Effect of histone deacetylase inhibitor on epithelial‐mesenchymal transition of liver fibrosis

Abstract

Liver fibrosis is an excessively reversible wound healing process and the fibrotic disorder is the activation of hepatic stellate cell that requires extensive alterations in gene expression. As reversible deacetylation of histone proteins modulate gene expression, we examined the effect of valproic acid (VPA) as selective histone deacetylase inhibitor on CCl-4 induced liver fibrosis. Thirty rats were divided into three equal groups; control group, fibrotic group and VPA-treated group. The rats were sacrificed after 6 weeks of liver fibrosis induction. The histopathological effect on liver tissue was examined. The expression of α-SMA and Smad-4 mRNA and serum levels of TGF-β1, alanine aminotransferase, and aspartate aminotransferase were determined. Treatment of rats with VPA attenuated carbon tetrachloride-induced liver fibrosis. Moreover, α-SMA and Smad-4 expression was repressed under VPA treatment and both serum TGF-β1 and liver enzymes were significantly decreased. The histone deacetylase inhibitor-1 VPA inhibits the epithelial-mesenchymal transition and affects hepatic stellate cell activation during liver fibrosis through downregulation of Smad4 and α-SMA expression which may serve as a promising agent in liver fibrosis treatment. © 2018 IUBMB Life, 70(6):511-518, 2018.

Liver Fibrosis in Non-alcoholic Fatty Liver Disease: From Liver Biopsy to Non-invasive Biomarkers in Diagnosis and Treatment

“…In addition to the ECM products, myofibroblasts also synthesize α-smooth muscle actin (α-SMA) (49). Ramzy et al indicated that an increase in α-SMA marks the activation of HSCs (50).…”

Epigenetics in Liver Fibrosis: Could HDACs be a Therapeutic Target?

“…Even though valproate (VPA) and its sodium salt, sodium valproate, can inhibit class II HDACs, they also strongly suppress class I HDACIs [ 29 , 127 ]. Sodium valproate has been well established as a long-term therapy of epilepsy, which attests to the safety of this molecule when chronically administered in humans, at least in patients without preexisting liver conditions [ 127 , 128 ]. However, it has also been proposed as a treatment for liver fibrosis by several experimental studies, therefore expanding its clinical applications ( Figure 2 ).…”

“…VPA is able to significantly reduce S. mansoni -induced fibrosis and inflammation through downregulation of profibrogenic factors and collagen deposition [ 131 ]. VPA antifibrogenic properties were corroborated in an in vivo rat model of CCl 4 -induced fibrosis, which were characterized by α-Sma downregulation, circulating AST and ALT reduction and decreased collagen deposition [ 127 ]. Although compelling evidences support the promising effects of HDACIs in liver fibrosis, the underlying mechanisms are still not well known.…”

New insights into the pathogenesis of Peyronie's disease: A narrative review

“…Some studies of animal models have shown that inhibitors of HDAC such as trichostatin A (TSA) and valproic acid (VPA) significantly decrease the level of Smad3/Smad4 complexes in TGF-β1/Smad signaling of fibroblasts that rely on the epigenetic modulation of collagen I type. 26 , 27 Choi et al 28 showed that in a mouse model of unilateral ureteral obstruction (UUO), CG200745, an inhibitor of HDAC attenuated oxidative stress, inflammatory cytokines and also markedly reduced the expression of α-SMA, fibronectin, collagen I, and TGF-β. Choi et al 29 showed that the overexpression gene of Smad7 inhibited the TGF-β1 induced production of ECM, myofibroblastic differentiation of PD-derived fibroblasts, phosphorylation, and nuclear translocation of Smad2/3.…”