{"doi":"10.1016/j.jcmgh.2021.05.015","title":"Modeling NASH and NASH-Induced Hepatocellular Carcinoma: Faster and Better","abstract":"Nonalcoholic steatohepatitis (NASH), a more severe manifestation of nonalcoholic fatty liver disease, is defined by excessive liver fat accumulation, lobular inflammation, and hepatocyte ballooning with or without perisinusoidal fibrosis. Progressive liver injury in NASH can eventually lead to cirrhosis, which confers an increased risk of developing hepatocellular carcinoma (HCC). Given the increasing prevalence of NASH, NASH-induced HCC is predicted to be the leading indication for liver transplantation in the United States within a decade.1Loomba R. Friedman S.L. Shulman G.I. Mechanisms and disease consequences of nonalcoholic fatty liver disease.Cell. 2021; 184: 2537-2564Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar NASH and NASH-related HCC are becoming a significant public health concern, which is confounded further by the lack of effective treatments. Therefore, there is a pressing need for novel therapeutic strategies guided by the molecular underpinnings of disease pathogenesis and progression. Preclinical studies using animal models are essential for understanding disease pathogenesis, identifying molecular targets, and developing mechanistically based therapeutic interventions. Despite the abundance of various animal models,2Ibrahim S.H. Hirsova P. Malhi H. et al.Animal models of nonalcoholic steatohepatitis: eat, delete, and inflame.Dig Dis Sci. 2016; 61: 1325-1336Crossref PubMed Scopus (134) Google Scholar most experts in the field would agree that there still is a necessity for improved models of NASH and, in particular, NASH-induced HCC that would be both time-efficient and closely mimic the etiology of human disease (eg, overnutrition-induced obesity and metabolic syndrome), underlying pathogenetic mechanisms (eg, pathways involved in disease onset and progression), histologic features, and disease progression from NASH to cirrhosis and NASH-associated HCC. In this issue of Cellular and Molecular Gastroenterology and Hepatology, Ganguly et al3Ganguly S. Aleman Muench G. Shang L. et al.Non-alcoholic steatohepatitis and HCC in a hyperphagic mouse accelerated by Western diet.Cell Mol Gastroenterol Hepatol. 2021; 12: 891-920Abstract Full Text Full Text PDF Scopus (6) Google Scholar 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 al3Ganguly S. Aleman Muench G. Shang L. et al.Non-alcoholic steatohepatitis and HCC in a hyperphagic mouse accelerated by Western diet.Cell Mol Gastroenterol Hepatol. 2021; 12: 891-920Abstract Full Text Full Text PDF Scopus (6) Google Scholar studied mice with a loss-of-function mutation in the Alms1 gene, also known as fat Aussie or Foz/Foz mice.4Arsov T. Silva D.G. O'Bryan M.K. et al.Fat aussie--a new Alstrom syndrome mouse showing a critical role for ALMS1 in obesity, diabetes, and spermatogenesis.Mol Endocrinol. 2006; 20: 1610-1622Crossref PubMed Scopus (116) Google Scholar The exact function of the ALMS1 protein remains unknown. However, mutations in ALMS1 in humans cause Alström syndrome, a rare genetic disorder associated with childhood obesity, insulin resistance, heart disease, and other symptoms affecting multiple organ systems of the body. The Foz/Foz mice are hyperphagic, have reduced physical activity, quickly become obese (within 4 months), and show multiple features of the metabolic syndrome, including insulin resistance, dyslipidemia, and hypertension.4Arsov T. Silva D.G. O'Bryan M.K. et al.Fat aussie--a new Alstrom syndrome mouse showing a critical role for ALMS1 in obesity, diabetes, and spermatogenesis.Mol Endocrinol. 2006; 20: 1610-1622Crossref PubMed Scopus (116) Google Scholar 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 al3Ganguly S. 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