A new histone deacetylase inhibitor improves liver fibrosis in BDL rats through suppression of hepatic stellate cells.
Bottom Line: In addition, HNHA induced apoptosis of HSCs, which was correlated with reduced COX-2 expression, NF-κB activation and cell death signals.HNHA restored liver function and decreased the accumulation of extracellular matrix in the liver via suppression of HSC activation in BDL rats in vivo.HNHA improved liver function, suppressed liver fibrosis and increased survival of BDL rats, accompanied by reduction of cell growth, activation and survival of HSCs.
Affiliation: Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea; Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.Show MeSH
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Mentions: Because the appearance of α-SMA-positive myofibroblasts is considered as a key event in the progression of liver fibrosis and TGF-β1, predominantly expressed by HSCs, is a key mediator for transdifferentiation, we assessed α-SMA or TGF-β1-positive cells by morphometric quantification to ascertain the accumulation of fibrogenic myofibroblasts. Activated myofibroblasts, as shown by positive staining for α-SMA, were predominant in the peri-ductular zone 1 area and, to a lesser degree, in the peri-sinusoidal area in zone 2 and zone 3. Immunohistochemical staining for TGF-β1 showed that the positively stained brown-coloured cells were mainly proliferating bile ductules and limiting plate hepatocytes. However, liver samples from rats treated with meloxicam, SAHA or HNHA for 3 weeks after BDL showed less bile duct proliferation and weak or no cytoplasmic immunostaining for α-SMA (Figure 3A) compared with BDL rats. Liver sections from meloxicam, SAHA and HNHA group rats showed weak or no cytoplasmic TGF-β1 staining in bile duct epithelial cells and limiting plate hepatocytes (Figure 3B). Treatment with HNHA was more effective in suppressing α-SMA and TGF-β1 in BDL-livers than treatment with meloxicam or SAHA. We then compared COX-2 expression in liver tissue samples. With vehicle treatment after BDL, COX-2 was expressed mainly in the proliferating bile ductules and, to a lesser degree, in hepatocytes. In livers from BDL rats receiving meloxicam, SAHA or HNHA, there was decreased hepatic COX-2 expression (Figure 3C) with the lowest expression in the HNHA-treated group. These results were confirmed by Western blot analysis of total lysates of livers, which showed that production of COL-I, α-SMA, TGF-β1, COX-2, MMP-2 and MMP-9 appeared to be most reduced in the BDL + HNHA group compared with other groups (Figure 3D). The acetylation of histone H3 in liver tissue was much stronger in the HNHA-treated group than in the BDL group (Supporting Information Fig. S2), whereas the level of HDAC1 was decreased in the HNHA-treated group compared with the BDL group (Supporting Information Fig. S3).
Affiliation: Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea; Department of Surgery, Yonsei University College of Medicine, Seoul, Korea.