Modeling the Complex Disorder of NASH

An Increasingly Prevalent and Complex Disease to Study

About 25% of adults worldwide are estimated to have NAFLD, with higher rates in South America (about 30%) and the Middle East (over 31%)¹. NASH, the more severe form, is estimated to occur in about 1.5% to 6.45% of the population, a figure medical experts expect to increase significantly in conjunction with rising rates of obesity and diabetes². Both NAFLD and NASH impair liver function and are a leading reason for liver transplants.

NAFLD is a spectrum of disease, ranging from simple fatty liver disease, with little or no inflammation of the liver or the liver cells, to NASH, which is characterized by inflammation of the liver and damaged liver cells and which can include fibrosis. NAFLD can progress to cirrhosis, end-stage liver failure, and hepatocellular carcinoma. There are no FDA- or EMA-approved NASH therapeutics as of this writing; however, there is a robust pipeline of drug candidates against a wide range of targets.

The study of NASH is particularly complex for a variety of reasons. First, it is increasingly viewed not as a single disease but rather as a spectrum of conditions. Typically, NAFLD presents initially as fatty liver, which can, but does not always, proceed to an inflammatory state and more severe disease. NASH may occur concurrently with conditions like obesity, type 2 diabetes, insulin or glucose resistance, high cholesterol, or metabolic syndrome, though that is not always the case.

Additionally, researchers believe that disease development involves multiple pathways. In their review of NASH-related liver cancer development, Kutlu et al. noted that both clinical and epidemiological studies suggest multiple mechanisms are at work in the progression from simple fatty liver to NASH3. Factors implicated in NASH progression include lipotoxicity, inflammation, the microbiome, and more.

Further complicating matters, NASH may be largely asymptomatic in many instances, eluding both patients and physicians until it reaches a late stage. Most often a firm diagnosis is made only after a liver biopsy—a procedure that comes with risks, such as scarring, and the potential for inaccuracy, since it is based on a small tissue sample. Although various imaging and other diagnostic modalities are making great progress, liver biopsy remains the gold standard for NASH identification. Diagnostic difficulties and the lack of effective therapies for advanced NASH make this a challenging disease.

Taking NASH Research to the Next Level

Though no FDA- or EMA-approved NASH therapeutics exist, encouraging progress is being made on both the preclinical and clinical fronts. Drug targets for NASH fall into three categories: metabolic, anti-inflammatory, and anti-fibrotic. Most candidates are in the metabolic category, including FXR, FGF21, PPAR, and GLP-1 agonists. The anti-inflammatory field has not been as well developed, and anti-fibrotic therapeutics are a huge area of unmet need. There are a number of therapies currently in phase 3 clinical trials. Another promising area of research is combination therapy, and there are several phase 2 trials underway exploring this approach.

With the incidence of severe liver disease rising rapidly across the globe, NASH will remain an active area of investigation, both from a basic science and drug discovery perspective. By leveraging a variety of preclinical NASH models, the research community will continue to make strides toward understanding the pathogenesis of this complex disease and bringing effective therapeutics to market.

Multiple Mouse Models May Hold the Answer for NASH

These complexities have made preclinical research on NASH quite challenging. To study NASH effectively will likely require a range of research models, each focused on assessing different disease-related changes and relevant mechanisms. Various preclinical mouse models have been used and will continue to play a role in exploring both the mechanisms of NASH and potential therapeutics.

A number of strategies have been employed to induce fatty liver, inflammation, and fibrosis in a mouse model, including nutrient-deficient diets, high-fat diets, and chemical induction. These methods have been used in a variety of standard and mutant mouse strains. Chemical induction of liver fibrosis using carbon tetrachloride has been widely used but does not necessarily represent relevant mechanisms of metabolic syndrome-induced liver injury. Combining chemical induction with dietary manipulation is now becoming more commonly used as a strategy to combine rapid fibrosis development with relevant metabolic phenotypes.

Since diet is a known factor in NASH development and progression, the most common approach to modeling the disease in a mouse model has been diet modification through the administration of either a high-fat diet or a nutrient-deficient diet.

References:

1. Younossi, Zobair M. MD, MPH1; Marchesini, Giulio MD2; Pinto-Cortez, Helena MD3; Petta, Salvatore MD4 Epidemiology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis: Implications for Liver Transplantation, Transplantation: January 2019 - Volume 103 - Issue 1 - p 22-27 doi: 10.1097/TP.0000000000002484.
2. 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. 2016 Jul;64(1):73-84. doi: 10.1002/hep.28431. Epub 2016 Feb 22. PMID: 26707365.
3. Ozlem Kutlu, Humeyra Nur Kaleli, Ebru Ozer, "Molecular Pathogenesis of Nonalcoholic Steatohepatitis- (NASH-) Related Hepatocellular Carcinoma", Canadian Journal of Gastroenterology and Hepatology, vol. 2018, Article ID 8543763, 9 pages, 2018. https://doi.org/10.1155/2018/8543763.