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Histone deacetylase inhibitor givinostat alleviates liver fibrosis by regulating hepatic stellate cell activation

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). Targeting the mechanisms underlying HSC activation may provide a powerful therapeutic strategy for the prevention and treatment of liver fibrosis. 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, Dmkn, Msln and 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. Knocking down 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE161981 | GEO | 2020/12/01

REPOSITORIES: GEO

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Project description:Background: In the search of genetic determinants of Duchenne Muscular Dystrophy (DMD) severity, LTBP4, a member of the latent TGF-β binding protein family, emerged as an important predictor of functional outcome trajectories in mice and humans. Nonsynonymous single nucleotide polymorphisms in LTBP4 gene associate with prolonged ambulation in DMD patients, whereas an in-frame insertion polymorphism in the mouse LTBP4 locus modulates disease severity in mice by altering proteolytic stability of the Ltbp4 protein and release of transforming growth factor-β (TGF-β). Givinostat, a pan-histone deacetylase inhibitor currently in phase III clinical trials for DMD treatment, significantly reduces fibrosis in muscle tissue and promotes the increase of cross sectional area (CSA) of muscles in mdx mice. In this study we investigated the activity of Givinostat in mdx and in D2.B10 mice, two mouse models expressing different Ltbp4 variants and developing mild or more severe disease as a function of Ltbp4 polymorphism. Methods: Givinostat and steroids were administrated for 15 weeks in both DMD murine models and their efficacy was evaluated by grip strength and run to exhaustion functional tests. Histological examinations of skeletal muscles were also performed to asses the percentage of fibrotic area and CSA increase. Results: Givinostat treatment increased maximal normalized strength to levels that were comparable to those of healthy mice in both DMD models. The effect of Givinostat in both grip strength and exhaustion tests was dose-dependent in both strains and, in D2.B10 mice, Givinostat outperformed steroids at its highest dose. The in vivo treatment with Givinostat was effective in improving muscle morphology in both mdx and D2.B10 mice by reducing fibrosis. Conclusion: Our study provides evidence that Givinostat has a significant effect in ameliorating both muscle function and histological parameters in mdx and D2.B10 murine models suggesting a potential benefit also for patients with a poor prognosis LTBP4 genotype.

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Histone deacetylase inhibitor givinostat alleviates liver fibrosis by regulating hepatic stellate cell activation

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