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A diet-induced murine model for non-alcoholic fatty liver disease with obesity and insulin resistance that rapidly develops steatohepatitis and fibrosis

Abstract

Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease worldwide. Patients with NAFLD often suffer steatohepatitis, which can progress to cirrhosis and hepatocellular carcinoma. The presence of visceral obesity or type 2 diabetes mellitus (T2DM) is a major risk factor and potential therapeutic target for NAFLD. The establishment of animal models with these metabolic comorbidities and with the rapid progression of the disease is needed for developing treatments for NAFLD but remains to be archived. In the present study, KK-Ay mice, widely used as T2DM models, or C57BL6 mice were fed a high-fat, high-fructose, and high-cholesterol diet supplemented with cholic acid (NAFLD diet). The KK-Ay mice fed a NAFLD diet exhibited remarkable obesity and insulin resistance. A prominent accumulation of triglycerides and cholesterol in the liver was observed at 4 weeks. These mice developed steatohepatitis at 4 weeks and fibrosis at 12 weeks. In contrast, C57BL6 mice fed a NAFLD diet remained lean, although they still developed steatohepatitis and fibrosis. In summary, we established a diet-induced murine NAFLD model with the rapid development of steatohepatitis and fibrosis, bearing obesity and insulin resistance. This model could be useful as preclinical models for drug development of NAFLD.

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Fig. 1: Metabolic features of mice with dietary intervention.
Fig. 2: Lipid profile in the liver of mice with dietary intervention.
Fig. 3: Histological features of mice with dietary intervention.
Fig. 4: Profile of liver inflammation in mice with dietary intervention.
Fig. 5: Profile of liver fibrosis in mice with dietary intervention.
Fig. 6: Quantification of gene expression related to lipid metabolism in the liver.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors would like to thank Enago (www.enago.jp) for the English language review.

Funding

M.N. is supported by JSPS KAKENHI Grant Number JP19K16532.

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Contributions

M.N., T.C. and N.K. conceived and designed the study. T.S., T.I., M.K., R.K., A.J., M.Y., K.Kanayama, H.H. and M.N. conducted experiments and acquired data. T.S., M.N. and T.K. evaluated liver sections. H.U., N.F., K.Koroki, K.Kobayashi, N.Kanogawa, S.K., T.K., T.S., S.O. R.N., S.N., R.M. and J.K. gave administrative and technical supports. T.S., M.N., T.C. and N.Kato analyzed and interpreted the data. T.S. and M.N. drafted the paper and made figures. All authors edited and approved the final paper.

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Correspondence to Masato Nakamura.

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Sakuma, T., Nakamura, M., Chiba, T. et al. A diet-induced murine model for non-alcoholic fatty liver disease with obesity and insulin resistance that rapidly develops steatohepatitis and fibrosis. Lab Invest (2022). https://doi.org/10.1038/s41374-022-00807-6

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