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.

He-ming Huang;Shi-jie Fan;Xiao-ru Zhou;Yan-jun Liu;Xiao Li;Li-ping Liao;Jing Huang;Cui-cui Shi;Liang Yu;Rong Fu;Jian-gao Fan;Yuan-yuan Zhang;Cheng Luo;Guang-ming Li

Department of Gastroenterology,Xinhua Hospital,School of Medicine,Shanghai Jiaotong University,Shanghai 200092,China;Drug Discovery and Design Center,State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;University of Chinese Academy of Sciences,Beijing 100049,China

中国药理学报（英文版）

[1]He-ming Huang;Shi-jie Fan;Xiao-ru Zhou;Yan-jun Liu;Xiao Li;Li-ping Liao;Jing Huang;Cui-cui Shi;Liang Yu;Rong Fu;Jian-gao Fan;Yuan-yuan Zhang;Cheng Luo;Guang-ming Li-.Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis)[J].中国药理学报（英文版）,2022(04):941-953

givinostat,givoinostat,Givinostat

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