Non-Alcoholic Steatohepatitis: A Review of Its Mechanism, Models and Medical Treatments

Abstract

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.

Keywords: animal models; metabolic syndrome; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; obesity; pharmacological treatments; steatosis.

FIGURE 1

Different phases of NAFLD: progressing from healthy to cirrhosis NAFLD represents a spectrum of fatty liver diseases ranging from fatty liver to cirrhosis. Approximately 25% of the population worldwide is estimated to have fatty liver, characterized by more than 5% fat accumulating in the liver. If left untreated, fatty liver can progress onto the more severe form; NASH, defined by severe liver injury and inflammation in addition to fat. Currently, a further 25% of the NAFLD population is estimated to have NASH (which is roughly calculated to be 6.3% of the population). NASH patients are estimated to have a higher risk of developing cirrhosis, which is the extensive liver tissue scarring. Figure is designed and drawn using Inkscape (http://www.inkscape.org/.).

FIGURE 2

Proposed mechanism of NASH FFAs released from adipose tissue due to insulin resistance and dietary-sugar-induced DNL increase the FFA pool in the liver. FFAs can be stored as TG in the hepatocyte or be metabolized into lipotoxic lipids. Lipid mediators may induce oxidative stress and ER stress, which ultimately results in cell injury and inflammation. Cell injury induces inflammatory cell recruitment and activation. A leaky gut due to gut dysbiosis can further contribute to liver inflammation. The combination of inflammation and tissue damage triggers HSC activation and collagen deposition. FFA: free fatty acid, KC: Kupffer cell, HSC: hepatic stellate cell, TG: triglyceride, DNL: de novo lipogenesis, IL-18: interleukin 18, IL-1β: interleukin one beta, TNF-α: tumor necrosis factor α, ATF6: activating transcription factor 6; TXBP-1: total X-box protein-1; CHOP: C/EBP Homologous Protein, eIF2α: eukaryotic translation initiation factor 2α. Figure is designed and drawn using Inkscape (http://www.inkscape.org/.).

FIGURE 3

Current NASH/NAFLD pipeline drugs with targeted pathways Pipeline drugs labeled with its pharmaceutical company are placed in their corresponding trial phases. The circle color indicates its targeted pathway(s) as shown in the legend within the figure. Information are gathered from clinicaltrials.gov and pharmaceutical company websites. Figure is designed and drawn using Microsoft Powerpoint.