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Preclinical Research Models of NAFLD/NASH

by Jody Barbeau PhD, August 7, 2018 at 01:00 PM | Tags

Most preclinical models of NAFLD/NASH are limited to studying specific aspects of the disease. In this blog post, you can review ideal applications for currently available NAFLD/NASH models and discover a new, more translatable choice for preclinical drug development.

Challenges of Modelling NAFLD/NASH

While a range of preclinical models are available for NAFLD/NASH studies, none completely capture the human, clinical experience of this disease, such as over nutrition, insulin resistance, inflammation, and fibrosis.

The main problem is finding a model which combines the metabolic aspects of the disease with the appropriate liver pathology and/or injury. Some models show the correct pathology, but don’t have the right metabolic context, including missing slow and chronic disease progression. Other models are metabolically appropriate, but only have limited characterization and pathology.

Many researchers get past this issue by using multiple models in their preclinical studies, to capitalize on the different features that each model can bring.

Commonly Used NAFLD/NASH Rodent Models

The most commonly used NAFLD/NASH rodent models at the moment are:

  • Nutritional deficit
  • Over nutrition
  • Streptozotocin (STZ) induction
  • Acute liver injury.

Dietary Models of NASH

Nutritional Deficit Models

Nutritional deficit models include MCD (methionine-choline deficient) and CDAA (choline deficient amino acid defined) models. Methionine and choline are both essential for hepatic β-oxidation and the production of very low-density lipoprotein (VLDL). Therefore, a lack of either nutrient leads to extensive lipid build up in the liver. Steatohepatitis follows, resembling the pathology of human NASH.

MCD is the most widely used diet to induce NAFLD/NASH, and usually includes high sucrose levels and moderate fat. The MCD diet produces a progressive liver pathology, with rapid development of steatosis plus inflammation and fibrosis – severe NASH is observed in as little as eight weeks of administration.

However, these animals also show severe weight loss and aren’t insulin resistant, so lack the metabolic syndrome components of NASH seen in humans. CDAA diet models also lack obesity.

Over Nutrition Models

Over nutrition, or high fat diets, are also used to induce NAFLD, but a heterogeneous mix of these diets are used and comparison across institutions difficult. Western diets are also used to induce NAFLD/NASH (high fat, some cholesterol, plus fructose in the drinking water), and while these do result in obesity and insulin resistance similar to human disease, the induced NASH may not be very severe, and may represent only “simple” steatosis for high fat diets.

The first mouse model available which develops NASH solely from Western Diet consumption are DIAMOND™ mice from Sanyal Biotechnology.

Chemotoxic Agent Models

STZ is used to induce diabetes in mice, as it’s particularly toxic to pancreatic β cells. Combining STZ and a high fat diet has now been shown to induce NASH.

Steatosis occurs in a reasonably short time frame, along with pericellular fibrosis, replicating human-disease like pathology. However, as with MCD-induced NASH, metabolic components such as obesity and insulin resistance are missing.

Acute Liver Injury Models

Acute liver injury models include the carbon tetrachloride (CCl4)-induced mouse model and the thioacetamide (TAA)-induced liver fibrosis rat model.

The CCl4-induced model is currently popular, and has historically been used for liver injury and regeneration studies requiring acute liver injuries. CCl4 induces an oxidative stress response in the liver, leading to a build up of toxic lipid and protein peroxidation products, which in turn produces a strong necrotic response and resulting liver damage.

While these models are definitely useful for studying fibrosis and liver injury in NASH, they lack metabolic components of the disease, as well as common comorbidities seen with the dietary NASH models.

Translational NASH Rodent Models

While not perfect, the models above have been used to generate preclinical data in support of agent clinical trials. A more translatable and efficient approach to NASH/NAFLD drug discovery, requires animal models which address both the metabolic and liver fibrosis components of NASH. This saves valuable study time and resources, while more effectively testing how an agent works against the multiple aspects of NASH.

An optimal animal model for NASH should develop the correct liver pathology, in an appropriate metabolic context, to more accurately model the human, clinical presentation of this disease.

The FATZO Mouse

The FATZO polygenic mouse model is a next generation type 2 diabetes and obesity model. Featuring a functional leptin pathway, the model spontaneously develops obesity, dyslipidemia, and insulin resistance on a standard chow diet, closely mimicking human disease. When the FATZO mouse model is given a Western diet, plus fructose in the drinking water, NAFLD/NASH develops. This provides an inherently dysmetabolic, obese, and diabetic mouse model for highly translational NAFLD/NASH drug development.

NASH/NAFLD Development in the FATZO Mouse

Features of NAFLD/NASH development in the FATZO mouse include increased liver weight and liver triglycerides, as well as highly significant increases in ALT and AST levels. This provides a window of opportunity for assessing effects and observing the efficacy of novel NASH treatments. Histological changes are also observed with fat accumulating in the liver.

Scoring livers from these animals using elements from the NAS score shows significant elevations in steatosis, ballooning, inflammation, and fibrosis, with an overall NAS score over 4. Treatment with OCA (currently in Phase III clinical trial to treat NASH) significantly improves liver function in the FATZO-NAFLD/NASH mice, while causing improvement in liver histology markers.

Summary

Assessing novel treatments for NASH is currently hindered by a lack of animal models which recapitulate both the metabolic and liver fibrosis components of NASH. New preclinical models, such as the FATZO-NAFLD/NASH mouse, need to more-fully recapitulate the disease to support further drug development and progression to the clinic.


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