Novel Insights on Notch signaling pathways in liver fibrosis

European Journal of Pharmacology 826 (2018) 66–74

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European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar

Novel Insights on Notch signaling pathways in liver fibrosis a

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Ming-ming Ni , Ya-rui Wang Jun Lic a b c

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b

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a,⁎

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, Wen-wen Wu , Chong-cai Xia , Yi-he Zhang , Jing Xu , Tao Xu ,

Department of Pharmacy, Children's Hospital of Nanjing Medical University, No.72 Guangzhou Road, Nanjing 210001,China TCM Research Institution, Nanjing Municipal Hospital of T.C.M, The Third Affiliated Hospital of Nanjing University of T.C.M, Nanjing 210001,China Institute for Liver Diseases of Anhui Medical University(AMU), Anhui Medical University, Hefei 230032, Anhui Province, China

A R T I C L E I N F O

A B S T R A C T

Keywords: Notch signaling pathway Liver fibrosis Hepatic stellate cell Therapeutic target

Liver fibrosis is characterized by an increased and altered deposition of extracellular matrix (ECM) proteins that make up excessive tissue scarring and promote chronic liver injury. Activation of hepatic stellate cells (HSCs) is a pivotal cellular event in the progression of liver fibrosis. However, the mechanisms involved in the development of liver fibrosis are only now beginning to be unveiled. The Notch pathway is a fundamental and highly conserved pathway able to control cell-fate, including cell proliferation, differentiation, apoptosis, regeneration and other cellular activities. Recently, the deregulation of Notch cascade has been found involved in many pathological processes, including liver fibrosis. These data give evidence for a role for Notch signaling in liver fibrosis. In addition，more and more date are available on the role of Notch pathways in the process. Therefore, this review focuses on the current knowledge about the Notch signaling pathway, which dramatically takes part in HSC activation and liver fibrosis, and look ahead on new perspectives of Notch signaling pathway research. Furthermore, we will summarize this new evidence on the different interactions in Notch signaling pathwayregulated liver fibrosis, and support the potentiality of putative biomarkers and unique therapeutic targets.

1. Introduction Liver fibrosis is considered to be the end result of a subgroup of chronic liver injury, such as alcohol abuse, viral infection, chronic hepatitis, persistent alcoholic toxicity and overload of metal ions. In response to liver injury, HSCs become activated and proliferate, which unequivocally plays the main role in the pathogenesis of liver fibrosis (Ni et al., 2016). In general, the natural history of liver fibrogenic response is characterized by an excessive accumulation of extracellular matrix (ECM) of predominantly type I collagen. The activated HSCs synthesize and secrete an excessive amount of ECM, which distort hepatic architecture and leads to cirrhosis and many complications: portal hypertension, liver failure, and hepatocellular carcinoma (Karsdal et al., 2015; Xu et al., 2016). Accumulated evidence has confirmed that the central effector cells are the activated HSCs, which serve as the body responsibility for the excessive synthesis and deposition of ECM in hepatic interstitium, leading to liver fibrosis. Following multiple injurious agents or exposure to inflammatory cytokines, activated HSCs lose their lipid droplets, and then transform into myofibroblast-like cells, which is defined by excessive synthesis of ECM (Baghy et al., 2012; B et al., 2017). Although genetic and environmental factors have

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been incriminated, the mechanisms that are directly involved in the pathogenesis of the disease remain unknown. There is a pressing need to develop novel therapeutic approaches aimed at attenuating or preventing liver fibrosis. In the past few years, there have been considerable recent advances towards a better understanding of the biological mechanism of liver fibrosis, leading to changes in the approach to and management of the disease. During recent years，emerging studies indicated that several signaling pathways are involved in the liver fibrosis pathogenesis, such as the Notch signaling pathway, which recognized as a major player to steer developmental interactions and in liver biology and pathophysiology (Gil-Garcia and Baladron, 2016). It has become clear that Notch signaling is involved in cell proliferation, survival, apoptosis, and differentiation events at all stages of development, thus controlling organ formation and morphogenesis (Bray, 2016). And recent reports have implied that Notch cascade is activated in liver fibrotic model and abnormally increased in fibrotic patients, while Notch inhibitions protect against fibrotic disorders (Zhang et al., 2016b). Notch signaling mediates both adaptive and maladaptive responses to liver injury, depending upon the balance between its actions as a regulator of progenitor cell growth and its ability to promote liver inflammation and

Corresponding author. E-mail address: [email protected] (J. Xu). They contribute equality to this work.

https://doi.org/10.1016/j.ejphar.2018.02.051 Received 21 June 2017; Received in revised form 27 February 2018; Accepted 28 February 2018 Available online 01 March 2018 0014-2999/ © 2018 Elsevier B.V. All rights reserved.

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Fig. 1. Schematic representation of Notch signaling pathway. A. Illustration of phenotype displayed as transmembrane Notch proteins (Notch 1–4). The extracellular domain contains the EGF-like repeats that bind ligand and the LIN12-Notch repeats (LNR) that prevent premature receptor activation. The main regions of the intracellular domain are the RAM domain that is required for the interaction with members of the RBP-J family of transcription factors, the ankyrin repeats (ANK) that bind the Mastermind (MAML) family of co-activators, two nuclear localisation sequences (NLS), and a transcriptional activation domain (TAD). B. The core “canonical” Notch signaling pathway. The mammalian Notch receptors are synthesized in the ER as a co-linear precursor which is cleaved by a Furin-like convertase within the Golgi. Schematic view of two cells is shown, one expressing the Notch receptor, and an adjacent cell expressing the Notch ligand Jagged/DLL. Upon ligand binding, Notch is activated and cleaved to release the extracellular domain, which is then endocytosed along with the ligand. Further cleavage of the receptor by the gamma-secretase complex releases the Notch intracellular domain (NICD). NICD migrates into the nucleus where it binds to the transcription factor CBF1, driving the expression of Notch target genes transcription. C. “Non-canonical” Notch signaling and cross-talk with other signaling pathways. Non-canonical Notch signaling is independent of CSL/RBP-J, and instead, interacts with Wnt/β-catenin, TGFβ/Smad, PI3K/AKT, Shh, HIF-1α, or NF-Κb pathway at either the cytoplasmic or nuclear levels.

fibrogenic repair. Synthesis of Notch ligands is stimulated by diverse factors that trigger liver regeneration and fibrogenic repair (Geisler and Strazzabosco, 2015). Furthermore, Notch signaling genes are targets for pathogenic mutations, including those associated with liver fibrosis (Fung and Tsukamoto, 2015). Recent lineage tracing studies show that Notch signaling pathway activation in HSCs promotes them to become myofibroblasts through epithelial-mesenchymal transition (EMT), which is the process of fully differentiated epithelial cells acquiring the invasive and motile characteristics of fully differentiated mesenchymal cells (fibroblasts or myofibroblasts). EMT in liver fibrosis leads to increased deposition of

the ECM, which contribute to the parenchyma destruction in advanced fibrosis (Zhang et al., 2015c) Moreover, several researches suggested that the Notch signaling pathway may selectively mediate fibrogenic properties of transforming growth factor-β1 (TGF-β1), which was essential to promote the production and deposition of ECM (Nyhan et al., 2010; Dees et al., 2011). Despite growing evidence for Notch signaling pathway involvement in liver fibrosis, study of Notch pathway in this pathogenesis is still in its infancy. Therefore, the goal of this review is to discuss new perspectives of Notch signaling pathway activation in liver fibrotic diseases and HSC fate, including DNA methylation, microRNA (miRNA) and other signal pathways influence Notch signaling pathway

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receptor.(Yin et al., 2010). After the extracellular cleavage by ADAMs, the membrane-embedded γ-secretase complex，an enzyme complex that contains presenilin1 and 2, nicastrin, presenilin enhancer 2(PEN2) and anterior-pharynx defective-1(APH1), cleaves the truncated Notch receptor. After the second cleavage, the NICD then is released into the cytosol and translocates into the nucleus to bind with the CSL protein complex (CBF1/RBP-J in humans, Su (H) in Drosophila, and Lag-1 in Caenorhabditis elegans), which we refer to as RBP-J in this review (Borggrefe and Oswald, 2009; Teodorczyk and Schmidt, 2014; Kovall et al., 2017). RBP-J has been described as both a transcriptional activator and transcriptional repressor. It is important to note that in the absence of NICD, RBP-J functions as a transcriptional repressor by binding to nuclear receptor corepressor 2 (NCOR2 or SMRT) and SKIinteracting protein (SKIP), which recruit one of several co-repressor complexes containing histone deacetylases (HDAC)(Contreras-Cornejo et al., 2016). Once in the nucleus, NICD binds with high affinity to CBF1/SKIP and replaces the co-repressor complex. The complex of NICD/CBF1/SKIP is further stabilized by binding of the transcriptional co-activator Mastermind-like (MAML) and of histone acetyltransferases (HAT) to activate transcription of Notch target genes that include the Hairy enhancer of split homologs transcription factors (Hes and Hey), Vascular endothelial growth factor (VEGF), cyclin D1, c-myc, Peroxisome-proliferator-activated receptor (PPAR) and the Notch receptors themselves (Minter and Osborne, 2012; Yao et al., 2017). This core signal transduction pathway is significantly dependent on the Notch master transcriptional regulator RBP-J and is known as the ‘canonical’ pathway (Fig. 1B).

transduction. And we will provide current literature around Notch signaling pathway and its role in liver fibrosis and summarize recent advances in therapeutic targeting of the Notch signaling pathway. 2. Overview of the Notch signaling cascade Notch Signaling Cascade, an evolutionary conserved signaling system in normal embryonic development, plays a key role in the regulation of tissue homeostasis and maintenance of stem cells in adults (Guo et al., 2014; Nowell and Radtke, 2017). The pathway system comprises of ligands, receptors, transcriptional complex components and downstream genes. And Notch families are single-pass transmembrane proteins that have dual functions as both cell surface receptors and nuclear transcriptional regulators (Yin et al., 2010). Currently, Notch is discovered in all metazoans, and mammals possess four different Notch receptors, whose principal function to regulate several fundamental cellular processes, including proliferation, survival, apoptosis and differentiation. Intriguingly, the Notch signaling pathway molecules have been implicated to play a critical role in mediating communication with neighboring cells by cell-cell ligand-receptor interaction to convey the signal into a transcriptional response (Alketbi and Attoub, 2015; Geisler and Strazzabosco, 2015). 2.1. Structure of Notch receptors and ligands Notch proteins are presented on the cell surface with a highly conserved expression among vertebrates and invertebrates during evolution (LaFoya et al., 2016). In mammals, there are four Notch proteins (Notch 1–4) and five ligands belonging to the Jagged (Jagged1, 2) and Delta-like (Delta-like, Dll1, 3, and 4) family. These homologs share highly conserved domain architecture (Chillakuri et al., 2012). Notch proteins define a family of transmembrane receptors (300–350 kDa), consisting of an extracellular domain (NECD，Notch Extra-Cellular Domain), an intracellular domain (NICD, Notch IntraCellular Domain), and a transmembrane domain. Extracellular domain of Notch has 29–36 epidermal growth factor (EGF)-like repeats domains, which is responsible for the binding of the ligand, and followed by a conserved negative regulatory region (NRR or LNR) consisting of three LIN repeats (Wang, 2011). The intracellular portion of Notch receptors contain: a regulation of amino-acid metabolism (RAM) domain, nuclear localisation sequences, six ankyrin (ANK) repeats, a transactivation domain (TAD) and a C-terminal PEST (Prolin, Glutamic acid, Serin, Threonin) domain that is pivotal for the stability of the protein. Vertebrates and mammals have four different Notch receptors that differ mainly in the number of EGF like repeats and C-terminal sequences located between the ANK and PEST domains (D'Souza et al., 2010). (Fig. 1A)

2.2.2. Non-canonical Notch signaling pathway In addition to the canonical activation of the Notch pathway, emerging evidence shows Notch can signal in RBP-J independent modes. The non-canonical signals discussed are broadly defined and mainly contain the following: DSL ligands (Delta-like (Dll) 1, Dll4, Jagged1 and Jagged2)-independent activations, CSL-independent signaling, interactions with non-DSL ligands, differential posttranslational modifications, signal transduction without cleavage, and competition/ protection for a cofactor (Heitzler, 2010; Andersen et al., 2012). And the non-canonical Notch signaling involved in several physiological and pathological cellular processes in the manner of interacting with other signaling pathways such as the TGFβ/Smad, Wnt/β-catenin, PI3K/AKT, Shh, HIF-1α,or NF-κB pathway, through direct or indirect interactions with Notch signaling components (Ayaz and Osborne, 2014) (Fig. 1C). 3. Notch signaling pathway activation and liver fibrosis Pathologic repair leads to liver fibrosis, the main major cause of liver disease progression (Bissell, 1998). The activated HSC proliferates and synthesizes ECM proteins in the process of liver pathologic repair to produce the fibrous scar (Lu et al., 2004; Zhang et al., 2016a). Of interest, Notch components play various context and cell-type specific roles in liver and altering their activity levels have strongly associated with the development and progression of liver fibrosis (Wu et al., 2015). By the way, Numb protein gets asymmetrically localized to one daughter cell during cell divisions that generates distinct progeny. High levels of Numb received in HSCs down-regulate suppresses extrinsic Notch signaling, whereas the cell with low levels of Numb maintains Notch activity during liver fibrosis. In the adult liver, all 4 Notch proteins (Notch 1–4) are expressed in both the epithelial and mesenchymal compartments (Chen et al., 2012b). Notch1 and Notch2 are detected in epithelial liver cells whereas Notch3 and Notch4 are expressed in mesenchymal and endothelial cells (Nijjar et al., 2001; Boulter et al., 2012; Fiorotto et al., 2013). And Notch3 and Jagged1 has been found to be significantly up-regulated in fibrotic live (Nijjar et al., 2002). The ligand Jagged-1 as an autocrine for myofibroblasts is strongly upregulated in activated HSCs and animal models, and deemed to be important to maintain the stem cell niche and HSC quiescence (Boulter et al.,

2.2. Tuning of Notch signaling activation 2.2.1. Canonical Notch signaling pathway Notch is originally synthesized in the endoplasmic reticulum as preNotch, where chaperone O-fucosyltransferase (O-Fut) fucosylates the Notch protein, which is crucial for the production of a functional receptor (Aithal and Rajeswari, 2013). Then the fucose is extended by the glycosyltransferase activity of Fringe, altering the ability of specific ligands to activate Notch. The mature receptor cleaved into two associated peptides by protein convertases in the Golgi apparatus and then the two fragments are reassembled as a heterodimer by noncovalent interactions at the cell surface (Blaumueller et al., 1997; ArtavanisTsakonas et al., 1999; Kopan and Ilagan, 2009). Binding of a range of cell-surface ligands to Notch receptors in signal-receiving cells leads to conformational changes of the receptor—possibly caused by mechanical force upon ligand endocytosis of the ligand expressing cell (signalgiving cell)—leading to the exposure of the cleavage site for ADAM (A Disintegrin And Metalloproteinase) in the extracellular domain of the 68

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regulating the inflammatory response and the function of macrophages (Kimball et al., 2017; Wang et al., 2017b). Emerging concepts have shown that the Notch pathway was implicated in macrophage activation and plasticity in liver fibrosis. Notch receptors were up-regulated in activated macrophages, and inhibiting processing of Notch receptor could modulate expression of inflammatory cytokine expression (Palaga et al., 2008). Dll4 increased in human macrophages exposed to proinflammatory stimuli such as lipopolysaccharide or interleukin-1β, and induced inflammatory pathways and genes, suggested that Dll4-triggered Notch signaling may mediate inflammatory responses in macrophages. Moreover, Notch3 selectively increased during macrophage differentiation and Notch3 silencing during macrophage differentiation decreased the transcription of genes that promote inflammation (Fung et al., 2007). Quttz et al. found that macrophage recruitment and macrophage cytokine secretion in response to lipopolysaccharide/ interferon-γ were decreased in Notch1 + /− mice, which established that Notch1 was important for the inflammatory response during wound healing (Outtz et al., 2010). Therefore, in Notch1 + /− mice, reduced M1 polarization was accompanied by a reduction in TLR4-triggered inflammatory responses (Zhang et al., 2012). He el al. showed that disruption of RBP-J，the transcription factor trans-activated from four mammalian Notch receptors in macrophages attenuated liver fibrosis by inhibiting NF-κB activation (He et al., 2015). Fiona and colleagues indicated that the recruitment of CBF1 and its associated HDAC was apparently associated with HSC activation by binding to the IκBα promoter, and then enhanced NF-κB activity, which could provoke activation of surrounding tissue macrophages and thus cause liver fibrosis (Oakley et al., 2003; Sunami et al., 2012). Of further interest, Notch signaling may mediate macrophage function by controlling genes involved in an antimicrobial phenotype polarization. Ruchi and colleagues recently demonstrated that Notch inhibitor could inhibit differentiation and contractility of HSC, and blocking of Notch signaling significantly inhibited M1 driven-fibroblasts activation and fibroblastsdriven M1 polarization (Bansal et al., 2015; Sun et al., 2017). In fact TLR4 and RBP-J have been shown to cooperate to induce the translation of key transcription factors, interferon regulatory factor 8 (IRF8) that induced downstream M1 macrophages-associated genes (Xu et al., 2012). Further, Notch signaling could be blockaded by blunting macrophage activation and M2 polarization (Zhang et al., 2010). And inhibition of Notch1/Jagged1 signaling could block macrophage M2 polarization and ameliorate liver granulomata and fibrosis in a murine model of Schistosomiasis japonica (Zheng et al., 2016). These findings suggest that Notch signaling is a crucial determinant of HSC activation and macrophages polarization in liver fibrosis. Thus, the aggregate findings predict that injury-related activation of the Notch pathway would play a crucial role in HSC fates, liver fibrosis and inflammatory responses. This review critically discusses the most recent advances on the role of Notch signaling in liver fibrosis (Fig. 2B).

2012). Moreover, myofibroblasst-derived Jagged-1 is supposed to promote differentiation of Notch-regulated progenitor for hepatocytes and cholangiocytes into Notch-sensitive cells that express markers of HSC in a paracrine manner (Liu et al., 2012). It is intriguing that in patients with AGS (Alagille Syndrome), where Jag1 is defective; there is limited deposition of fibrotic tissue, consistent with the slow progression to cirrhosis seen in AGS patients. Moreover, Jagged1-neutralizing antibody restrains the migratory and proliferative capacities of the cholangiocytes, which undergoing EMT could become a source of invasive fibroblasts that contribute to liver fibrosis (Nefedova et al., 2004). Chen el al. recently reported that obviously intense expression of Notch3 was observed in fibrotic liver tissues of patients with chronic active hepatitis, whereas in normal liver tissues Notch3 was not detected. Furthermore, the expression of myofibroblastic markers were dramatically enhanced by over-expression of Notch3 in HSC-T6 cells, while Notch3 silencing significantly decreased the expression of myofibroblastic markers and antagonized the expression of α-smooth muscle actin(αSMA) and collagen I induced by TGF-β1 (Chen et al., 2012c). Furthermore, transfection of Notch3 shRNA in experimental CCl4-induced liver fibrosis rat model reversed EMT in fibrotic livers via reducing TGFβ1 expression (Zheng et al., 2013). Evidence suggests that Notch1 receptor and its downstream target gene, Hes1, play essential roles in liver fibrosis. Notch1 inhibited the promoter activities of α-SMA, collagen I and collagen II, while Hes1 enhanced the α-SMA and collagen II promoter activities in HSC-T6 cells. Over-expression of Hes1 increased the expression of α-SMA and collagen II. This pleiotropic effect could be blocked by Hes1 auto-negative feedback, which allows Notch1 keep Hes1 protein expression at a reasonable level to repress the expression of α-SMA and collagen II (Zhang et al., 2015a). Xie and co-workers demonstrated that Notch-1, as a Notch signaling inhibitor, could inhibit HSCs transformation to myofibroblasts. And more importantly, Notch1mediated signaling is essential to maintain the quiescent stage of HSCs (Miroshnichenko and Zhilskaya, 1975; Xie et al., 2013). Chen et al. reported that activation of Notch1 resulting in HSCs growth inhibition is stimulated by bone marrow-derived mesenchymal stem cells through juxtacrine signaling, and blocking Notch signaling with Notch1 siRNA abrogated the proliferative suppression of HSCs (Chen et al., 2011). Of interesting, several researches suggested that profibrogenic actions of TGF-β were mediated by its ability to activating Notch signaling. Notch signaling could promote TGF-β1-induced EMT in liver fibrosis (Trehanpati et al., 2012; Gao et al., 2017; Wang et al., 2017c). Furthermore, ischemia/reperfusion (I/R) injury which is characterized significant cellular damage and liver dysfunction (Jaeschke and Lemasters, 2003), induced activation of Notch signaling, resulting in accumulation of reactive oxygen species (ROS) and aggravated nonparenchymal cell death including rat HSC-T6 cells and macrophages in the process of liver injury (Yu et al., 2011). Damaged kupffer cells (KC) and hepatocytes both released ROS, as well as fibrogenic and inflammatory mediators that recruited inflammatory cells and induced HSC activation (Lee et al., 2011; Yang et al., 2014). Nowadays it is believed that oxidative stress is involved in liver fibrosis (Mortezaee and Khanlarkhani, 2018). Oxidative stress usually results from excessive ROS generation. Increased production of ROS drives a higher level of activity on ADAM17 metalloproteinase. Consequently, ADAM17 produces a proteolytic release of the active form of Notch proteins (also called NICD) and its transport to the nucleus, where it induces transcriptional activation of genes related to fibrosis (GonzalezForuria et al., 2017). Moreover, Notch1 siRNA and Notch inhibition significantly inhibit oxidative stress, which demonstrate that Notch signaling plays a regulatory role in oxidative stress (Yang et al., 2013) (Fig. 2A). HSCs are considered as the major producers of ECM during liver fibrosis, but activation of macrophages is also an essential step in the initiation of fibrogenesis and they are signified as positive modulators of fibrosis (Pradere et al., 2013; Sasaki et al., 2017; Zhou et al., 2017). It is noteworthy that Notch signaling may be involved in liver fibrosis by

4. New perspectives of the Notch pathway in liver fibrosis 4.1. Regulation of Notch with DNA methylation modulation in liver fibrosis Epigenetic mechanisms are required for the maintenance of HSC cells and their differentiation during asymmetric division (Gotze et al., 2015). Indeed, DNA methylation is an important epigenetic modification on chromosomes that correlates with the permanent suppression of gene expression (Rondelet and Wouters, 2017). Methylation of DNA at the carbon 5 of cytosine residues that precede guanines is a reversible modification and during the last decade its correlation to liver fibrosis pathogenesis has been well established (Wu et al., 2016). Moreover, DNA methylation has a direct impact on Notch receptors (Sun et al., 2016). Aberrant methylation of a few selected genes such as Notch plays a vital role in facilitating fibrotic fibroblast activation and in driving fibrosis (Moran-Salvador and Mann, 2017). Recently, a study has demonstrated that Notch methylation status in chronic liver injury 69

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Fig. 2. Notch signaling pathway activation and liver fibrosis. A. Members of the Notch signaling pathway in liver fibrosis. Compared to quiescent HSCs, activated HSCs demonstrated much lower expression of Notch-1 and Numb but much higher expression of Jagged-1, Notch-2 and Notch-3, while expression of another Notch ligand (Jagged-2) and other Notch receptor (Notch-4) was detected at much lower levels. B．Notch pathway involved in macrophage activation and plasticity in liver fibrosis. Notch signaling may be implicated in liver fibrosis by modulating the inflammatory response and the function of macrophage.

is involved in liver fibrosis progression. Reister S et al. found the Notch1 expression became apparently suppressed by DNA methylation during culture of HSC. The freshly isolated HSC exhibited low degree methylation of Notch1, while the methylation level of Notch1 DNA was as high as 57% ± 10% in HSC cultured for 7 days. As the same a high degree of methylation of Nocth1 was also found in fibrotic liver tissues of patients with chronic active hepatitis, suggesting a modulation of Notch1 expression by DNA methylation in HSCs. Compared with this, Notch3 is involved in the differentiation of quiescent HSCs and became obviously upregulated during activation of HSCs in culture. Of potential interest, the Notch3 elevation showed a different pattern, with demethylation occurring in myofibroblasts and in day 7 samples. The

upregulation of Notch3 in activated HSCs by DNA demethylated is in good agreement with the process of liver fibrosis. Therefore, DNA methylation was apparently involved in regulation of the expression of Notch1 and Notch3 receptors in HSCs, but the genes have different regulatory effects on quiescent and activated HSCs, leading to a shift from Notch1 to Notch3 during HSC activation (Reister et al., 2011). (Fig. 3) 4.2. Association of Notch with miRNAs modulation MiRNAs were short noncoding RNAs molecules that suppress the expression of protein coding genes at the posttranscriptional level by 70

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fibrogenesis in the TGF-β1 pathway, acting as transcription factors (Meng et al., 2015; Zhang et al., 2015b). TGF-β was demonstrated to induce transport, Golgi organization and unfolded protein response, thereby facilitating fibrogenesis in murine liver fibrosis (Maiers et al., 2017). Moreover, accumulating evidence indicated TGF-β pathway was involved in EMT and fibroblast activation. And Notch signaling could promote TGF-β1-induced EMT, resulting in the development of liver fibrosis (Bi et al., 2012; Zhu et al., 2017). A recent study suggested blocking Notch pathway could ameliorate renal fibrosis via inhibition of the TGF-β/Smad pathway (Xiao et al., 2014). However, the exact interaction between Notch and TGF-β/Smad pathway signaling was very complicated. Wang and partners employing targeted ectopic elevated expression of Notch and Notch ligands have provided insights into the processes controlled or influenced by Notch signaling in liver fibrosis. Their experiment turned out that Notch inhibitor restricted the TGF-β/Smad pathway in liver fibrosis, and Notch signaling exerted fibrogenesis mediated by the TGF-β/Smad signaling pathway. Furthermore, TGF-β signaling upregulated Notch signaling, which promoted TGF-β signaling. The positive feedback reinforced interaction between Notch and TGF-β/Smad pathway in liver fibrosis (Wang et al., 2017c).

Fig. 3. New advances of the Notch pathway activation in liver fibrosis. Molecular and genetic studies have identified multiple mechanisms for liver fibrosis.

binding to the 3´-untranslated region (3´-UTR) of target gene mRNAs. They regulated gene expression essential for cell development and function through miRNA degradation or translational inhibition (Mehboob Awan et al., 2017). Moreover, miRNAs have been found to play a crucial role in regulation of inflammation leading to liver fibrosis (Lee et al., 2014; Wang et al., 2017a). Bioinformatics analysis of gene expression identified dysregulation of miRNA-449a induced YKL40, an inflammatory marker upregulated in patients with liver fibrosis (Sarma et al., 2012). Prior research showed that the activated Notch signaling, a key regulator for inflammation and liver fibrosis, induced the severe liver fibrosis closely connection with NF-κB signaling. It has been shown that Notch1 was one of the upstream regulators of NF-κB complex and downregulation of Notch1 impaired its function (Cheng et al., 2001; Cao et al., 2010). Interestingly, Notch1 was a direct target of miRNA-449a, and result that miRNA-449a regulated the expression of YKL40 by inhibiting components of upstream Notch1/ NF-κB transcriptional regulatory complexes. Furthermore，Yang and colleagues found that miR-200a controlled HSCs activation and fibrosis via SIRT1/ Notch1 signal pathway, loss of miR-200a correlated with Notch1 downregulation in HSCs cell (Yang et al., 2017). These results demonstrated that Notch regulated inflammation by cooperating with the action of miRNA, may eventually contribute to liver fibrosis.

5. Therapeutic approaches to Notch signaling inhibition With regards to increasing activity of Notch signaling has been involved in the pathogenesis of liver fibrosis, there is a continued excitement over the possible application of Notch Signaling inhibitor for this disease. There are different methods to suppress Notch signaling, such as application of antagonists, administration of siRNA, usage of soluble receptors, treatment with transcription factor competitor and transcription inhibitors (Zhang et al., 2012). For example, γ-secretase inhibition would impair Notch signaling by inhibiting the cleavage of transmembrane notch proteins into their active intracellular domain fragments, resulting in Notch signal transduction disorder. Gama-secretase inhibitors (GSIs) efficiently inhibited Notch signaling in mouse models of cholestatic liver disease and reduced fibrosis in CCL4-treated rodents (Chen et al., 2012b). It is possible to speculate that GSIs could suppress the activation of HSCs, thereby reducing the extent of liver fibrosis. DAPT, one γ-secretase inhibitor, significantly attenuated liver fibrosis and decreased the expression of various myofibroblasts genes in a rat HSC line (HSC-T6). DAPT alleviated CCl4-related fibrosis in rats accompanied by reduced the expression of TGF-β (Chen et al., 2012b). However, GSIs are non-specific inhibitors of Notch signaling and have even broader biological effects than predicted that GSIs have a considerable toxicity profile. The clinical trials with GSIs have revealed several adverse events, most importantly gut functionality worsening, as a result of combined Notch1 and Notch2 inhibitions disrupting intestinal stem cells biology (van Es et al., 2005). General inhibition of Notch signaling have deleterious side effect. Thus, more selective monoclonal antibodies against Notch1, Notch3 or Jag1 may provide a considerable advantage. Phytochemical curcumin, a natural yellow polyphenol, inhibited Notch activity and decreased Notch1 activation, expression of Jagged-1 and its downstream target Hes-1 (Subramaniam et al., 2012). Qiu and co-workers indicated that curcumin has the potential to protect against CCl4-induced fibrogenesis and inflammation via suppression of Dlk1 activity and downstream PPAR-gamma in HSCs (Qiu et al., 2014). Zheng et al. demonstrated that inhibition of Notch3 by tail vein injection of recombinant adeno-associated virus1 (rAAV1)-Notch3-shRNA could restrain Notch signaling activation and significantly impeded the development of liver fibrosis. In addition, rAAV1-Notch3-shRNA administration could protect hepatocytes from undergoing apoptosis and reverse the EMT (Zheng et al., 2013). Although several aspects of these functions remain to be fully understood, these findings provide an intriguing rationale for investigating Notch-based therapies in patients with liver fibrosis.

4.3. Notch crosstalk with hedgehog signaling in liver fibrosis Liver repair involved phenotypic changes in HSC via developmental morphogenic pathways, such as Notch and hedgehog signaling pathway (Witek et al., 2009; Choi et al., 2011). A new study in a rat model of liver fibrosis induced by carbon tetrachloride (CCl4) suggested that activating Notch was involved EMT and fibroblast activation, resulting in the development of liver fibrosis(Chen et al., 2012a). And primary HSC used the Notch signaling pathway to regulate their trans-differentiation. Xie and coworkers found that cultured HSCs transdifferentiated into myofibroblasts accompany with Notch signaling activation, then they underwent an EMT and increased hedgehog signaling pathway. Blocking the hedgehog pathway suppressed the activity of Notch signaling, inhibiting whole liver expression of various Notch target genes and also induced an EMT. More recently, Notch signaling activity has been associated with a shift in HSCs differentiation toward myofibroblasts. Jag-1 and Notch-2 seem to play a role in facilitating hedgehog signaling in fibrosis (Xie et al., 2013). Thus, it seems likely that The Notch and Hedgehog pathways interact to control the fate of key cell types involved in liver repair by modulating EMT. 4.4. Notch regulates HSC fate by crosstalk with TGF-β/Smad pathway TGF-β plays crucial and complex roles in all stages of disease progression in liver, from initial liver injury through inflammation and fibrosis, to cirrhosis and cancer. Smad (Smad2, and especially Smad3) proteins have been studied extensively as critical mediators of 71

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6. Conclusion and future directions

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Nuclear factor-kappaB/p65 responds to changes in the Notch signaling pathway in murine BV-2 cells and in amoeboid microglia in postnatal rats treated with the gamma-secretase complex blocker DAPT. J. Neurosci. Res. 88, 2701–2714. Chen, S., Xu, L., Lin, N., Pan, W., Hu, K., Xu, R., 2011. Activation of Notch1 signaling by marrow-derived mesenchymal stem cells through cell-cell contact inhibits proliferation of hepatic stellate cells. Life Sci. 89, 975–981. Chen, Y., Zheng, S., Qi, D., Guo, J., Zhang, S., Weng, Z., 2012a. Inhibition of Notch signaling by a gamma-secretase inhibitor attenuates hepatic fibrosis in rats. PLoS One 7, e46512. Chen, Y., Zheng, S., Qi, D., Zheng, S., Guo, J., Zhang, S., Weng, Z., 2012b. Inhibition of Notch signaling by a gamma-secretase inhibitor attenuates hepatic fibrosis in rats. PloS One 7, e46512. Chen, Y.X., Weng, Z.H., Zhang, S.L., 2012c. Notch3 regulates the activation of hepatic stellate cells. World J. Gastroenterol. 18, 1397–1403. 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Liver fibrosis is a medical problem worldwide with significant morbidity and mortality, without effective therapy, advanced liver fibrosis can be diagnosed as liver cirrhosis and may ultimately develop into hepatic failure or even hepatocellular carcinoma. Unfortunately, effective clinical therapies are still lacking (Kurokawa and Ohkohchi, 2017). Notch is being increasingly recognized as a major signaling mechanism in liver biology and in multiple pathophysiological conditions, from liver repair to carcinogenesis (Giovannini et al., 2016). Emerging data suggest that Notch also plays a significant role in the pathogenesis of liver fibrosis. Transgenic and knock-out studies indicate that activation of Notch in HSCs causes liver fibrosis development (Zheng et al., 2013). Moreover, Pharmacological studies also suggested that decreasing this signaling would have strong clinical application for liver fibrosis (Fung and Tsukamoto, 2015; Zhang et al., 2015c). Based on these observations, Notch emerges as a potential therapeutic target. However, the chances of success of Notch-targeted strategies depend on a variety of factors. First of all, Notch activation has different effects depending on cellular and tissue context, in both physiologic and pathologic states. Second, Notch is strictly connected with other signaling mechanisms (for example Hedgehog, TGF/SMAD), indicating that combination therapies targeting may be more effective to target pathologic liver repair. And the toxicity of current Notch inhibitors is another obstacle (Rizzo et al., 2014). Thus, more efforts are needed to understand the molecular mechanisms regulating Notch activation in specific cell context and the complex interplay with additional partners involved. In summary, aberrant activation of the Notch signaling pathway promotes HSCs proliferation and activation, epithelial cell transformation, or interaction with other profibrotic factors, leading to liver fibrosis. As we discussed above, epigenetics is also involved in the mediation of Notch signaling pathway during liver fibrosis, suggesting that alteration of epigenetic modifications may open a perspective for novel therapeutic approaches for this disease. Based on our current understanding of Notch molecular structures and post-translational modifications, now a set of Notch pathway inhibitors have been developed and some inhibitors with current chemotherapeutical drugs have recently entered clinical trials which give us the potential therapeutic feasibility. While the γ-secretase inhibitors are the only form of Notch inhibitors in clinical trials, other forms of Notch inhibition have been developed or are theoretically feasible. Encouragingly, now the difficulties in successfully bringing Notch inhibition to the clinic all appear surmountable (Purow, 2012). Thereby, there is growing optimism that modulation of the Notch pathway may present as a suitable and promising therapeutic strategy in the future. Acknowledgements This project was supported by grants from the National Natural Science Foundation of China (81273526, 81473268). Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References Aithal, M.G., Rajeswari, N., 2013. Role of Notch signaling pathway in cancer and its association with DNA methylation. J. Genet. 92, 667–675. Alketbi, A., Attoub, S., 2015. Notch signaling in cancer: rationale and strategies for targeting. Curr. Cancer Drug Targets 15, 364–374. Andersen, P., Uosaki, H., Shenje, L.T., Kwon, C., 2012. Non-canonical Notch signaling: emerging role and mechanism. Trends Cell Biol. 22, 257–265. Artavanis-Tsakonas, S., Rand, M.D., Lake, R.J., 1999. Notch signaling: cell fate control and signal integration in development. Science 284, 770–776.

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