Translating scientific discovery: the need for preclinical models of nonalcoholic steatohepatitis
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Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the Western world, affecting about 1/3 of the US general population and remaining as a significant cause of morbidity and mortality. The hallmark of the disease is the excessive accumulation of fat within the liver cells (hepatocytes), which eventually paves the way to cellular stress, injury and apoptosis. NAFLD is strongly associated with components of the metabolic syndrome and is fast emerging as a leading cause of liver transplant in the USA. Based on clinico-pathologic classification, NAFLD may present as isolated lipid collection (steatosis) within the hepatocytes (referred to as non-alcoholic fatty liver; NAFL); or as the more aggressive phenotype (known as non-alcoholic steatohepatitis; NASH). There are currently no regulatory agency- approved medication for NAFLD, despite the enormous work and resources that have gone into the study of this condition. Therefore, there remains a huge unmet need in developing and utilizing pre-clinical models that will recapitulate the disease condition in humans. In line with progress being made in developing appropriate disease models, this review highlights the cutting-edge preclinical in vitro and animal models that try to recapitulate the human disease pathophysiology and/or clinical manifestations.
KeywordsNon-alcoholic fatty liver disease (NAFLD) Non-alcoholic steatohepatitis (NASH) Organotypic liver system Lipitoxic system Diet induced animal model of non-alcoholic fatty liver disease (DIAMOND) Farnesoid X receptor (FXR)
Support: RO1 DK 105961 (National Institute of Diabetes and Digestive and Kidney Diseases). T32 DK007150/DK/NIDDK NIH HHS/United States [National Institute of Diabetes and Digestive and Kidney Diseases (US)]. R44 DK115301 (SBIR, HemoShear Therapeutics).
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Conflict of interest
Abdul M. Oseini, MD No conflicts to disclose, Danny Issa, MD No conflicts to disclose, Ryan E. Feaver, PhD Employee of HemoShear, Banumathi K. Cole, PhD Employee of HemoShear. Dr. Sanyal is President of Sanyal Biotechnology and has stock options in Genfit, Akarna, Tiziana, Indalo, Durect, Exhalenz and Hemoshear. He has served as a consultant to AbbVie, Astra Zeneca, Nitto Denko, Ardelyx, Conatus, Nimbus, Amarin, Salix, Tobira, Takeda, Fibrogen, Jannsen, Gilead, Boehringer, Lilly, Zafgen, Novartis, Pfizer, Jannsen and Genfit. He has been an unpaid consultant to Intercept, Echosens, Immuron, Galectin, Fractyl, Syntlogic, Novo Nordisk, Affimune, Chemomab, Nordic Bioscience and Bristol Myers Squibb. His institution has received grant support from Gilead, Salix, Tobira, Bristol Myers, Shire, Intercept, Merck, Astra Zeneca, Malinckrodt, Cumberland and Novartis. He receives royalties from Elsevier and UptoDate.
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