosis and necroptosis in the liver: a matter of life and death. Nat Rev Gastroenterol Hepatol. 2018;15(12):738–52. 2018/09/27).CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017;14(7):397–411. 2017/05/11).CrossRefPubMedGoogle Scholar
  20. 20.
    Nagashimada M, Ota T. Role of vitamin E in nonalcoholic fatty liver disease. IUBMB Life. 2019;71(4):516–22. 2018/12/29).CrossRefPubMedGoogle Scholar
  21. 21.
    Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362(18):1675–85. 2010/04/30).CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Chalasani NP, Sanyal AJ, Kowdley KV, Robuck PR, Hoofnagle J, Kleiner DE, et al. Pioglitazone versus vitamin E versus placebo for the treatment of non-diabetic patients with non-alcoholic steatohepatitis: PIVENS trial design. Contemp Clin Trials. 2009;30(1):88–96. 2008/09/23).CrossRefPubMedGoogle Scholar
  23. 23.
    Roeb E, Steffen HM, Bantel H, Baumann U, Canbay A, Demir M, et al. S2k Guideline non-alcoholic fatty liver disease. Z Gastroenterol. 2015;53(7):668–723. 2015/07/15).CrossRefPubMedGoogle Scholar
  24. 24.
    Barreyro FJ, Holod S, Finocchietto PV, Camino AM, Aquino JB, Avagnina A, et al. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int. 2015;35(3):953–66. 2014/04/23).CrossRefPubMedGoogle Scholar
  25. 25.
    Ichijo H, Nishida E, Irie K, ten Dijke P, Saitoh M, Moriguchi T, et al. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science (New York, NY). 1997;275(5296):90–4. 1997/01/03).CrossRefGoogle Scholar
  26. 26.
    Yamamoto E, Dong YF, Kataoka K, Yamashita T, Tokutomi Y, Matsuba S, et al. Olmesartan prevents cardiovascular injury and hepatic steatosis in obesity and diabetes, accompanied by apoptosis signal regulating kinase-1 inhibition. Hypertension (Dallas, Tex : 1979). 2008;52(3):573–80. Scholar
  27. 27.
    Anstee QM, Lawitz EJ, Alkhouri N, Wong VW, Romero-Gomez M, Okanoue T, et al. Noninvasive tests accurately identify advanced fibrosis due to NASH: baseline data from the STELLAR trials. Hepatology (Baltimore, Md). 2019. Scholar
  28. 28.
    Gilead Sciences I. Gilead Announces Topline Data From Phase 3 STELLAR-3 Study of Selonsertib in Bridging Fibrosis (F3) Due to Nonalcoholic Steatohepatitis (NASH) [Press release]. Gilead Sciences, Inc.; 2019 [updated 25.04.2019; cited 2019 17.07.2019].
  29. 29.
    Gilead Sciences I. Gilead Announces Topline Data From Phase 3 STELLAR-4 Study of Selonsertib in Compensated Cirrhosis (F4) Due to Nonalcoholic Steatohepatitis (NASH) [Press release]. Gilead Sciences, Inc.; 2019 [updated 11.02.2019; cited 2019 17.07.2019]. Scholar
  30. 30.
    Arab JP, Arrese M, Trauner M. Recent insights into the pathogenesis of nonalcoholic fatty liver disease. Annu Rev Pathol. 2018;13:321–50. 2018/02/).CrossRefPubMedGoogle Scholar
  31. 31.
    Fisher FM, Chui PC, Nasser IA, Popov Y, Cunniff JC, Lundasen T, et al. Fibroblast growth factor 21 limits lipotoxicity by promoting hepatic fatty acid activation in mice on methionine and choline-deficient diets. Gastroenterology. 2014;147(5):1073-83.e6. 2014/08/02).CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387(10019):679–90. 2015/11/27).CrossRefPubMedGoogle Scholar
  33. 33.
    Gross B, Pawlak M, Lefebvre P, Staels B. PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD. Nat Rev Endocrinol. 2017;13(1):36–49. 2016/11/04).CrossRefPubMedGoogle Scholar
  34. 34.
    Fuchs CD, Traussnigg SA, Trauner M. Nuclear receptor modulation for the treatment of nonalcoholic fatty liver disease. Semin Liver Dis. 2016;36(1):69–86. 2016/02/13).CrossRefPubMedGoogle Scholar
  35. 35.
    Jain MR, Giri SR, Bhoi B, Trivedi C, Rath A, Rathod R, et al. Dual PPARalpha/gamma agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models. Liver Int. 2018;38(6):1084–94. 2017/11/23).CrossRefPubMedGoogle Scholar
  36. 36.
    Abu-Elheiga L, Jayakumar A, Baldini A, Chirala SS, Wakil SJ. Human acetyl-CoA carboxylase: characterization, molecular cloning, and evidence for two isoforms. Proc Natl Acad Sci. 1995;92(9):4011–5. Scholar
  37. 37.
    Fickert P, Fuchsbichler A, Moustafa T, Wagner M, Zollner G, Halilbasic E, et al. Farnesoid X receptor critically determines the fibrotic response in mice but is expressed to a low extent in human hepatic stellate cells and periductal myofibroblasts. Am J Pathol. 2009;175(6):2392–405. 2009/11/17).CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Cipriani S, Mencarelli A, Palladino G, Fiorucci S. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res. 2010;51(4):771–84. 2009/09/29).CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Verbeke L, Farre R, Trebicka J, Komuta M, Roskams T, Klein S, et al. Obeticholic acid, a farnesoid X receptor agonist, improves portal hypertension by two distinct pathways in cirrhotic rats. Hepatology (Baltimore, Md). 2014;59(6):2286–98. 2013/11/22).CrossRefGoogle Scholar
  40. 40.
    Practice guideline autoimmune liver diseases—AWMF-Reg. No. 021-27. Z Gastroenterol. 2017;55(11):1135–226. doi: 10.1055/s-0043-120199.Google Scholar
  41. 41.
    Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van Natta ML, Abdelmalek MF, 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):956–65. 2014/12/04).CrossRefPubMedGoogle Scholar
  42. 42.
    Ratziu V, Sanyal AJ, Loomba R, Rinella M, Harrison S, Anstee QM, et al. Regenerate: design of a pivotal, randomised, phase 3 study evaluating the safety and efficacy of obeticholic acid in patients with fibrosis due to nonalcoholic steatohepatitis. Contemp Clin Trials. 2019. 2019/07/02).CrossRefPubMedGoogle Scholar
  43. 43.
    Staels B, Rubenstrunk A, Noel B, Rigou G, Delataille P, Millatt LJ, et al. Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology (Baltimore, Md). 2013;58(6):1941–52. 2013/05/25).CrossRefGoogle Scholar
  44. 44.
    Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al. Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150(5):1147-59.e5. 2016/02/14).CrossRefGoogle Scholar
  45. 45.
    Sanyal A, Charles ED, Neuschwander-Tetri BA, Loomba R, Harrison SA, Abdelmalek MF, et al. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet. 2019;392(10165):2705–17. 2018/12/18).CrossRefPubMedGoogle Scholar
  46. 46.
    Knudsen LB, Lau J. The discovery and development of liraglutide and semaglutide. Front Endocrinol (Lausanne). 2019;10:155. 2019/04/30).CrossRefGoogle Scholar
  47. 47.
    Rakipovski G, Rolin B, Nohr J, Klewe I, Frederiksen KS, Augustin R, et al. The GLP-1 analogs liraglutide and semaglutide reduce atherosclerosis in ApoE(−/−) and LDLr(−/−) mice by a mechanism that includes inflammatory pathways. JACC Basic Transl Sci. 2018;3(6):844–57. 2019/01/10).CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Iogna Prat L, Tsochatzis EA. The effect of antidiabetic medications on non-alcoholic fatty liver disease (NAFLD). Hormones (Athens). 2018;17(2):219–29. 2018/06/03).CrossRefGoogle Scholar
  49. 49.
    Petit JM, Cercueil JP, Loffroy R, Denimal D, Bouillet B, Fourmont C, et al. Effect of liraglutide therapy on liver fat content in patients with inadequately controlled type 2 diabetes: the lira-NAFLD study. J Clin Endocrinol Metab. 2017;102(2):407–15. 2016/10/13).CrossRefPubMedGoogle Scholar
  50. 50.
    Loomba R, Kayali Z, Noureddin M, Ruane P, Lawitz EJ, Bennett M, et al. GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease. Gastroenterology. 2018;155(5):1463-73.e6. 2018/07/31).CrossRefGoogle Scholar
  51. 51.
    Lawitz EJ, Coste A, Poordad F, Alkhouri N, Loo N, McColgan BJ, et al. Acetyl-CoA carboxylase inhibitor GS-0976 for 12 weeks reduces hepatic de novo lipogenesis and steatosis in patients with nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2018;16(12):1983-91.e3. 2018/05/01).CrossRefGoogle Scholar
  52. 52.
    Delacroix DL, Hodgson HJ, McPherson A, Dive C, Vaerman JP. Selective transport of polymeric immunoglobulin A in bile. Quantitative relationships of monomeric and polymeric immunoglobulin A, immunoglobulin M, and other proteins in serum, bile, and saliva. J Clin Investig. 1982;70(2):230–41. Scholar
  53. 53.
    Seki E, De Minicis S, Osterreicher CH, Kluwe J, Osawa Y, Brenner DA, et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nature medicine. 2007;13(11):1324–32. 2007/10/24).CrossRefPubMedGoogle Scholar
  54. 54.
    De Minicis S, Rychlicki C, Agostinelli L, Saccomanno S, Candelaresi C, Trozzi L, et al. Dysbiosis contributes to fibrogenesis in the course of chronic liver injury in mice. Hepatology (Baltimore, Md). 2014;59(5):1738–49. 2013/08/21).CrossRefGoogle Scholar
  55. 55.
    Hartmann P, Chen P, Wang HJ, Wang L, McCole DF, Brandl K, et al. Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice. Hepatology (Baltimore, Md). 2013;58(1):108–19. 2013/02/15).CrossRefGoogle Scholar
  56. 56.
    Wree A, Geisler LJ, Tacke F. Microbiome & NASH—partners in crime driving progression of fatty liver disease. Z Gastroenterol. 2019;57(7):871–82. 2019/07/10).CrossRefPubMedGoogle Scholar
  57. 57.
    Zhou M, Learned RM, Rossi SJ, DePaoli AM, Tian H, Ling L. Engineered FGF19 eliminates bile acid toxicity and lipotoxicity leading to resolution of steatohepatitis and fibrosis in mice. Hepatol Commun. 2017;1(10):1024–42. 2018/02/07).CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Luo J, Ko B, Elliott M, Zhou M, Lindhout DA, Phung V, et al. A nontumorigenic variant of FGF19 treats cholestatic liver diseases. Sci Transl Med. 2014;6(247):247ra100. 2014/08/01).CrossRefPubMedGoogle Scholar
  59. 59.
    Harrison SA, Rossi SJ, Paredes AH, Trotter JF, Bashir MR, Guy CD, et al. NGM282 improves liver fibrosis and histology in 12 weeks in patients with nonalcoholic steatohepatitis. Hepatology (Baltimore, Md). 2019. 2019/02/26).CrossRefGoogle Scholar
  60. 60.
    Harrison SA, Rinella ME, Abdelmalek MF, Trotter JF, Paredes AH, Arnold HL, et al. NGM282 for treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2018;391(10126):1174–85. 2018/03/10).CrossRefPubMedGoogle Scholar
  61. 61.
    Wells RG, Schwabe RF. Origin and function of myofibroblasts in the liver. Semin Liver Dis. 2015;35(2):e1. 2015/05/270).CrossRefPubMedGoogle Scholar
  62. 62.
    Krenkel O, Hundertmark J, Ritz TP, Weiskirchen R, Tacke F. Single cell RNA sequencing identifies subsets of hepatic stellate cells and myofibroblasts in liver fibrosis. Cells. 2019. 2019/05/30).CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Barry-Hamilton V, Spangler R, Marshall D, McCauley S, Rodriguez HM, Oyasu M, et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nature medicine. 2010;16(9):1009–17. 2010/09/08).CrossRefPubMedGoogle Scholar
  64. 64.
    Ikenaga N, Peng ZW, Vaid KA, Liu SB, Yoshida S, Sverdlov DY, et al. Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal. Gut. 2017;66(9):1697–708. 2017/01/12).CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Yang J, Savvatis K, Kang JS, Fan P, Zhong H, Schwartz K, et al. Targeting LOXL2 for cardiac interstitial fibrosis and heart failure treatment. Nat Commun. 2016;7:13710. 2016/12/15).CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Harrison SA, Abdelmalek MF, Caldwell S, Shiffman ML, Diehl AM, Ghalib R, et al. Simtuzumab is ineffective for patients with bridging fibrosis or compensated cirrhosis caused by nonalcoholic steatohepatitis. Gastroenterology. 2018;155(4):1140–53. 2018/07/11).CrossRefPubMedGoogle Scholar
  67. 67.
    Raghu G, Brown KK, Collard HR, Cottin V, Gibson KF, Kaner RJ, et al. Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, controlled, phase 2 trial. Lancet Respir Med. 2017;5(1):22–32. 2016/12/13).CrossRefPubMedGoogle Scholar
  68. 68.
    Marra F, Tacke F. Roles for chemokines in liver disease. Gastroenterology. 2014;147(3):577-94.e1. 2014/07/30).CrossRefGoogle Scholar
  69. 69.
    Karlmark KR, Weiskirchen R, Zimmermann HW, Gassler N, Ginhoux F, Weber C, et al. Hepatic recruitment of the inflammatory Gr1+ monocyte subset upon liver injury promotes hepatic fibrosis. Hepatology (Baltimore, Md). 2009;50(1):261–74. 2009/06/26).CrossRefGoogle Scholar
  70. 70.
    Zimmermann HW, Seidler S, Nattermann J, Gassler N, Hellerbrand C, Zernecke A, et al. Functional contribution of elevated circulating and hepatic non-classical CD14CD16 monocytes to inflammation and human liver fibrosis. PloS One. 2010;5(6):e11049. 2010/06/16).CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Seki E, de Minicis S, Inokuchi S, Taura K, Miyai K, van Rooijen N, et al. CCR71 promotes hepatic fibrosis in mice. Hepatology (Baltimore, Md). 2009;50(1):185–97. 2009/05/15).CrossRefGoogle Scholar
  72. 72.
    Baeck C, Wehr A, Karlmark KR, Heymann F, Vucur M, Gassler N, et al. Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. Gut. 2012;61(3):416–26. 2011/08/05).CrossRefPubMedGoogle Scholar
  73. 73.
    Krenkel O, Puengel T, Govaere O, Abdallah AT, Mossanen JC, Kohlhepp M, et al. Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis. Hepatology (Baltimore, Md). 2018;67(4):1270–83. 2017/09/25).CrossRefGoogle Scholar
  74. 74.
    Parker R, Weston CJ, Miao Z, Corbett C, Armstrong MJ, Ertl L, et al. CC chemokine receptor 2 promotes recruitment of myeloid cells associated with insulin resistance in nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol. 2018;314(4):G483-g93. 2018/02/09).CrossRefGoogle Scholar
  75. 75.
    Lefebvre E, Moyle G, Reshef R, Richman LP, Thompson M, Hong F, et al. Antifibrotic effects of the dual CCR75/CCR75 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PloS One. 2016;11(6):e0158156. 2016/06/28).CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Weston CJ, Shepherd EL, Claridge LC, Rantakari P, Curbishley SM, Tomlinson JW, et al. Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis. J Clin Investig. 2015;125(2):501–20. 2015/01/07).CrossRefPubMedGoogle Scholar
  77. 77.
    Traber PG, Chou H, Zomer E, Hong F, Klyosov A, Fiel MI, 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. 2013/10/17).CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Harrison SA, Marri SR, Chalasani N, Kohli R, Aronstein W, Thompson GA, et al. Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, vs placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis. Aliment Pharmacol Ther. 2016;44(11–12):1183–98. Scholar
  79. 79.
    Lee L, Alloosh M, Saxena R, Van Alstine W, Watkins BA, Klaunig JE, et al. Nutritional model of steatohepatitis and metabolic syndrome in the Ossabaw miniature swine. Hepatology (Baltimore, Md). 2009;50(1):56–67. 2009/05/13).CrossRefGoogle Scholar
  80. 80.
    Liang W, Menke AL, Driessen A, Koek GH, Lindeman JH, Stoop R, et al. Establishment of a general NAFLD scoring system for rodent models and comparison to human liver pathology. PloS One. 2014;9(12):e115922. Scholar
  81. 81.
    Rinella ME, Tacke F, Sanyal AJ, Anstee QM. Report on the AASLD/EASL joint workshop on clinical trial endpoints in NAFLD. J Hepatol. 2019. 2019/07/14).CrossRefPubMedGoogle Scholar
  82. 82.
    Farrell GC, Mridha AR, Yeh MM, Arsov T, Van Rooyen DM, Brooling J, et al. Strain dependence of diet-induced NASH and liver fibrosis in obese mice is linked to diabetes and inflammatory phenotype. Liver Int. 2014;34(7):1084–93. 2013/10/11).CrossRefPubMedGoogle Scholar
  83. 83.
    McGettigan B, McMahan R, Orlicky D, Burchill M, Danhorn T, Francis P, et al. Dietary lipids differentially shape nonalcoholic steatohepatitis progression and the transcriptome of kupffer cells and infiltrating macrophages. Hepatology (Baltimore, Md). 2019;70(1):67–83. 2018/12/06).CrossRefGoogle Scholar
  84. 84.
    Hansen HH, Feigh M, Veidal SS, Rigbolt KT, Vrang N, Fosgerau K. Mouse models of nonalcoholic steatohepatitis in preclinical drug development. Drug Discov Today. 2017;22(11):1707–18. Scholar
  85. 85.
    Santhekadur PK, Kumar DP, Sanyal AJ. Preclinical models of non-alcoholic fatty liver disease. J Hepatol. 2018;68(2):230–7. 2017/11/13).CrossRefPubMedGoogle Scholar
  86. 86.
    Febbraio MA, Reibe S, Shalapour S, Ooi GJ, Watt MJ, Karin M. Preclinical models for studying NASH-driven HCC: how useful are they? Cell Metab. 2019;29(1):18–26. 2018/11/20).CrossRefPubMedGoogle Scholar
  87. 87.
    Feaver RE, Cole BK, Lawson MJ, Hoang SA, Marukian S, Blackman BR, et al. Development of an in vitro human liver system for interrogating nonalcoholic steatohepatitis. JCI Insight. 2016;1(20):e90954. 2016/12/13).CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Rennert K, Steinborn S, Groger M, Ungerbock B, Jank AM, Ehgartner J, et al. A microfluidically perfused three dimensional human liver model. Biomaterials. 2015;71:119–31. 2015/09/01).CrossRefGoogle Scholar
  89. 89.
    Ouchi R, Togo S, Kimura M, Shinozawa T, Koido M, Koike H, et al. Modeling steatohepatitis in humans with pluripotent stem cell-derived organoids. Cell Metabolism. 2019. Scholar
  90. 90.
    (CDER) USDoHaHSFaDACfDEaR. Nonalcoholic Steatohepatitis with Compensated Cirrhosis: Developing Drugs for Treatment Guidance for Industry [Guidance document]. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER); 2019 [updated June 2019; cited 2019 17.07.2019].
  91. 91.
    (EMA) EMA. Draft reflection paper on regulatory requirements for the development of medicinal products for chronic non-infectious liver diseases (PBC, PSC, NASH) [guidance paper]. European Medicines Agency (EMA); 2018 [updated 12.12.2018; cited 2019 22.07.2019].
  92. 92.
    Budas G, Karnik S, Jonnson T, Shafizadeh T, Watkins S, Breckenridge D, et al. Reduction of liver steatosis and fibrosis with an ask1 inhibitor in a murine model of nash is accompanied by improvements in cholesterol, bile acid and lipid metabolism. J Hepatol. 2016;64(2):S170. Scholar
  93. 93.
    Loomba R, Lawitz E, Mantry PS, Jayakumar S, Caldwell SH, Arnold H, et al. The ASK1 inhibitor selonsertib in patients with nonalcoholic steatohepatitis: a randomized, phase 2 trial. Hepatology (Baltimore, Md). 2018;67(2):549–59. 2017/09/12).CrossRefGoogle Scholar
  94. 94.
    Markham A, Keam SJ. Obeticholic acid: first global approval. Drugs. 2016;76(12):1221–6. 2016/07/14).CrossRefPubMedGoogle Scholar
  95. 95.
    Yu D, Cai SY, Mennone A, Vig P, Boyer JL. Cenicriviroc, a cytokine receptor antagonist, potentiates all-trans retinoic acid in reducing liver injury in cholestatic rodents. Liver Int. 2018;38(6):1128–38. 2018/01/23).CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Puengel T, Krenkel O, Kohlhepp M, Lefebvre E, Luedde T, Trautwein C, et al. Differential impact of the dual CCR96/CCR96 inhibitor cenicriviroc on migration of monocyte and lymphocyte subsets in acute liver injury. PloS One. 2017;12(9):e0184694. 2017/09/15).CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Kruger AJ, Fuchs BC, Masia R, Holmes JA, Salloum S, Sojoodi M, et al. Prolonged cenicriviroc therapy reduces hepatic fibrosis despite steatohepatitis in a diet-induced mouse model of nonalcoholic steatohepatitis. Hepatol Commun. 2018;2(5):529–45. 2018/05/16).CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Mossanen JC, Krenkel O, Ergen C, Govaere O, Liepelt A, Puengel T, et al. Chemokine (C-C motif) receptor 2-positive monocytes aggravate the early phase of acetaminophen-induced acute liver injury. Hepatology (Baltimore, Md). 2016;64(5):1667–82. 2016/10/22).CrossRefGoogle Scholar
  99. 99.
    Friedman S, Sanyal A, Goodman Z, Lefebvre E, Gottwald M, Fischer L, et al. Efficacy and safety study of cenicriviroc for the treatment of non-alcoholic steatohepatitis in adult subjects with liver fibrosis: CENTAUR Phase 2b study design. Contemp Clin Trials. 2016;47:356–65. 2016/03/06).CrossRefPubMedGoogle Scholar
  100. 100.
    Ratziu V, Sanyal A, Francque S, Wai-Sun Wong V, Loomba R, Goodman Z, Lefebvre E, Aithal GP, Harrison, SA, Abdelmalek MF, Friedman SL, Tacke F. Cenicriviroc treatment for adults with non-alcoholic steatohepatitis: year 2 analysis of the phase 2b CENTAUR study [conference talk]. International Liver Congress 2019, EASL, Paris: EASL; 2018 [updated 16.04.2018; cited 2019 17.07.2019].
  101. 101.
    Cao W, An X, Cong L, Lyu C, Zhou Q, Guo R. Application of deep learning in quantitative analysis of 2-dimensional ultrasound imaging of nonalcoholic fatty liver disease. J Ultrasound Med. 2019. 2019/06/22).CrossRefPubMedGoogle Scholar
  102. 102.
    Singh A, Dhaliwal AS, Singh S, Kumar A, Lopez R, Gupta M, et al. Awareness of nonalcoholic fatty liver disease is increasing but remains very low in a representative US cohort. Dig Dis Sci. 2019. 2019/06/13).CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Corey KE, Wilson LA, Altinbas A, Yates KP, Kleiner DE, Chung RT, et al. Relationship between resolution of non-alcoholic steatohepatitis and changes in lipoprotein sub-fractions: a post-hoc analysis of the PIVENS trial. Aliment Pharmacol Ther. 2019;49(9):1205–13. 2019/03/12).CrossRefPubMedGoogle Scholar
  104. 104.
    Tully DC, Rucker PV, Chianelli D, Williams J, Vidal A, Alper PB, et al. Discovery of tropifexor (LJN452), a highly potent non-bile acid FXR agonist for the treatment of cholestatic liver diseases and nonalcoholic steatohepatitis (NASH). J Med Chem. 2017;60(24):9960–73. 2017/11/18).CrossRefPubMedGoogle Scholar
  105. 105.
    Kaul U, Parmar D, Manjunath K, Shah M, Parmar K, Patil KP, et al. New dual peroxisome proliferator activated receptor agonist—Saroglitazar in diabetic dyslipidemia and non-alcoholic fatty liver disease: integrated analysis of the real world evidence. Cardiovasc Diabetol. 2019;18(1):80. Scholar
  106. 106.
    Odegaard JI, Ricardo-Gonzalez RR, Red Eagle A, Vats D, Morel CR, Goforth MH, et al. Alternative M2 activation of Kupffer cells by PPARdelta ameliorates obesity-induced insulin resistance. Cell Metab. 2008;7(6):496–507. 2008/06/05).CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Lee CH, Olson P, Hevener A, Mehl I, Chong LW, Olefsky JM, et al. PPARdelta regulates glucose metabolism and insulin sensitivity. Proc Natl Acad Sci USA. 2006;103(9):3444–9. 2006/02/24).CrossRefPubMedGoogle Scholar
  108. 108.
    Leone TC, Weinheimer CJ, Kelly DP. A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci USA. 1999;96(13):7473–8. 1999/06/23).CrossRefPubMedGoogle Scholar
  109. 109.
    Harriman G, Greenwood J, Bhat S, Huang X, Wang R, Paul D, et al. Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats. Proc Natl Acad Sci. 2016;113(13):E1796–805. Scholar
  110. 110.
    Struik D, Dommerholt MB, Jonker JW. Fibroblast growth factors in control of lipid metabolism: from biological function to clinical application. Curr Opin Lipidol. 2019;30(3):235–43. 2019/03/21).CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    McCommis KS, Hodges WT, Brunt EM, Nalbantoglu I, McDonald WG, Holley C, et al. Targeting the mitochondrial pyruvate carrier attenuates fibrosis in a mouse model of nonalcoholic steatohepatitis. Hepatology (Baltimore, Md). 2017;65(5):1543–56. 2016/12/28).CrossRefGoogle Scholar
  112. 112.
    McCommis KS, Chen Z, Fu X, McDonald WG, Colca JR, Kletzien RF, et al. Loss of mitochondrial pyruvate carrier 2 in the liver leads to defects in gluconeogenesis and compensation via pyruvate-alanine cycling. Cell Metab. 2015;22(4):682–94. 2015/09/08).CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Bricker DK, Taylor EB, Schell JC, Orsak T, Boutron A, Chen YC, et al. A mitochondrial pyruvate carrier required for pyruvate uptake in yeast, Drosophila, and humans. Science (New York, NY). 2012;337(6090):96–100. 2012/05/26).CrossRefGoogle Scholar
  114. 114.
    Nagampalli RSK, Quesnay JEN, Adamoski D, Islam Z, Birch J, Sebinelli HG, et al. Human mitochondrial pyruvate carrier 2 as an autonomous membrane transporter. Sci Rep. 2018;8(1):3510. 2018/02/24).CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Kelly MJ, Pietranico-Cole S, Larigan JD, Haynes NE, Reynolds CH, Scott N, et al. Discovery of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydropyridazin-3-yloxy)phenyl]-3,5-dio xo-2,3,4,5-tetrahydro[1,2,4]triazine-6-carbonitrile (MGL-3196), a Highly Selective Thyroid Hormone Receptor beta agonist in clinical trials for the treatment of dyslipidemia. J Med Chem. 2014;57(10):3912–23. 2014/04/10).CrossRefPubMedGoogle Scholar
  116. 116.
    Taub R, Chiang E, Chabot-Blanchet M, Kelly MJ, Reeves RA, Guertin MC, et al. Lipid lowering in healthy volunteers treated with multiple doses of MGL-3196, a liver-targeted thyroid hormone receptor-beta agonist. Atherosclerosis. 2013;230(2):373–80. 2013/10/01).CrossRefPubMedGoogle Scholar
  117. 117.
    Dibba P, Li AA, Perumpail BJ, John N, Sallam S, Shah ND, et al. Emerging therapeutic targets and experimental drugs for the treatment of NAFLD. Diseases. 2018. 2018/09/22).CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Roth JD, Veidal SS, Fensholdt LKD, Rigbolt KTG, Papazyan R, Nielsen JC, et al. Combined obeticholic acid and elafibranor treatment promotes additive liver histological improvements in a diet-induced ob/ob mouse model of biopsy-confirmed NASH. Sci Rep. 2019;9(1):9046. 2019/06/23).CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Lindstrom P. The physiology of obese-hyperglycemic mice [ob/ob mice]. Sci World J. 2007;7:666–85. 2007/07/11).CrossRefGoogle Scholar
  120. 120.
    Mayer J, Bates MW, Dickie MM. Hereditary diabetes in genetically obese mice. Science (New York, NY). 1951;113(2948):746–7. 1951/06/29).CrossRefGoogle Scholar
  121. 121.
    Hummel KP, Dickie MM, Coleman DL. Diabetes, a new mutation in the mouse. Science (New York, NY). 1966;153(3740):1127–8. 1966/09/02).CrossRefGoogle Scholar
  122. 122.
    Hum D SA, Harrison S, et al. Elafibranor: a liver targeted PPARα/δ agonist for a global management of nash patients. In: EASL, editor. Poster session presented at: The International Liver Congress Meeting, EASL; 2016 April 13–17; Barcelona, Spain. 2016.Google Scholar
  123. 123.
    Poekes L, Legry V, Farrell G, Leclercq I. Role of ciliary dysfunction in a new model of obesity and non-alcoholic steatohepatitis: the foz/fozmice. Arch Publ Health. 2014;72(1):O7. Scholar
  124. 124.
    Heydet D, Chen LX, Larter CZ, Inglis C, Silverman MA, Farrell GC, et al. A truncating mutation of Alms1 reduces the number of hypothalamic neuronal cilia in obese mice. Dev Neurobiol. 2013;73(1):1–13. 2012/05/15).CrossRefPubMedGoogle Scholar
  125. 125.
    Arsov T, Silva DG, O’Bryan MK, Sainsbury A, Lee NJ, Kennedy C, et al. Fat Aussie—a new alström syndrome mouse showing a critical role for ALMS1 in obesity, diabetes, and spermatogenesis. Mol Endocrinol. 2006;20(7):1610–22. Scholar
  126. 126.
    Liepelt A, Wehr A, Kohlhepp M, Mossanen JC, Kreggenwinkel K, Denecke B, et al. CXCR127 protects from inflammation and fibrosis in NEMO(LPC-KO) mice. Biochim Biophys Acta Mol Basis Dis. 2019;1865(2):391–402. 2018/11/27).CrossRefPubMedGoogle Scholar
  127. 127.
    Luedde T, Beraza N, Kotsikoris V, van Loo G, Nenci A, De Vos R, et al. Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell. 2007;11(2):119–32. 2007/02/13).CrossRefPubMedGoogle Scholar
  128. 128.
    Horie Y, Suzuki A, Kataoka E, Sasaki T, Hamada K, Sasaki J, et al. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J Clin Investig. 2004;113(12):1774–83. Scholar
  129. 129.
    Stiles B, Wang Y, Stahl A, Bassilian S, Lee WP, Kim Y-J, et al. Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity. Proc Natl Acad Sci. 2004;101(7):2082–7. Scholar
  130. 130.
    Cole BK, Feaver RE, Wamhoff BR, Dash A. Non-alcoholic fatty liver disease (NAFLD) models in drug discovery. Expert Opin Drug Discov. 2018;13(2):193–205. 2017/12/01).CrossRefPubMedGoogle Scholar
  131. 131.
    Kawashita E, Ishihara K, Nomoto M, Taniguchi M, Akiba S. A comparative analysis of hepatic pathological phenotypes in C57BL/6J and C57BL/6N mouse strains in non-alcoholic steatohepatitis models. Sci Rep. 2019;9(1):204. 2019/01/20).CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Mells JE, Fu PP, Sharma S, Olson D, Cheng L, Handy JA, et al. Glp-1 analog, liraglutide, ameliorates hepatic steatosis and cardiac hypertrophy in C57BL/6J mice fed a Western diet. Am J Physiol Gastrointest Liver Physiol. 2012;302(2):G225–35. 2011/11/01).CrossRefPubMedGoogle Scholar
  133. 133.
    Matsumoto M, Hada N, Sakamaki Y, Uno A, Shiga T, Tanaka C, et al. An improved mouse model that rapidly develops fibrosis in non-alcoholic steatohepatitis. Int J Exp Pathol. 2013;94(2):93–103. Scholar
  134. 134.
    Fujii M, Shibazaki Y, Wakamatsu K, Honda Y, Kawauchi Y, Suzuki K, et al. A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma. Med Mol Morphol. 2013;46(3):141–52. 2013/02/23).CrossRefPubMedGoogle Scholar
  135. 135.
    Lo L, McLennan SV, Williams PF, Bonner J, Chowdhury S, McCaughan GW, et al. Diabetes is a progression factor for hepatic fibrosis in a high fat fed mouse obesity model of non-alcoholic steatohepatitis. J Hepatol. 2011;55(2):435–44. 2010/12/28).CrossRefPubMedGoogle Scholar
  136. 136.
    Stefano JT, Pereira IV, Torres MM, Bida PM, Coelho AM, Xerfan MP, et al. Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model. Braz J Med Biol Res. 2015;48(5):408–14. 2015/02/26).CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Kluwe J, Pradere JP, Gwak GY, Mencin A, De Minicis S, Österreicher CH, et al. Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition. Gastroenterology. 2010;138(1):347–59. Scholar
  138. 138.
    Tag CG, Sauer-Lehnen S, Weiskirchen S, Borkham-Kamphorst E, Tolba RH, Tacke F, et al. Bile duct ligation in mice: induction of inflammatory liver injury and fibrosis by obstructive cholestasis. J Vis Exp. 2015. Scholar
  139. 139.
    Asgharpour A, Cazanave SC, Pacana T, Seneshaw M, Vincent R, Banini BA, et al. A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer. J Hepatol. 2016;65(3):579–88. 2016/06/05).CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Hernandez ED, Zheng L, Kim Y, Fang B, Liu B, Valdez RA, et al. Tropifexor-mediated abrogation of steatohepatitis and fibrosis is associated with the antioxidative gene expression profile in rodents. Hepatol Commun. 2019;3(8):1085–97. 2019/08/08).CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Tetri LH, Basaranoglu M, Brunt EM, Yerian LM, Neuschwander-Tetri BA. Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. Am J Physiol Gastrointest Liver Physiol. 2008;295(5):G987–95. Scholar
  142. 142.
    Schierwagen R, Maybuchen L, Zimmer S, Hittatiya K, Back C, Klein S, et al. Seven weeks of Western diet in apolipoprotein-E-deficient mice induce metabolic syndrome and non-alcoholic steatohepatitis with liver fibrosis. Sci Rep. 2015;5:12931. 2015/08/12).CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Sun G, Jackson CV, Zimmerman K, Zhang LK, Finnearty CM, Sandusky GE, et al. The FATZO mouse, a next generation model of type 2 diabetes, develops NAFLD and NASH when fed a Western diet supplemented with fructose. BMC Gastroenterol. 2019;19(1):41. 2019/03/20).CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Shalapour S, Lin XJ, Bastian IN, Brain J, Burt AD, Aksenov AA, et al. Inflammation-induced IgA+ cells dismantle anti-liver cancer immunity. Nature. 2017;551(7680):340–5. 2017/11/17).CrossRefPubMedPubMedCentralGoogle Scholar
  145. 145.
    Nakagawa H, Umemura A, Taniguchi K, Font-Burgada J, Dhar D, Ogata H, et al. ER stress cooperates with hypernutrition to trigger TNF-dependent spontaneous HCC development. Cancer Cell. 2014;26(3):331–43. Scholar
  146. 146.
    Weglarz TC, Degen JL, Sandgren EP. Hepatocyte transplantation into diseased mouse liver Kinetics of parenchymal repopulation and identification of the proliferative capacity of tetraploid and octaploid hepatocytes. Am J Pathol. 2000;157(6):1963–74. Scholar

Copyright information

© Asian Pacific Association for the Study of the Liver 2019

Authors and Affiliations

  1. 1.Department of Medicine II, Nephrology/Rheumatology/Clinical ImmunologyUniversity Hospital RWTH AachenAachenGermany
  2. 2.Department of Hepatology and GastroenterologyCharité University Medical CenterBerlinGermany

Personalised recommendations