Histone deacetylase 8 inhibition alleviates cholestatic liver injury and fibrosis

• Published in: Biochemical pharmacology 2021-01, Vol.183, p.114312, Article 114312
• Main Authors: Lee, Chang Hun, Choi, Yunjung, Cho, Hyewon, Bang, In Hyuk, Hao, Lihua, Lee, Seung-Ok, Jeon, Raok, Bae, Eun Ju, Park, Byung-Hyun
• Format: Article
• Language: English
• Subjects: Animals; Bile duct ligation; Cholestasis; Cholestasis - drug therapy; Cholestasis - enzymology; HDAC8; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylase Inhibitors - therapeutic use; Histone Deacetylases - metabolism; Human; Humans; Liver Cirrhosis - drug therapy; Liver Cirrhosis - enzymology; Liver fibrosis; Male; Mice; Mice, Inbred C57BL
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2020.114312

[Display omitted] Cholestasis is a pathological condition involving blockage of bile flow that results in hepatotoxicity, inflammation, and fibrosis. Although recent studies have shown that histone deacetylases (HDACs) are involved in the progression of fibrosis in various organs, the role of HDAC8 on liver fibrosis has until now remained unexplored. This study presents a newly-synthesized, selective HDAC8 inhibitor SPA3014 composed of a vinyl disulfide-sulfoxide core, and evaluates its therapeutic efficacy against cholestatic liver injury and fibrosis in bile duct-ligated (BDL) mice. We first observed the increase in HDAC8 protein levels in mice with BDL and patients with cholestatic liver disease. Mice with BDL that were pretreated with SPA3014 had lower liver damage and fibrosis, based on gross examination, histopathologic findings, and biochemical analyses, than did vehicle-treated mice. Studies with LX-2 human hepatic stellate cells showed that SPA3014 exerted protective effects by inhibiting TGF-β-mediated activation of MAPK-Smad2/3 and JAK2-STAT3 pathways and by upregulating PPARγ expression. Overall, these results strongly suggest that HDAC8 inhibition constitutes a new therapeutic strategy for treatment of cholestatic liver injury.