Abstract
Nonalcoholic steatohepatitis (NASH) is a common chronic liver disease that is increasingly prevalent worldwide. Liver inflammation is an important contributor to disease progression from nonalcoholic fatty liver (NAFL) to NASH, but there is a lack of efficient therapies. In the current study we evaluated the therapeutic potential of givinostat, a histone deacetylase (HDAC) inhibitor, in the treatment of NASH in vivo and in vitro. Liver inflammation was induced in mice by feeding a methionine- and choline-deficient diet (MCD) or a fructose, palmitate, cholesterol diet (FPC). The mice were treated with givoinostat (10 mg·kg−1·d−1, ip) for 8 or 10 weeks. At the end of the experiment, the livers were harvested for analysis. We showed that givoinostat administration significantly alleviated inflammation and attenuated hepatic fibrosis in MCD-induced NASH mice. RNA-seq analysis of liver tissues form MCD-fed mice revealed that givinostat potently blocked expression of inflammation-related genes and regulated a broad set of lipid metabolism-related genes. In human hepatocellular carcinoma cell line HepG2 and human derived fetal hepatocyte cell line L02, givinostat significantly decreased palmitic acid-induced intracellular lipid accumulation. The benefit of givinostat was further confirmed in FPC-induced NASH mice. Givinostat administration significantly attenuated hepatic steatosis, inflammation as well as liver injury in this mouse model. In conclusion, givinostat is efficacious in reversing diet-induced NASH, and may serve as a therapeutic agent for the treatment of human NASH.
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Acknowledgements
We are extremely grateful to the National Centre for Protein Science Shanghai (Shanghai Science Research Center, Protein Expression and Purification system) for their instrument support and technical assistance. We gratefully acknowledge financial support from the National Natural Science Foundation of China (81070344 to GL, 81803554 to YYZ, 91853205, 81625022, and 81821005 to CL), the Ministry of Science and Technology of China (2015CB910304 to YYZ) and National Science & Technology Major Project of China (2018ZX09711002 to YYZ).
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HMH, YJL, RF, LY and SJF performed immunofluorescence, Western-blot analysis, and NASH experiments, analyzed data, and wrote the manuscript. XRZ, JH, XL, LPL and SJF contributed to manuscript revising, and analyzed the RNA-seq data. GML, CL, CCS, JGF and YYZ conceived and supervised the project and revised the manuscripts.
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Huang, Hm., Fan, Sj., Zhou, Xr. et al. Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis. Acta Pharmacol Sin 43, 941–953 (2022). https://doi.org/10.1038/s41401-021-00725-1
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DOI: https://doi.org/10.1038/s41401-021-00725-1
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