Nonalcoholic steatohepatitis (NASH) is one of the most prevalent chronic liver diseases. The number of patients suffering from NASH is increasing dramatically and is associated with metabolic syndrome, diabetes and obesity. TNO develops unique in vivo preclinical models that accurately mimic the etiology of this disease in humans and are of great value for target identification, efficacy testing and the establishment of translational biomarkers.
Nonalcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of disease conditions, ranging from fat accumulation in the liver to NASH, liver fibrosis and liver cirrhosis and is associated with increased rates of morbidity and mortality. NAFLD is seen as the final disease area with blockbuster potential.
TNO has developed several diet-inducible models of nonalcoholic fatty liver disease (NAFLD)/NASH and liver fibrosis in which the disease process can be studied in the context of obesity, insulin resistance and dyslipidemia. Animals sequentially develop steatosis, NASH and liver fibrosis, including hallmarks of human disease such as infiltration of specific inflammatory cells, activation of distinct proinflammatory transcription factors, formation of cholesterol crystals, and collagen deposition in macrovesicular rich areas. Notably, this can be achieved under experimental conditions that are translational to the situation in humans, such as obesity, hyperinsulinemia and dyslipidemia. Importantly, the TNO models for NASH are sensitive to nutritional and pharmalogical interventions (e.g. drugs, including PPARgamma activators such as Glitazones and FXR activators such as obeticholic acid (OCA); nutrients and anti-MIR).
Intervention studies are usually started during the ongoing disease process, to mimic therapeutic regiments in the clinical practice. This can either be during the steatosis process, during NASH or even when fibrosis is observed (see figure). Experimental lesions resemble those of human disease and are characterized by macrovesicular steatosis, mixed-type inflammatory cell aggregates, and liver fibrosis. Features of experimental disease have been validated in human tissue and are scored according to a NASH grading system that is based on the human NAS scoring system.
Depending on diets employed, the models also develop other complications associated with the metabolic syndrome, insulin resistance and type 2 diabetes such as atherosclerosis, adipose tissue inflammation, reduced heart function as well as microvascular complications in kidney and eyes. These additional complications are currently further developed in precompetitive research programs.
TNO validates experimental models together with clinicians using human tissue. The unique in vivo models with diet induced NASH and fibrosis are representative for the human situation and are suitable for therapeutic protocols, intervening at specific stages of the disease process. With more than 25 years of experience and over 200 preclinical studies, TNO provides tailor made experimental set-ups. and can offer in vitro and in vivo models, PK/PD and toxicology studies and can therefore be considered as a one-stop shop for translational research.
Further to the in vivo models of NAFLD, TNO is currently setting up in vitro models too, making use of human hepatocytes and stellate cells. If you wish to participate in this research program please do not hesitate to contact us.
The above mentioned models are available for testing the effect of your compounds in NASH. Additionally you can contact us if you wish to co-develop in the following areas:
- Identification of biomarkers of NASH
- Development of in vitro models of NASH
On 2nd of march 2021 the TNO webinar 'Organ cross-talk and biomarker discovery in NASH/fibrosis using translational preclinical models' took place. The translational mouse models for preclinical research of NAFLD have been discussed. You can watch the webinar on Youtube.