Sodium valproate blocks the transforming growth factor (TGF)-β1 autocrine loop and attenuates the TGF-β1-induced collagen synthesis in a human hepatic stellate cell line

Abstract

Abstract. Histone acetylation and deacetylation have been thought to be related to gene expression, and there are many reports indicating that histone deacetylase inhibitors (HDACis) exert antifibrogenic effects in several organs. In injured livers, hepatic stellate cells (HSCs) are activated in response to profibrogenic mediators and produce large amounts of extracellular matrix. In particular, transforming growth factor-β1 (TGF-β1) is considered as a key factor in accelerating hepatic fibrosis because it is released from activated HSCs and further stimulates them. The present study aimed to clarify whether sodium valproate (VPA) has suppressive effects on cultured human HSCs (LI90). We showed that treatment with VPA had no significantly suppressive effect on cell proliferation at a concentration of 1 mM, which corresponded approximately to the serum concentration obtained by the administration of a clinical dose. However, VPA prevented the morphological changes characteristic for activation and inhibited the expression of collagen type 1 α1 (COL1A1) and TGF-β1 in activated LI90 cells at the mRNA and protein levels. Our results support the hypothesis that VPA exerts antifibrogenic activity with little cytotoxicity at 1 mM, and HDACis are expected to be used in clinical practice for the treatment of fibrotic diseases. IntroductionHepatic stellate cells (HSCs) are considered as the main source of extracellular matrix (ECM) proteins in chronic liver diseases leading to fibrosis. In a normal liver, these cells are liver-specific pericytes that serve as major vitamin A storage sites and show little proliferative activity (1). In an injured liver, however, HSCs undergo phenotypic changes termed activation in response to profibrogenic mediators such as platelet-derived growth factor (PDGF), connective tissue growth factor (CTGF), endothelin (ET)-1, and members of the transforming growth factor-β (TGF-β) family. During this phenotypic transition, HSCs express α smooth muscle actin (αSMA) and acquire the capacity to proliferate and produce excessive quantities of ECM proteins (2,3). It is reported that TGF-β and its intracellular mediators, i.e., Smad proteins, play important roles in stimulating collagen synthesis. In particular, production of TGF-β1 is enhanced by activated HSCs, and it has been considered that the effects of TGF-β1 on HSCs involve predominantly autocrine stimulation (4,5). Therefore, inhibition of TGF-β1 signals seems to be a potential target for therapeutic intervention in patients with liver fibrosis.It is considered that histone modification, particularly histone acetylation, is a key principle of epigenetic regulation of gene expression (6-8). Histone acetylation and deacetylation is controlled by histone acetyltransferases and histone deacetylases. In recent years, histone deacetylase inhibitors (HDACis) showed anti-cancer activities and are, therefore, of clinical interest (9-12). There are also several reports showing an antifibrogenic effect of HDACis, but the underlying mechanism is still un...

Epigenetic modifications by histone deacetylases: Biological implications and therapeutic potential in liver fibrosis

“…Data indicate that suppressed BAMBI promoter activity and expression by TLR4 in HSC is probable through the interaction with HDAC1, followed by the activation of HSC [11]. HDAC inhibitors, sodium valproate [72] and largazole [75], exert their anti-fibrotic effect partially through inhibiting TGF-b1 signaling. Additionally, HGF, a promising anti-fibrogenic mediator, can antagonize the pro-fibrotic effects of TGF-b1 by suppressing TGF-b1 expression and decreasing thrombospondin-1 (TSP-1)-dependent activation of latent TGF-b1 [42].…”

“…VPA administration also inhibits stellate cell activation and proliferation in vitro and in vivo, as well as increases histone H4 acetylation. The observed effects were partially due to inhibition of Class I HDAC activity, since the VPA effects could be in part mimicked by knock-down of the Class I HDACs [29,72].…”

Epigenetics and Liver Fibrosis

“…As an example, the class I inhibitor largazole can induce apoptosis and suppress proliferation of HSC by increasing the acetylation of histones H3 and H4 67 . Likewise, valproate sodium, a broad class I and II HDAC inhibitor, exerts its antifibrogenic properties by inhibiting the expression of collagen 1A1 and transforming growth factor β1 without causing cytotoxic damage 68 . Valproate sodium has also been shown to block myofibroblast differentiation and fibrogenesis in mouse models of liver fibrosis 69 .…”

Histone deacetylases as targets for treatment of multiple diseases

“…In a humanHSC line, sodium valproate, a class I HDACI, exerts antifibrogenic activity by blocking the TGF- β 1 autocrine loop and inhibiting TGF- β 1-induced collagen type 1 α 1 expression [67]. Another HDACI, TSA, affects the development of the actin cytoskeleton and inhibits collagen types I and III and α -SMA in HSCs, thereby abrogating the process ofHSC transdifferentiation [68,69].…”