Sennoside A prevents liver fibrosis by binding DNMT1 and suppressing DNMT1‐mediated PTEN hypermethylation in HSC activation and proliferation

Abstract

Hepatic stellate cell (HSC) activation is an essential event during liver fibrogenesis. Phosphatase and tension homolog deleted on chromosome 10 (PTEN) is a negative regulator of this process. DNA methyltransferase 1 (DNMT1), which catalyzes DNA methylation and subsequently leads to the transcriptional repression of PTEN, is selectively induced in myofibroblasts from diseased livers. Sennoside A (SA), a major purgative constituent of senna and the Chinese herb rhubarb, is widely used in China and other Asian countries as an irritant laxative. SA is reported to improve hepatic steatosis. However, the effect and mechanism of SA on liver fibrosis remain largely unknown. We recently identified a novel strategy for protecting liver fibrosis via epigenetic modification by targeting DNMT1. A Surface Plasmon Resonance (SPR) assay first reported that SA could directly bind DNMT1 and inhibit its activity. Administration of SA significantly prevented liver fibrosis, as evidenced by the dramatic downregulation of α-smooth muscle actin (α-SMA) and type I collagen alpha-1 (Col1α1) protein levels in a CCl 4-induced mouse hepatic fibrosis model and in TGF-β1-activated HSC-T6 cells, in vivo and in vitro. SA decreased the expression of Cyclin D1, CDK, and C-myc, indicating that SA may inhibit the activation and proliferation of TGF-β1-induced HSC-T6. Moreover, SA significantly promoted the expression of PTEN and remarkably inhibited the expression of p-AKT and pERK in vitro. Blocking PTEN or overexpressing DNMT1 could reduce the effect of SA on liver fibrosis. These data suggest that SA directly binds and inhibits the activity and that attenuated DNMT1-mediated PTEN hypermethylation caused the loss of PTEN expression, followed by the inhibition of the AKT and ERK pathways and prevented the development of liver fibrosis. Hence, SA might be employed as a promising natural supplement for liver fibrosis drug therapy.

The Epigenetic Regulation of Microenvironment in Hepatocellular Carcinoma

“…Treatment with 5'aza-2'-deoxycytidine in activated HSCs model reduced fibrosisassociated gene expression as well as DNMT1 expression while simultaneously enhancing H19 expression and attenuated HSCs activation. Consistently, sennoside A can prevent liver fibrosis by binding DNMT1 and suppress DNMT1-mediated PTEN hypermethylation in HSC activation and proliferation (53).…”

Integrative analysis of genome-wide DNA methylation and single-nucleotide polymorphism identified ACSM5 as a suppressor of lumbar ligamentum flavum hypertrophy

“…In this study, we identified for the first time that the low expression and hypermethylation of ACSM5 gene in tissues and cells of HLF, and overexpression of ACSM5 restrained proliferation, anti-apoptosis, and fibrosis of HLF cells in vitro. DNMT1, a type of DNA methyltransferases (DNMTs), can maintain and catalyze abnormal DNA hypermethylation of CpG islands to cause the loss expression of genes specific, thereby regulating the occurrence and development of various fibrosis-related diseases [ 46 – 48 ]. Our data demonstrated that the low expression of ACSM5 in HLF cells was negatively regulated by DNMT1, and suppression of DNMT1 restrained the proliferation, anti-apoptosis, and fibrosis of HLF cells in vitro, which can be reversed by silencing ACSM5.…”

Pharmacology, Toxicology, and Metabolism of Sennoside A, A Medicinal Plant-Derived Natural Compound

“…The SA showed mitochondrial protective effect and inhibited hepatic steatosis ( Le et al, 2018 ). Concurrently, SA could also inhibit the proliferation of hepatic stellate cells (HSCs) and suppress the progression of liver fibrosis ( Zhu et al, 2020 ).…”

“…Interestingly, by using surface plasmonic resonance assay, Zhu et al showed that SA (30 mg/kg in vivo and 10 μM in vitro ) could directly interact with DNMT1 and inhibit DNMT1 in HSCs, resulting in restored PTEN expression and decreased PI3K/Akt activation. Therefore, SA may serve as a promising natural supplement for the treatment of liver fibrosis ( Zhu et al, 2020 ).…”

“…The chemical structure of SA and SB are shown in Figure 1 . In addition to the laxative effect ( Kon et al, 2014 ; Cao et al, 2018 ), SA has been shown to possess other potential pharmacological and therapeutic applications, including anti-obesity ( Greenway et al, 2006 ; Le et al, 2019 ; Wei et al, 2020 ), hypoglycemic ( Choi et al, 2006 ; Le et al, 2019 ; Wei et al, 2020 ), hepatoprotective ( Le et al, 2018 ; Zhu et al, 2020 ), anti-inflammatory ( Chen et al, 1999 ; Hwang and Jeong, 2015 ; Kwon et al, 2016 ) and anti-cancer effects ( Lee et al, 2017 ; Le et al, 2020 ) ( Figure 2 ; Table 1 ). Thus, SA has great potential to treat various illnesses, such as constipation, obesity, diabetes, fatty liver, many inflammatory and cancers.…”