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Non-Alcoholic Steatohepatitis: A Review of Its Mechanism, Models and Medical Treatments
journal contributionposted on 18.01.2021, 00:02 by C Peng, AG Stewart, OL Woodman, Rebecca Ritchie, CX Qin
© Copyright © 2020 Peng, Stewart, Woodman, Ritchie and Qin. Non-alcoholic steatohepatitis (NASH) develops from non-alcoholic fatty liver disease (NAFLD). Currently, around 25% of the population is estimated to have NAFLD, and 25% of NAFLD patients are estimated to have NASH. NASH is typically characterized by liver steatosis inflammation, and fibrosis driven by metabolic disruptions such as obesity, diabetes, and dyslipidemia. NASH patients with significant fibrosis have increased risk of developing cirrhosis and liver failure. Currently, NASH is the second leading cause for liver transplant in the United States. More importantly, the risk of developing hepatocellular carcinoma from NASH has also been highlighted in recent studies. Patients may have NAFLD for years before progressing into NASH. Although the pathogenesis of NASH is not completely understood, the current “multiple-hits” hypothesis suggests that in addition to fat accumulation, elevated oxidative and ER stress may also drive liver inflammation and fibrosis. The development of clinically relevant animal models and pharmacological treatments for NASH have been hampered by the limited understanding of the disease mechanism and a lack of sensitive, non-invasive diagnostic tools. Currently, most pre-clinical animal models are divided into three main groups which includes: genetic models, diet-induced, and toxin + diet-induced animal models. Although dietary models mimic the natural course of NASH in humans, the models often only induce mild liver injury. Many genetic and toxin + diet-induced models rapidly induce the development of metabolic disruption and serious liver injury, but not without their own shortcomings. This review provides an overview of the “multiple-hits” hypothesis and an evaluation of the currently existing animal models of NASH. This review also provides an update on the available interventions for managing NASH as well as pharmacological agents that are currently undergoing clinical trials for the treatment of NASH.
This work was supported in part by the CASS Foundation (CXQ), Victoria Medical Acceleration Grant (RHR), and the Victorian Government's Operational Infrastructure Support Program. RHR was supported by the National Health and Medical Research Council (NHMRC) of Australia (ID1059960, ID1158013), and CXQ is Australia National Heart Foundation Future Fellow. Victorian Medical Research Acceleration Fund (RR, CXQ, AGS).
JournalFrontiers in Pharmacology
Article NumberARTN 603926
PublisherFRONTIERS MEDIA SA
Rights StatementThe Author reserves all moral rights over the deposited text and must be credited if any re-use occurs. Documents deposited in OPAL are the Open Access versions of outputs published elsewhere. Changes resulting from the publishing process may therefore not be reflected in this document. The final published version may be obtained via the publisher’s DOI. Please note that additional copyright and access restrictions may apply to the published version.
Science & TechnologyLife Sciences & BiomedicinePharmacology & Pharmacyanimal modelspharmacological treatmentsmetabolic syndromeobesitynon-alcoholic fatty liver diseasenon-alcoholic steatohepatitissteatosisFATTY LIVER-DISEASEACTIVATED-RECEPTOR-ALPHANECROSIS-FACTOR-ALPHADE-NOVO LIPOGENESISNF-KAPPA-BSERUM ALANINE AMINOTRANSFERASEENDOPLASMIC-RETICULUM STRESSALPHA/DELTA AGONIST GFT505HEPATIC INSULIN-RESISTANCELIFE-STYLE MODIFICATION