Journal of gastroenterology and hepatology · 2025
Impairing Islets in Newborn Mice Promotes Liver Fibrosis and Carcinoma Development in a Rapid NASH Model.
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Zeng Xin, Li Zhao, Chen Yang, Yao Han, Li Lan, Cheng Jingqiu, Chen Younan
Аннотация
BACKGROUND AND AIM: Although many diet-induced models for nonalcoholic steatohepatitis (NASH) have been reported, most of them hardly conform to the clinical pathogenesis, particularly for the end-stage NASH with the occurrence of hepatocellular carcinoma (HCC). Here, we report a rapid mouse NASH model induced from newborn mice and characterized by progression of broad fibrosis and HCC.
METHODS: In newborn C57BL/6J mice, 100 mg/kg body weight streptozotocin (STZ) by a single intraperitoneal injection at 2 days after birth served as an accelerator with a special high-fat, high-fructose, and high cholesterol diet, combined with 4% fructose and 2% β-cyclodextrin in drinking water (FFC diet). The induction strategy was named SFD treatment.
RESULTS: Pre-treatment of STZ exacerbated the histological features of NASH in mice, which resulted in typical symptoms of NASH at 8 weeks after FFC diet, including liver dysfunction, glucose and lipid metabolism disorders, hepatic steatosis, inflammation, and fibrosis. Moreover, these pathological features worsened with longer durations of 16, 24, and 32 weeks, and advanced fibrosis was evidenced by activated hepatic stellate cells and ductular reaction. In particular, HCC development was observed at 16 weeks.
CONCLUSIONS: The sucking mice induced NASH model displayed rapid progression of grievous inflammation and fibrosis, and ultimately developed HCC, which provides new insight for the effects of adolescent metabolic disorder on NASH development. Notably, impairment of islet function in early life is a critical driving factor in this process. This NASH model would be a helpful medical tool for the study of pediatric hepatology and the drug development for NASH.
METHODS: In newborn C57BL/6J mice, 100 mg/kg body weight streptozotocin (STZ) by a single intraperitoneal injection at 2 days after birth served as an accelerator with a special high-fat, high-fructose, and high cholesterol diet, combined with 4% fructose and 2% β-cyclodextrin in drinking water (FFC diet). The induction strategy was named SFD treatment.
RESULTS: Pre-treatment of STZ exacerbated the histological features of NASH in mice, which resulted in typical symptoms of NASH at 8 weeks after FFC diet, including liver dysfunction, glucose and lipid metabolism disorders, hepatic steatosis, inflammation, and fibrosis. Moreover, these pathological features worsened with longer durations of 16, 24, and 32 weeks, and advanced fibrosis was evidenced by activated hepatic stellate cells and ductular reaction. In particular, HCC development was observed at 16 weeks.
CONCLUSIONS: The sucking mice induced NASH model displayed rapid progression of grievous inflammation and fibrosis, and ultimately developed HCC, which provides new insight for the effects of adolescent metabolic disorder on NASH development. Notably, impairment of islet function in early life is a critical driving factor in this process. This NASH model would be a helpful medical tool for the study of pediatric hepatology and the drug development for NASH.