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Review

Non-alcoholic fatty liver disease (NAFLD) models in drug discovery

, , & ORCID Icon
Pages 193-205 | Received 23 Sep 2017, Accepted 23 Nov 2017, Published online: 06 Dec 2017

References

  • Loomba R, Sanyal AJ. The global NAFLD epidemic. Nat Rev Gastroenterol Hepatol. 2013;10:686–690.
  • Falck-Ytter Y, Younossi ZM, Marchesini G, et al. Clinical features and natural history of nonalcoholic steatosis syndromes. Semin Liver Dis. 2001;21:17–26.
  • Medina J, Fernandez-Salazar LI, Garcia-Buey L, et al. Approach to the pathogenesis and treatment of nonalcoholic steatohepatitis. Diabetes Care. 2004;27:2057–2066.
  • Dongiovanni P, Anstee QM, Valenti L. Genetic predisposition in NAFLD and NASH: impact on severity of liver disease and response to treatment. Curr Pharm Des. 2013;19:5219–5238.
  • Cusi K, Sanyal AJ, Zhang S, et al. Non-alcoholic fatty liver disease (NAFLD) prevalence and its metabolic associations in patients with type 1 diabetes and type 2 diabetes. Diabetes Obes Metab. 2017;19:1630–1634.
  • ClinicalTrials.gov.[Internet].  Bethesda, MD: US National Library of Medicine; cited 2017. Available from: ClinicalTrials.gov
  • 2017. Available from: nashbiotechs.com[Internet]. cited 2017. Available from: nashbiotechs.com
  • Banini BA, Sanyal AJ. Current and future pharmacologic treatment of nonalcoholic steatohepatitis. Curr Opin Gastroenterol. 2017;33:134–141.
  • Galectin Therapeutics. Galectin therapeutics announces top-line data from exploratory phase 2a pilot trial (NASH-FX) with GR-MD-02 in NASH patients with advanced fibrosis. Galetin Therapeutics [Internet]. 2016 Sept 27; Press release:[about 4 screens]. Available from: http://investor.galectintherapeutics.com/news-releases/news-release-details/galectin-therapeutics-announces-top-line-data-exploratory-phase
  • Gilead. Gilead announces top-line phase 2 results for GS-4997 (Selonsertib) in nonalcoholic steatohepatitis (NASH), pulmonary arterial hypertension (PAH) and diabetic kidney disease (DKD). Gilead [Internet]. 2016 Oct 20; Press release:[about 3 screens]. Available from: http://www.gilead.com/news/press-releases/2016/10/gilead-announces-topline-phase-2-results-for-gs4997-selonsertib-in-nonalcoholic-steatohepatitis-nash-pulmonary-arterial-hypertension-pah-and-diabetic-kidney-disease-dkd
  • Raptor Pharmaceuticals. Raptor pharmaceutical provides topline results From phase 2b CyNCh study evaluating RP103 in pediatric nonalcoholic steatohepatitis. Nasdaq Globe Newswire [Internet]. 2015 Sept 14; Press release:[about 4 screens]. Available from: https://globenewswire.com/news-release/2015/09/14/767963/10149175/en/Raptor-Pharmaceutical-Provides-Topline-Results-From-Phase-2b-CyNCh-Study-Evaluating-RP103-in-Pediatric-Nonalcoholic-Steatohepatitis.html
  • Jacobs A, Warda AS, Verbeek J, et al. An overview of mouse models of nonalcoholic steatohepatitis: from past to present. Curr Protoc Mouse Biol. 2016;6:185–200.
  • Kanuri G, Bergheim I. In vitro and in vivo models of non-alcoholic fatty liver disease (NAFLD). Int J Mol Sci. 2013;14:11963–11980.
  • Sanches SC, Ramalho LN, Augusto MJ, et al. Nonalcoholic steatohepatitis: a search for factual animal models. Biomed Res Int. 2015;2015:574832.
  • Teufel A, Itzel T, Erhart W, et al. Comparison of gene expression patterns between mouse models of nonalcoholic fatty liver disease and liver tissues from patients. Gastroenterology. 2016;151:513–525 e510.
  • Karnik S, Charlton M, Li L, et al. Efficacy of an ASK1 inhibitor to reduce fibrosis and steatosis in a murine model of NASH is associated with normalization of lipids and hepatic gene expression and a reduction in serum biomarkers of inflammation and fibrosis. Poster session presented at: AALSD Liver Meeting; 2015 Nov 13-17; San Francisco, CA.
  • Ling L. Human FGF19 but not NGM282, an engineered variant of FGF19, causes hepatocellular carcinoma (HCC) in a diet-induced mouse model of non-alcoholic steatohepatitis (NASH). Poster session presented at: AALSD Liver Meeting; 2016 Nov 11-15; Boston, MA.
  • Barreyro FJ, Holod S, Finocchietto PV, et al. The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. Liver Int. 2015;35:953–966.
  • Tolbol KV, S.S., Kristiansen, M.; Vrang, N. Jelsing, J.; Feigh, M. The GLP-1 analogue, liraglutide, reduces NAFLD Activity Score and Fibrosis Stage and improves metabolic parameters in a diet-induced obese mouse model of biopsy-confirmed non-alcoholic steatohepatitis (NASH). Poster session presented at: AALSD Liver Meeting; 2016 Nov 11-15; Boston, MA.
  • Sanyal Biotechnology. Immuron initiates NASH MOA studies with sanyalbio and with Duke University. Sanyal Biotechnology [Internet]. 2017 Jan 19; Press release:[about 3 screens]. Available from: https://www.sanyalbio.com/immuron-initiates-nash-moa-studies-sanyalbio-duke-university/
  • Staels B, Rubenstrunk A, Noel B, 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. 2013;58:1941–1952.
  • Roth J, Feigh M, Veidal S, et al., et al. Obeticholic acid improves histological, biochemical and gene expression profiles in Gubra AMLN mice with biopsy-confirmed NASH. In: The International Liver 840 Congress Meeting, EASL. Amsterdam, The Netherlands; 2017.
  • Hum D, Sanyal A, Harrison S, et al. Elafibranor: a liver targeted PPARα/δ agonist for a global management of nash patients. Poster session presented at: The International Liver Congress Meeting, EASL; 2016 April 13-17; Barcelona, Spain.
  • Traber PG, Zomer E. Therapy of experimental NASH and fibrosis with galectin inhibitors. PLoS One. 2013;8:e83481.
  • Lefebvre E, Moyle G, Reshef R, et al. Antifibrotic effects of the dual CCR2/CCR5 antagonist cenicriviroc in animal models of liver and kidney fibrosis. PLoS One. 2016;11:e0158156.
  • Krupinski J. Effects of BMS-986036 (pegylated fibroblast growth factor 21) on hepatic steatosis and fibrosis in a mouse model of nonalcoholic steatohepatitis. Poster session presented at: AALSD Liver Meeting; 2016 Nov 11-15; Boston, MA.
  • Tetri LH, Basaranoglu M, Brunt EM, et al. 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:G987–G995.
  • Dowman JK, Hopkins LJ, Reynolds GM, et al. Development of hepatocellular carcinoma in a murine model of nonalcoholic steatohepatitis induced by use of a high-fat/fructose diet and sedentary lifestyle. Am J Pathol. 2014;184:1550–1561.
  • Asgharpour A, Cazanave SC, Pacana T, et al. A diet-induced animal model of non-alcoholic fatty liver disease and hepatocellular cancer. J Hepatol. 2016;65:579–588.
  • Rinella ME, Green RM. The methionine-choline deficient dietary model of steatohepatitis does not exhibit insulin resistance. J Hepatol. 2004;40:47–51.
  • Wang B, Chandrasekera PC, Pippin JJ. Leptin- and leptin receptor-deficient rodent models: relevance for human type 2 diabetes. Curr Diabetes Rev. 2014;10:131–145.
  • Kelesidis T, Kelesidis I, Chou S, et al. Narrative review: the role of leptin in human physiology: emerging clinical applications. Ann Intern Med. 2010;152:93–100.
  • Collin GB, Cyr E, Bronson R, et al. Alms1-disrupted mice recapitulate human Alstrom syndrome. Hum Mol Genet. 2005;14:2323–2333.
  • Sahai A, Malladi P, Pan X, et al. Obese and diabetic db/db mice develop marked liver fibrosis in a model of nonalcoholic steatohepatitis: role of short-form leptin receptors and osteopontin. Am J Physiol Gastrointest Liver Physiol. 2004;287:G1035–G1043.
  • Liedtke C, Luedde T, Sauerbruch T, et al. Experimental liver fibrosis research: update on animal models, legal issues and translational aspects. Fibrogenesis Tissue Repair. 2013;6:19.
  • Fujii M, Shibazaki Y, Wakamatsu K, et al. A murine model for non-alcoholic steatohepatitis showing evidence of association between diabetes and hepatocellular carcinoma. Med Mol Morphol. 2013;46:141–152.
  • Barter PJ, Brewer HB Jr., Chapman MJ, et al. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol. 2003;23:160–167.
  • Kowalski GM, Bruce CR. The regulation of glucose metabolism: implications and considerations for the assessment of glucose homeostasis in rodents. Am J Physiol Endocrinol Metab. 2014;307:E859–E871.
  • Martignoni M, Groothuis GM, de Kanter R. Species differences between mouse, rat, dog, monkey and human CYP-mediated drug metabolism, inhibition and induction. Expert Opin Drug Metab Toxicol. 2006;2:875–894.
  • Walsh NC, Kenney LL, Jangalwe S, et al. Humanized mouse models of clinical disease. Annu Rev Pathol. 2017;12:187–215.
  • Baker TK, Carfagna MA, Gao H, et al. Temporal gene expression analysis of monolayer cultured rat hepatocytes. Chem Res Toxicol. 2001;14:1218–1231.
  • Boess F, Kamber M, Romer S, et al. Gene expression in two hepatic cell lines, cultured primary hepatocytes, and liver slices compared to the in vivo liver gene expression in rats: possible implications for toxicogenomics use of in vitro systems. Toxicol Sci. 2003;73:386–402.
  • Rodriguez-Antona C, Donato MT, Boobis A, et al. Cytochrome P450 expression in human hepatocytes and hepatoma cell lines: molecular mechanisms that determine lower expression in cultured cells. Xenobiotica. 2002;32:505–520.
  • Wilkening S, Stahl F, Bader A. Comparison of primary human hepatocytes and hepatoma cell line Hepg2 with regard to their biotransformation properties. Drug Metab Dispos. 2003;31:1035–1042.
  • Nelson LJ, Treskes P, Howie AF, et al. Profiling the impact of medium formulation on morphology and functionality of primary hepatocytes in vitro. Sci Rep. 2013;3:2735.
  • Suckale J, Solimena M. Pancreas islets in metabolic signaling–focus on the beta-cell. Front Biosci. 2008;13:7156–7171.
  • Bertrand F, Philippe C, Antoine PJ, et al. Insulin activates nuclear factor kappa B in mammalian cells through a Raf-1-mediated pathway. J Biol Chem. 1995;270:24435–24441.
  • Cai D, Yuan M, Frantz DF, et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med. 2005;11:183–190.
  • Ke B, Zhao Z, Ye X, et al. Inactivation of NF-kappaB p65 (RelA) in liver improves insulin sensitivity and inhibits cAMP/PKA pathway. Diabetes. 2015;64:3355–3362.
  • Graaf IA, Groothuis GM, Olinga P. Precision-cut tissue slices as a tool to predict metabolism of novel drugs. Expert Opin Drug Metab Toxicol. 2007;3:879–898.
  • Olinga P, Schuppan D. Precision-cut liver slices: a tool to model the liver ex vivo. J Hepatol. 2013;58:1252–1253.
  • Neupert D, Glockner R, Neupert G, et al. Ultrastructural changes in hepatocytes of precision-cut rat liver slices after incubation for 24 and 48 hours. Exp Toxicol Pathol. 2003;54:481–488.
  • de Kanter R, Monshouwer M, Meijer DK, et al. Precision-cut organ slices as a tool to study toxicity and metabolism of xenobiotics with special reference to non-hepatic tissues. Curr Drug Metab. 2002;3:39–59.
  • Soldatow VY, Lecluyse EL, Griffith LG, et al. In vitro models for liver toxicity testing. Toxicol Res (Camb). 2013;2:23–39.
  • Dash A, Blackman BR, Wamhoff BR. Organotypic systems in drug metabolism and toxicity: challenges and opportunities. Expert Opin Drug Metab Toxicol. 2012;8:999–1014.
  • Dash A, Inman W, Hoffmaster K, et al. Liver tissue engineering in the evaluation of drug safety. Expert Opin Drug Metab Toxicol. 2009;5:1159–1174.
  • LeCluyse EL, Witek RP, Andersen ME, et al. Organotypic liver culture models: meeting current challenges in toxicity testing. Crit Rev Toxicol. 2012;42:501–548.
  • Ijssennagger N, Janssen AW, Milona A, et al. Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid. J Hepatol. 2016;64:1158–1166.
  • Janssen AW, Betzel B, Stoopen G, et al. The impact of PPARalpha activation on whole genome gene expression in human precision cut liver slices. BMC Genomics. 2015;16:760.
  • Davidson MD, Ballinger KR, Khetani SR. Long-term exposure to abnormal glucose levels alters drug metabolism pathways and insulin sensitivity in primary human hepatocytes. Sci Rep. 2016;6:28178.
  • Davidson MD, Kukla DA, Khetani SR. Microengineered cultures containing human hepatic stellate cells and hepatocytes for drug development. Integr Biol (Camb). 2017;9:662–677.
  • Kostrzewski T, Cornforth T, Snow SA, et al. Three-dimensional perfused human in vitro model of non-alcoholic fatty liver disease. World J Gastroenterol. 2017;23:204–215.
  • Feaver RE, Cole BK, Lawson MJ, et al. Development of an in vitro human liver system for interrogating nonalcoholic steatohepatitis. JCI Insight. 2016;1:e90954.
  • Dash A, Figler RA, Sanyal AJ, et al. Drug-induced steatohepatitis. Expert Opinion on Drug Metabolism & Toxicology 2016; 13:193-204.
  • Feaver R, Cole B, Hoang S, et al. Identification of novel targets for nonalcoholic steatohepatitis using a human surrogate system. Poster session presented at: AASLD Liver Meeting; 2017 Oct 20-24; Washington, D.C.
  • Guillouzo A, Corlu A, Aninat C, et al. The human hepatoma HepaRG cells: a highly differentiated model for studies of liver metabolism and toxicity of xenobiotics. Chem Biol Interact. 2007;168:66–73.
  • Hart SN, Li Y, Nakamoto K, et al. A comparison of whole genome gene expression profiles of HepaRG cells and HepG2 cells to primary human hepatocytes and human liver tissues. Drug Metab Dispos. 2010;38:988–994.
  • Riccalton-Banks L, Liew C, Bhandari R, et al. Long-term culture of functional liver tissue: three-dimensional coculture of primary hepatocytes and stellate cells. Tissue Eng. 2003;9:401–410.
  • Fausto N, Campbell JS, Riehle KJ. Liver regeneration. J Hepatol. 2012;57:692–694.
  • Krause P, Saghatolislam F, Koenig S, et al. Maintaining hepatocyte differentiation in vitro through co-culture with hepatic stellate cells. In Vitro Cell Dev Biol Anim. 2009;45:205–212.
  • Boulton R, Woodman A, Calnan D, et al. Nonparenchymal cells from regenerating rat liver generate interleukin-1alpha and −1beta: a mechanism of negative regulation of hepatocyte proliferation. Hepatology. 1997;26:49–58.
  • Schirmacher P, Geerts A, Pietrangelo A, et al. Hepatocyte growth factor/hepatopoietin A is expressed in fat-storing cells from rat liver but not myofibroblast-like cells derived from fat-storing cells. Hepatology. 1992;15:5–11.
  • Mullhaupt B, Feren A, Fodor E, et al. Liver expression of epidermal growth factor RNA. Rapid increases in immediate-early phase of liver regeneration. J Biol Chem. 1994;269:19667–19670.
  • Wake K. Cell-cell organization and functions of ‘sinusoids’ in liver microcirculation system. J Electron Microsc (Tokyo). 1999;48:89–98.
  • Weiskirchen R, Tacke F. Cellular and molecular functions of hepatic stellate cells in inflammatory responses and liver immunology. Hepatobiliary Surg Nutr. 2014;3:344–363.
  • Friedman SL. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev. 2008;88:125–172.
  • Duarte N, Coelho IC, Patarrao RS, et al. How inflammation impinges on NAFLD: a role for kupffer cells. Biomed Res Int. 2015;2015:984578.
  • Magee N, Zou A, Zhang Y. Pathogenesis of nonalcoholic steatohepatitis: interactions between liver parenchymal and nonparenchymal cells. Biomed Res Int. 2016;2016:5170402.
  • Chang SY, Weber EJ, Ness KV, et al. Liver and kidney on chips: microphysiological models to understand transporter function. Clin Pharmacol Ther. 2016;100:464–478.
  • Lin C, Ballinger KR, Khetani SR. The application of engineered liver tissues for novel drug discovery. Expert Opin Drug Discov. 2015;10:519–540.
  • Organovo. Organovo and its customers present data supporting 3D bioprinted liver tissues for drug toxicity testing and liver fibrosis modeling. Organovo [Internet]. 2016 March 10; Press release:[about 4 screens]. Available from: http://phx.corporate-ir.net/phoenix.zhtml?c=254194&p=irol-newsArticle&ID=2147586
  • Organovo. Organovo and UC San Diego receive $1.7 million grant from national institutes of health to study liver disease. 2017 July 31; Press release:[about 4 screens]. Available from: http://phx.corporate-ir.net/phoenix.zhtml?c=254194&p=irol-newsArticle&ID=2290135
  • Gori M, Simonelli MC, Giannitelli SM, et al. Investigating nonalcoholic fatty liver disease in a liver-on-a-chip microfluidic device. PLoS One. 2016;11:e0159729.
  • Lee PJ, Hung PJ, Lee LP. An artificial liver sinusoid with a microfluidic endothelial-like barrier for primary hepatocyte culture. Biotechnol Bioeng. 2007;97:1340–1346.
  • Domansky K, Inman W, Serdy J, et al. Perfused multiwell plate for 3D liver tissue engineering. Lab Chip. 2010;10:51–58.
  • Dash A, Figler RA, Blackman BR, et al. Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017;39:93–103.
  • Dash A, Simmers MB, Deering TG, et al. Hemodynamic flow improves rat hepatocyte morphology, function, and metabolic activity in vitro. Am J Physiol Cell Physiol. 2013;304:C1053–C1063.
  • Terelius Y, Figler RA, Marukian S, et al. Transcriptional profiling suggests that Nevirapine and Ritonavir cause drug induced liver injury through distinct mechanisms in primary human hepatocytes. Chem Biol Interact. 2015;255:31–44.
  • De Almeida IT, Cortez-Pinto H, Fidalgo G, et al. Plasma total and free fatty acids composition in human non-alcoholic steatohepatitis. Clin Nutr. 2002;21:219–223.
  • Puri P, Baillie RA, Wiest MM, et al. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology. 2007;46:1081–1090.
  • Smith U. Pioglitazone: mechanism of action. Int J Clin Pract Suppl. 2001;121:13-18.
  • Hirschfield GM, Mason A, Luketic V, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology. 2015;148(751–761):e758.
  • 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;385:956–965.
  • Ali AH, Carey EJ, Lindor KD. Recent advances in the development of farnesoid X receptor agonists. Ann Transl Med. 2015;3:5.
  • Cariou B, van Harmelen K, Duran-Sandoval D, et al. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem. 2006;281:11039–11049.
  • Sinal CJ, Tohkin M, Miyata M, et al. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell. 2000;102:731–744.
  • Zhang Y, Lee FY, Barrera G, et al. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci U S A. 2006;103:1006–1011.
  • Fisher CD, Lickteig AJ, Augustine LM, et al. Hepatic cytochrome P450 enzyme alterations in humans with progressive stages of nonalcoholic fatty liver disease. Drug Metab Dispos. 2009;37:2087–2094.
  • Lake AD, Novak P, Fisher CD, et al. Analysis of global and absorption, distribution, metabolism, and elimination gene expression in the progressive stages of human nonalcoholic fatty liver disease. Drug Metab Dispos. 2011;39:1954–1960.
  • Chtioui H, Semela D, Ledermann M, et al. Expression and activity of the cytochrome P450 2E1 in patients with nonalcoholic steatosis and steatohepatitis. Liver Int. 2007;27:764–771.

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