Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis

doi:10.1038/s41401-021-00725-1

	Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis
	Huang, He-ming 1,3; Fan, Shi-jie 1,2; Zhou, Xiao-ru 1; Liu, Yan-jun 1,3; Li, Xiao 1,2; Liao, Li-ping 1,2; Huang, Jing 1,2; Shi, Cui-cui 3; Yu, Liang 1; Fu, Rong 1,3
刊名	ACTA PHARMACOLOGICA SINICA
	2021-08-02
页码	13
关键词	nonalcoholic steatohepatitis inflammation histone deacetylase inhibitor givinostat epigenetics
ISSN号	1671-4083
DOI	10.1038/s41401-021-00725-1
通讯作者	Zhang, Yuan-yuan(zhangyy@simm.ac.cn) ; Luo, Cheng(cluo@simm.ac.cn) ; Li, Guang-ming(liguangming@xinhuamed.com.cn)
英文摘要	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 center dot kg(-1)center dot 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.
资助项目	National Natural Science Foundation of China[81070344] ; National Natural Science Foundation of China[81803554] ; National Natural Science Foundation of China[91853205] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81821005] ; Ministry of Science and Technology of China[2015CB910304] ; National Science & Technology Major Project of China[2018ZX09711002]
WOS关键词	HEPATIC-FIBROSIS ; KUPFFER CELLS ; DISEASE ; INFLAMMATION ; MACROPHAGES ; MANAGEMENT ; NASH
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000680322000001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298277]
专题	中国科学院上海药物研究所
通讯作者	Zhang, Yuan-yuan; Luo, Cheng; Li, Guang-ming
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.Shanghai Jiao Tong Univ, Xinhua Hosp, Sch Med, Dept Gastroenterol, Shanghai 200092, Peoples R China
推荐引用方式 GB/T 7714	Huang, He-ming,Fan, Shi-jie,Zhou, Xiao-ru,et al. Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis[J]. ACTA PHARMACOLOGICA SINICA,2021:13.
APA	Huang, He-ming.,Fan, Shi-jie.,Zhou, Xiao-ru.,Liu, Yan-jun.,Li, Xiao.,...&Li, Guang-ming.(2021).Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis.ACTA PHARMACOLOGICA SINICA,13.
MLA	Huang, He-ming,et al."Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis".ACTA PHARMACOLOGICA SINICA (2021):13.