Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis

• Published in: Acta pharmacologica Sinica 2022-04, Vol.43 (4), p.941-953
• Main Authors: Huang, He-ming, Fan, Shi-jie, Zhou, Xiao-ru, Liu, Yan-jun, Li, Xiao, Liao, Li-ping, Huang, Jing, Shi, Cui-cui, Yu, Liang, Fu, Rong, Fan, Jian-gao, Zhang, Yuan-yuan, Luo, Cheng, Li, Guang-ming
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; Carbamates; Cholesterol; Fatty liver; Fetuses; Fibrosis; Hepatocellular carcinoma; Histone deacetylase; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Immunology; Inflammation; Internal Medicine; Lipid metabolism; Liver; Liver - metabolism; Liver Cirrhosis - pathology; Liver diseases; Medical Microbiology; Methionine; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease - metabolism; Nutrient deficiency; Palmitic acid; Pharmacology/Toxicology; Steatosis; Vaccine
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/s41401-021-00725-1

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.