1. Histone deacetylase inhibitor givinostat alleviates liver fibrosis by regulating hepatic stellate cell activation.
- Author
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Huang HM, Zhou XR, Liu YJ, Fan SJ, Liao LP, Huang J, Shi CC, Yu L, Pen JJ, Luo C, Zhang YY, and Li GM
- Subjects
- Animals, Carbon Tetrachloride, Cell Line, Female, GPI-Linked Proteins genetics, GPI-Linked Proteins metabolism, Gene Expression Profiling methods, Gene Expression Regulation drug effects, Hepatic Stellate Cells metabolism, Histone Deacetylase Inhibitors pharmacology, Humans, Intercellular Signaling Peptides and Proteins genetics, Intercellular Signaling Peptides and Proteins metabolism, Liver metabolism, Liver pathology, Liver Cirrhosis chemically induced, Liver Cirrhosis genetics, Mesothelin, Mice, Mice, Inbred C57BL, Rats, Uroplakin III genetics, Uroplakin III metabolism, Carbamates pharmacology, Hepatic Stellate Cells drug effects, Liver drug effects, Liver Cirrhosis prevention & control
- Abstract
Hepatic fibrosis, a common pathological manifestation of chronic liver injury, is generally considered to be the end result of an increase in extracellular matrix produced by activated hepatic stellate cells (HSCs). The aim of the present study was to target the mechanisms underlying HSC activation in order to provide a powerful therapeutic strategy for the prevention and treatment of liver fibrosis. In the present study, a high‑throughput screening assay was established, and the histone deacetylase inhibitor givinostat was identified as a potent inhibitor of HSC activation in vitro . Givinostat significantly inhibited HSC activation in vivo , ameliorated carbon tetrachloride‑induced mouse liver fibrosis and lowered plasma aminotransferases. Transcriptomic analysis revealed the most significantly regulated genes in the givinostat treatment group in comparison with those in the solvent group, among which, dermokine (Dmkn), mesothelin (Msln) and uroplakin‑3b (Upk3b) were identified as potential regulators of HSC activation. Givinostat significantly reduced the mRNA expression of Dmkn , Msln and Upk3b in both a mouse liver fibrosis model and in HSC‑LX2 cells. Knockdown of any of the aforementioned genes inhibited the TGF‑β1‑induced expression of α‑smooth muscle actin and collagen type I, indicating that they are crucial for HSC activation. In summary, using a novel strategy targeting HSC activation, the present study identified a potential epigenetic drug for the treatment of hepatic fibrosis and revealed novel regulators of HSC activation.
- Published
- 2021
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