From the AGA Journals

How diet affects NASH-to-HCC progression

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A clinically relevant model emerges

The prevalence and incidence of nonalcoholic steatohepatitis and NASH-induced hepatocellular carcinoma (HCC) have rapidly increased worldwide in recent years. The growing number of patients with NASH and NASH-HCC poses a significant public health burden, further confounded by suboptimal approaches for disease management, including a lack of effective pharmacotherapy. To accelerate the development of novel treatment modalities, preclinical studies using animal models highly relevant to human disease are of utmost importance. The ideal experimental NASH model recapitulates the multifaceted human condition, including the etiology, underlying pathogenetic mechanisms, histologic features, and progression from NASH to NASH-related HCC.

Petra Hirsova, PharmD, PhD, is an assistant professor and investigator in the division of gastroenterology and hepatology at Mayo Clinic, Rochester, Minn

Dr. Petra Hirsova

The study by Ganguly and colleagues demonstrates that, when hyperphagic Foz/Foz mice are provided with a Western diet as desired, they consume excess calories, leading to obesity, insulin resistance, kidney injury, cardiovascular disease, and NASH. Notably, Foz/Foz mice develop NASH with a more severe phenotype and about twice as fast as wild-type mice. When continuing the Western diet for 6 months, Foz/Foz mice develop NASH-related HCC. In this experimental setting, NASH onset and progression to HCC are markedly accelerated, compared with other common models of NASH-induced carcinogenesis, which require significantly longer time or diets and manipulations that are less relevant to human disease etiology and pathophysiology. Thus, Western diet–fed Foz/Foz mice represent a unique, convenient, and clinically relevant approach to model NASH and NASH-to-HCC progression. Future in-depth molecular characterization of this murine NASH-HCC should reveal the transcriptomic and mutational landscape of the tumors and contrast these features to human NASH-HCC, further underscoring the clinical utility of this preclinical model.

Petra Hirsova, PharmD, PhD, is an assistant professor and investigator in the division of gastroenterology and hepatology at the Mayo Clinic, Rochester, Minn. Dr. Hirsova reported having no disclosures.



A new study sought to establish a new, clinically relevant mouse model of nonalcoholic steatohepatitis (NASH) that closely reflects human disease as well as the multitissue dynamics involved in the progression and regression of the condition, according to the researchers. This study focused on the association between progression of NASH and consumption of a Western diet, as well as the development of HCC.

The study used a model consisting of hyperphagic mice that lacked a functional ALMS1 gene (Foz/Foz), in addition to wild-type littermates. The model ultimately defined “the key signaling and cytokine pathways that are critical for disease development and resolution” associated with NASH, wrote Souradipta Ganguly, PhD, of the University of California, San Diego, and colleagues. The report was published in Cellular and Molecular Gastroenterology and Hepatology.

According to the researchers, this study is unique given “current rodent models of NASH do not reproduce the complete spectrum of metabolic and histologic” nonalcoholic fatty liver disease (NAFLD) phenotypes. Likewise, the lack of “systemic studies in a single rodent model of NASH that closely recapitulates the human pathology” reinforces the importance of the new model, the researchers added.

Over time, NASH can progress to cirrhosis and hepatocellular carcinoma (HCC). Studies that fed wild-type mice a Western diet have largely failed to mimic the full pathology of NASH to fibrosis to HCC. In addition, the models in these studies fail to reflect the multitissue injuries frequently observed in NASH.

To circumvent these challenges, Dr. Ganguly and colleagues used ALMS1-mutated mice to develop a rodent model of metabolic syndrome that included NASH with fibrosis, chronic kidney disease, and cardiovascular disease. The ALMS1 mutation also resulted in the mice becoming hyperphagic, which increases hunger and leads to early-onset obesity, among other conditions characteristic of metabolic syndrome.

Researchers fed the hyperphagic Foz/Foz mice and wild-type littermates a Western diet or standard diet during a 12-week period for NASH/fibrosis and a 24-week period for HCC. After NASH was established, mice were switched back to normal chow to see if the condition regressed.

Macronutrient distribution of the study’s Western diet included 40% fat, 15% protein, and 44% carbohydrates, based on total caloric content. In contrast, the standard chow included 12% fat, 23% protein, and 65% carbohydrates from total calories.

Within 1-2 weeks, Foz mice fed the Western diet were considered steatotic. These mice subsequently developed NASH by 4 weeks of the study and grade 3 fibrosis by 12 weeks. The researchers concurrently observed the development of chronic kidney injury in the animals. Mice continuing to the 24 weeks ultimately progressed to cirrhosis and HCC; these mice demonstrated reduced survival due to cardiac dysfunction.

Mice that developed NASH were then switched to a diet consisting of normal chow. Following this switch, NASH began to regress, and survival improved. These mice did not appear to develop HCC, and total liver weight was significantly reduced compared with the mice that didn’t enter the regression phase of the study. The researchers wrote that the resolution of hepatic steatosis was also consistent with improved glucose tolerance.

In transcriptomic and histologic analyses, the researchers found strong concordance between Foz/Foz mice NASH liver and human NASH.

The study also found that early disruption of gut barrier, microbial dysbiosis, lipopolysaccharide leakage, and intestinal inflammation preceded NASH in the Foz/Foz mice fed the Western diet, resulting in acute-phase liver inflammation. The early inflammation was reflected by an increase in several chemokines and cytokines by 1-2 weeks. As NASH progressed, the liver cytokine/chemokine profile continued to evolve, leading to monocyte recruitment predominance. “Further studies will elaborate the roles of these NASH-specific microbiomial features in the development and progression of NASH fibrosis,” wrote the researchers.

The study received financial support Janssen, in addition to funding from an ALF Liver Scholar award, ACTRI/National Institutes of Health, the SDDRC, and the NIAAA/National Institutes of Health. The authors disclosed no conflicts.

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