Molecular pathogenesis of nash through the dysregulation of metabolic organ network in the nash derived hcc model mouse treated with streptozotocin-high fat diet

Introduction: Nonalcoholic steatohepatitis (NASH) is a chronic liver disease, often associated with type II diabetes, which sometimes progresses to hepatocellular carcinoma (HCC) . NASH has become a health problem worldwide, but therapeutic agents for NASH have not yet been approved. Although the mechanism of NASH progression has not been fully elucidated, the multiple parallel hits hypothesis suggests abnormalities in adipocytokines, endotoxins, etc could contribute to the development of NASH. The STAM™ model is a clinically-correlated murine NASH model which shows the same pathological progression as human patients. Diabetes is a well-known comorbidity of NASH, and it is evident in the STAM™ model but analysis has focused mostly on the liver. Considering organ crosstalk interactions between the liver, and the gut and adipose tissue in the model should be clarified. Methods: NASH was induced by injection of 200 µg streptozotocin solution 2 days after birth and feeding with HFD after 4 weeks of age. The mice were sacrificed at NASH stage. Colon samples were snap frozen in liquid nitrogen and stored at -80°C for tight junction-related protein analysis. Adipose tissue was prepared into paraffin blocks for HE staining. Blood adiponectin was analyzed to confirm changes in adipocytokine profile. Results: Tight junction-related proteins in the intestine of STAM™ showed that expression of ZO-1 decreased with the progression of disease. Increased expression of endotoxin in the blood and decreased expression of adiponectin were also observed. HE staining of adipose tissue revealed hypertrophy of adipocytes. Conclusion: The data suggested the occurrence of leaky gut, and abnormalities in adipocytokine secretion. Together with the liver, phenotypes in these organs are highly similar to human NASH patients, and might be involved in the pathogenesis of NASH. Disclosure L.P.Bui: None. Y.Sakakibara: None. R.Tanaka: None. E.H.Pigney: None. T.Hashiguchi: None.