Nonalcoholic Steatohepatitis and HCC in a Hyperphagic Mouse Accelerated by Western Diet

Abstract

This study establishes a relevant mouse model of nonalcoholic steatohepatitis-fibrosis-hepatocellular carcinoma that closely recapitulates human disease. With this model, we elucidate multitissue dynamics of nonalcoholic steatohepatitis/hepatocellular carcinoma progression, as well as regression. We define the key signaling and cytokine pathways that are critical for disease development and resolution.BACKGROUND & AIMS: How benign liver steatosis progresses to nonalcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC) remains elusive. NASH progression entails diverse pathogenic mechanisms and relies on complex cross-talk between multiple tissues such as the gut, adipose tissues, liver, and the brain. Using a hyperphagic mouse fed with a Western diet (WD), we aimed to elucidate the cross-talk and kinetics of hepatic and extrahepatic alterations during NASH-HCC progression, as well as regression.METHODS: Hyperphagic mice lacking a functional Alms1 gene (Foz/Foz) and wild-type littermates were fed WD or standard chow for 12 weeks for NASH/fibrosis and for 24 weeks for HCC development. NASH regression was modeled by switching back to normal chow after NASH development.RESULTS: FozþWD mice were steatotic within 1 to 2 weeks, developed NASH by 4 weeks, and grade 3 fibrosis by 12 weeks, accompanied by chronic kidney injury. FozþWD mice that continued on WD progressed to cirrhosis and HCC within 24 weeks and had reduced survival as a result of cardiac dysfunction. However, NASH mice that were switched to normal chow showed NASH regression, improved survival, and did not develop HCC. Transcriptomic and histologic analyses of Foz/Foz NASH liver showed strong concordance with human NASH. NASH was preceded by an early disruption of gut barrier, microbial dysbiosis, lipopolysaccharide leakage, and intestinal inflammation. This led to acute-phase liver inflammation in FozþWD mice, characterized by neutrophil infiltration and increased levels of several chemokines/cytokines. The liver cytokine/chemokine profile evolved as NASH progressed, with subsequent predominance by monocyte recruitment. CONCLUSIONS:The FozþWD model closely mimics the pathobiology and gene signature of human NASH with fibrosis and subsequent HCC. FozþWD mice provide a robust and

Genetics, Immunity and Nutrition Boost the Switching from NASH to HCC

“…Ultimately, it has been recently demonstrated that mice carrying a loss-of-function mutation in the Alms1 gene, also known as Foz / Foz mice, display hyperphagia and multiple aspects of metabolic syndrome, among which obesity, IR, dyslipidemia and hypertension [ 223 , 224 ]. In addition, when Foz / Foz mice are fed with a WD rapidly develop NASH in 4 weeks and advanced fibrosis in 12 weeks of diet, mimicking human pathobiology.…”

Modeling NASH and NASH-Induced Hepatocellular Carcinoma: Faster and Better

“… 4 Foz / Foz mice fed high-calorie diets have been used previously to model NASH in a couple of studies. In the present report, however, Ganguly et al 3 selected a Western diet and performed a comprehensive characterization of the model. Strikingly, Foz / Foz mice on the Western diet developed severe obesity and histologic features of NASH within 4 weeks of feeding, and NASH with grade 3 fibrosis after 12 weeks on the diet.…”

“…Conversely, Western diet–fed Foz / Foz mice resemble human disease etiology and develop NASH-HCC in a reasonable time frame for preclinical research. An aspect not reported in the study by Ganguly et al 3 but worth further exploration is the in-depth molecular characterization of HCC tumors in Western diet–fed Foz / Foz mice. Future studies are necessary to comprehend the transcriptomic and mutational landscape of this murine HCC in comparison with human NASH-induced HCC, which will be the ultimate test of human pathophysiological relevance.…”

“…When kept on the Western diet for 24 weeks, the Foz/Foz mice developed cirrhosis and hepatocellular malignancy (75% of the mice), classified as either conventional (trabecular) HCC or steatohepatitic HCC. 3 Again, this represents very fast disease progression given that C57Bl/6 mice usually do not develop HCC even after 52 weeks of Western diet feeding. The majority of current mouse models of NASH-related HCC rely on tumor induction that has limited relevance to human NASH-HCC.…”

“…In this issue of Cellular and Molecular Gastroenterology and Hepatology , Ganguly et al 3 characterize a novel, accelerated mouse model of Western diet–induced NASH and NASH-driven HCC, and provide insights into the cross-talk and kinetics of hepatic and extrahepatic alterations, especially in the gut, during NASH progression. To this end, Ganguly et al 3 studied mice with a loss-of-function mutation in the Alms1 gene, also known as fat Aussie or Foz/Foz mice. 4 The exact function of the ALMS1 protein remains unknown.…”