Histone deacetylase inhibitor givinostat attenuates nonalcoholic steatohepatitis and liver fibrosis.

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.

• Authors: 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
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 43 Issue 4 Pg. 941-953 (Apr 2022) ISSN: 1745-7254 [Electronic] United States
• PMID: 34341511 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s), under exclusive licence to CPS and SIMM.

Chemical References

• Carbamates
• Histone Deacetylase Inhibitors
• givinostat
• Methionine

Topics

• Animals
• Carbamates
• Histone Deacetylase Inhibitors (pharmacology, therapeutic use)
• Liver (metabolism)
• Liver Cirrhosis (pathology)
• Methionine
• Mice
• Mice, Inbred C57BL
• Non-alcoholic Fatty Liver Disease (metabolism)