TY - JOUR
T1 - Mouse model of NASH that replicates key features of the human disease and progresses to fibrosis stage 3
AU - St. Rose, Kristy
AU - Yan, Jun
AU - Xu, Fangxi
AU - Williams, Jasmine
AU - Dweck, Virginia
AU - Saxena, Deepak
AU - Schwabe, Robert F.
AU - Caviglia, Jorge Matias
N1 - Publisher Copyright:
© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.
PY - 2022/10
Y1 - 2022/10
N2 - Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the United States and the world; with no Food and Drug Administration–approved pharmacological treatment available, it remains an area of unmet medical need. In nonalcoholic steatohepatitis (NASH), the most important predictor of clinical outcome is the fibrosis stage. Moreover, the Food and Drug Administration recommends that clinical trials for drugs to treat this disease include patients with fibrosis stage 2 or greater. Therefore, when using animal models for investigating the pathophysiology of NAFLD and for the preclinical evaluation of new drugs, it is important that the animals develop substantial fibrosis. The aim of this study was to develop a mouse model of NAFLD that replicated the disease in humans, including obesity and progressive liver fibrosis. Agouti yellow mutant mice, which have hyperphagia, were fed a Western diet and water containing high-fructose corn syrup for 16 weeks. Mice became obese and developed glucose intolerance. Their gut microbiota showed dysbiosis with changes that replicate some of the changes described in humans with NASH. They developed NASH with activity scores of 5–6 and fibrosis, which was stage 1 after 16 weeks, and stage 3 after 12 months. Changes in liver gene expression assessed by gene-set enrichment analysis showed 90% similarity with changes in human patients with NASH. Conclusion: Ay mice, when fed a Western diet similar to that consumed by humans, develop obesity and NASH with liver histology, including fibrosis, and gene expression changes that are highly similar to the disease in humans.
AB - Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in the United States and the world; with no Food and Drug Administration–approved pharmacological treatment available, it remains an area of unmet medical need. In nonalcoholic steatohepatitis (NASH), the most important predictor of clinical outcome is the fibrosis stage. Moreover, the Food and Drug Administration recommends that clinical trials for drugs to treat this disease include patients with fibrosis stage 2 or greater. Therefore, when using animal models for investigating the pathophysiology of NAFLD and for the preclinical evaluation of new drugs, it is important that the animals develop substantial fibrosis. The aim of this study was to develop a mouse model of NAFLD that replicated the disease in humans, including obesity and progressive liver fibrosis. Agouti yellow mutant mice, which have hyperphagia, were fed a Western diet and water containing high-fructose corn syrup for 16 weeks. Mice became obese and developed glucose intolerance. Their gut microbiota showed dysbiosis with changes that replicate some of the changes described in humans with NASH. They developed NASH with activity scores of 5–6 and fibrosis, which was stage 1 after 16 weeks, and stage 3 after 12 months. Changes in liver gene expression assessed by gene-set enrichment analysis showed 90% similarity with changes in human patients with NASH. Conclusion: Ay mice, when fed a Western diet similar to that consumed by humans, develop obesity and NASH with liver histology, including fibrosis, and gene expression changes that are highly similar to the disease in humans.
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U2 - 10.1002/hep4.2035
DO - 10.1002/hep4.2035
M3 - Article
C2 - 35923109
AN - SCOPUS:85135518528
SN - 2471-254X
VL - 6
SP - 2676
EP - 2688
JO - Hepatology Communications
JF - Hepatology Communications
IS - 10
ER -