Nonalcoholic Steatohepatitis (NASH) is a progressive form of Nonalcoholic Fatty Liver Disease (NAFLD) and has emerged to be a critical public health issue. It is anticipated that NASH will become the most common indication for liver transplantation in next ten years in the United States. NASH has strong association with diabetes, obesity and metabolic syndrome, and this disease is characterized by excessive triglyceride storage in the liver, insulin resistance and progress through stages of inflammation, fibrosis to cirrhosis and associated with the risk of hepatocellular cancer. There is currently no FDA-approved therapy for NASH and thus it becomes one of the major unmet medical needs of the present time.
Triangulum offers CRO services with extensive expertise in the following mouse models of NASH to our clients:
- DIO-NASH Model
Normal mice fed with diet enriched in fat (40% kcal), fructose (22% by wt), and cholesterol (2% by wt). This model develops clinically relevant features of NASH over a prolonged period of time.
- ob/ob mice fed with high fat diet Model
These mice are severely obese due to leptin deficiency and predisposed to develop steatohepatitis. ob/ob mice fed with diet enriched in fat (40% kcal), fructose (22% by wt), and cholesterol (2% by wt) develop clinically relevant features of NASH in a shorter duration.
- Normal mice fed with MCD diet Model
MCD diet fed model shows the features of NASH-related inflammation and fibrosis that have been implicated in human NASH progression.
- db/db mice fed with MCD diet Model
These mice are obese with insulin resistance, severe type 2 diabetes, and fatty livers due to a functional defect in their leptin receptor. MCD diet in this model exhibit the features of NASH-related inflammation and fibrosis that have been implicated in human NASH progression
- CCL4 induced hepatic fibrosis mouse Model
The carbon tetrachloride (CCl4)-induced hepatic fibrosis mouse model is widely used to investigate the preclinical efficacy of test compounds in resolving inflammation and hepatic fibrosis. CCl4 is a well-known hepatotoxin which causes oxidative stress and chemical injury. Its biotransformation in the liver produces toxic metabolites like the highly reactive tri-chloro-methyl free radical which is further converted into peroxy-trichloro-methyl radical. These reactive oxidant species likely contribute to the onset and progression of inflammation and fibrosis. Unlike the diet models, the CCl4 model offers a quick phenotype development of hepatic fibrosis and allows investigators to rapidly test their investigative compounds.
Triangulum Biopharma has optimized the CCl4 model in mice and offers preclinical efficacy, proof-of-concept and mechanism of action studies. In addition to the live phase, Triangulum Biopharma also conducts clinical chemistry for liver enzymes, biochemical and ELISA assays, gene expression analysis by qPCR, hydroxyproline assays, histological processing of samples and histopathology.
- DIO-Streptozotocin Model
Normal mice are fed with diet enriched in fat and diabetes is induced by streptozotocin administration. This model develops clinically relevant features of NASH where diabetes exacerbates the NASH phenotype.
We offer preclinical efficacy, proof-of-concept, and mechanism of action studies in the model of your choice with your drug candidates. We work with our clients in providing scientific guidance in the model selection, customized study design, end-point analysis, histopathology services, and assist you with professional interpretation of the data. Please contact us with your specific needs.
Relevant publications by our scientists:
1. Yu XX, Murray SF, Pandey SK, Booten SL, Bao D, Song XZ, Kelly S, Chen S, McKay R, Monia BP, Bhanot S. Hepatology. 2005 Aug;42(2):362-71. PMID: 16001399
2. Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M, Watts L, Booten SL, Graham M, McKay R, Subramaniam A, Propp S, Lollo BA, Freier S, Bennett CF, Bhanot S, Monia BP. Cell Metab. 2006 Feb;3(2):87-98. PMID: 16459310
3. Yamaguchi K, Yang L, McCall S, Huang J, Yu XX, Pandey SK, Bhanot S, Monia BP, Li YX, Diehl AM. Hepatology. 2007 Jun;45(6):1366-74. PMID: 17476695
4. Choi CS, Savage DB, Kulkarni A, Yu XX, Liu ZX, Morino K, Kim S, Distefano A, Samuel VT, Neschen S, Zhang D, Wang A, Zhang XM, Kahn M, Cline GW, Pandey SK, Geisler JG, Bhanot S, Monia BP, Shulman GI. J Biol Chem. 2007 Aug 3;282(31):22678-88. PMID: 17526931
5. Yamaguchi K, Yang L, McCall S, Huang J, Yu XX, Pandey SK, Bhanot S, Monia BP, Li YX, Diehl AM. Hepatology. 2008 Feb;47(2):625-35. PMID: 18000880