Pathophysiological Analysis of the Progression of Hepatic Lesions in STAM Mice

Abstract

Nonalcoholic steatohepatitis (NASH) is a current health issue since the disease often leads to hepatocellular carcinoma; however, the pathogenesis of the disease has still not been fully elucidated. In this study, we investigated the pathophysiological changes observed in hepatic lesions in STAM mice, a novel NASH model. STAM mice, high fat-diet (HFD) fed mice, and streptozotocin (STZ) treated mice were prepared, and changes over time, such as biological parameters, mRNA expression, and histopathological findings, were evaluated once animal reached 5, 7, and 10 weeks of age. STZ mice presented with hyperglycemia and an increase in oxidative stress in immunohistochemical analyses of Hexanoyl-lysine: HEL from 5 weeks, with fibrosis in the liver also being observed from 5 weeks. HFD mice presented with hyperinsulinemia from 7 weeks and the slight hepatosteatosis was observed at 5 weeks, with changes significantly increasing until 10 weeks. STAM mice at 10 weeks showed significant hepatic changes, including hepatosteatosis, hypertrophic hepatocytes, and fibrosis, indicating pathological changes associated with NASH. These results suggested that the increase in oxidative stress with hyperglycemia triggered hepatic lesions in STAM mice, and insulin resistance promoted lesion formation with hepatic lipid accumulation. STAM mice may be a useful model for elucidating the pathogenesis of NASH with diabetes.

Omaveloxolone and TX63682 are hepatoprotective in the STAM mouse model of nonalcoholic steatohepatitis

“…As expected in the STAM model of NASH, [22,24] livers from the vehicle group exhibited severe microvesicular and macrovesicular fat deposition, hepatocellular ballooning, and inflammatory cell infiltration, which were reflected by a marked increase in NAFLD activity scores compared to normal mice (Figure 2A,B). Treatment with either omaveloxolone or TX63682 ameliorated these histopathological features (Figure 2A) and resulted in dose-dependent decreases in NAFLD activity scores with statistical significance achieved at 10 mg/kg for both compounds ( Figure 2B).…”

“…The decrease in body weight and increase in liver weight between normal mice and vehicle-treated STAM mice are consistent with previous findings. [24] 3.3 | Omaveloxolone and TX63682 improve liver architecture and decrease collagen and fat deposits…”

“…This NASH model is characterized by insulin resistance, hyperglycemia, dyslipidemia, and accumulation of hepatic lipids, which facilitates oxidative stress, inflammation, and liver fibrosis. [24] 2 | METHODS…”

Mouse Models of Nonalcoholic Steatohepatitis: Toward Optimization of Their Relevance to Human Nonalcoholic Steatohepatitis

“…Another attempt to model NASH has been to use a low, nonhepatotoxic dose of streptozotocin to destroy pancreatic beta cells, the streptozotocin‐treated neonatal mice on HFD (STAM) mouse . Most reports have been based on evaluations by the commercial provider.…”

Roles of Hepatic Innate and Innate-Like Lymphocytes in Nonalcoholic Steatohepatitis

“…When mice administered with STZ were fed with HFD, they developed NASH with oxidative stress ( 24 , 44 ). In the STAM model, low-dose STZ (200 μg) is administered to neonatal mice via a single subcutaneous injection immediately after birth, followed by feeding HFD (32% fat) at 4 weeks of age ( 25 ). Carbon tetrachloride (CCl 4 ) can serve as an accelerator in inducing NASH through significantly promoting the activation of HSCs and up-regulating ductular reaction and hepatocyte proliferation ( 23 ).…”