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CircRNAs and Hepatic Stellate Cell Activation
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This entry is adapted from the peer-reviewed paper 10.3390/cells12030378

Chronic liver injury induces the activation of hepatic stellate cells (HSCs) into myofibroblasts, which produce excessive amounts of extracellular matrix (ECM), resulting in tissue fibrosis.

non-coding RNA circular RNA microRNA

1. Introduction

HSC activation is associated with several cytokines and regulatory networks and promotes expression of HSC activation markers, including α-smooth muscle actin (α-SMA) and type I collagen [1]. Many signaling pathways have been linked to increasing expression levels of α-SMA and/or type I collagen, including TGF-β [2], JAK/STAT [3], PDGF [4], PI3K/Akt [5], Wnt/β-catenin [6], Notch [7], Hedgehog [8][9], Hippo [10], and inflammasome signaling pathways [11]. Thus, circRNAs targeting these signaling pathways can regulate HSC activation and ultimately affect liver fibrosis (Figure 1 and Figure 2).
Figure 1. A diagram illustrating the regulatory networks of HSC activation modulated by anti-fibrotic circRNAs. Arrows represent activation, whereas bars symbolize inhibition. Abbreviation: COL1A1: collagen type I alpha 1 chain; CypD: Cyclophilin D; FBXW7: F-box/WD repeat-containing protein 7; KAT2B: lysine acetyltransferase 2B; LEMD3: LEM domain containing 3; Lefty2: left-right determination factor 2; mPTP: mitochondrial permeability transition pore; PINK1: PTEN-induced kinase 1; PTEN: phosphatase and tensin homolog; TGF-β: transforming growth factor beta; TLR4: toll-like receptor 4.
Figure 2. A diagram illustrating the regulatory networks of HSC activation modulated by pro-fibrotic circRNAs. Arrows represent activation, whereas bars symbolize inhibition. Abbreviation: COL1A1: collagen type I alpha 1 chain; HLF: hepatic leukemia factor; HDAC1: histone deacetylase 1; IL-6: interleukin 6; PTEN: phosphatase and tensin homolog; RAC1: Ras-related C3 botulinum toxin substrate 1; TGF-β: transforming growth factor beta; TLR4: toll-like receptor 4.

2. Anti-Fibrotic circRNAs

TGF-β signaling is regarded as the primary fibrogenic pathway that stimulates HSC activation and ECM synthesis [2]. TGF-β is found in trace amounts in healthy livers [12]. Following liver damage, macrophages start producing TGF-β and PDGF, which can activate excessive ECM production from HSCs and lead to the development of liver fibrosis [13]. Most reported circRNAs involved in HSC activation target miRNAs and proteins in the TGF-β pathway. One of these circRNAs is circPSD3 (mmu_circ_0001682), which is downregulated in primary HSCs and liver tissues from mice with carbon tetrachloride (CCl4)-induced liver fibrosis [14]. CircPSD3 can function as a miR-92b-3p sponge, consequently promoting Smad7 expression [14]. Smad7 can block the activation of receptor-regulated Smads (R-Smads) and thus inhibits the TGF-β signaling pathway [15][16]. Furthermore, circPSD3 can preclude HSC proliferation and forestall fibrosis progression in vivo [14].
CircCREBBP acts as a miR-1291 sponge, consequently increasing the expression of left-right determination factor 2 (LEFTY2) [17], which can inhibit the phosphorylation of Smad2/3 [18][19], a key signaling molecule in the TGF-β pathway [20]. Moreover, circCREBBP can also inhibit cell proliferation and arrest the cell cycle in HSCs [17]. With a similar mode of action, hsa_circ_0070963, also known as circSCLT1, has the ability to sponge miR-223-3p, which can target LEM domain containing 3 (LEMD3) [21], an inhibitory molecule that can antagonize Smad2/3 signaling and perturb the TGF-β signaling pathway [22]. In addition to suppressing HSC activation, the overexpression of circSCLT1 can induce cell cycle arrest and suppress cell proliferation in HSCs [21]. However, the circSCLT1/miR-223 axis is subject to further investigation as most studies suggest the anti-fibrotic roles of miR-223 in various fibrosis models [23][24][25][26]. Another circRNA is mmu_circ_34116, which is shown to suppress HSC activation upon overexpression [27]. Using bioinformatic techniques, mmu_circ_34116 is predicted to target the miR-22-3p/BMP7 axis [27]. Bone morphogenetic protein 7 (BMP7) can activate Smad1/5/8 but inhibits Smad3 activation, thus antagonizing TGF-β signaling [28][29].
CircMTO1 has been extensively studied for their anti-fibrotic roles. Its expression levels are observed to downregulate in liver tissues of fibrosis patients [30]. Patients with higher liver fibrosis stages have significantly less circMTO1 expression [30]. By interacting with miR-17-5p, circMTO1 can positively regulate the expression of Smad7 and thereby negatively regulate the TGF-β signaling pathway [30]. Moreover, circMTO1 is found to act as a miR-181b-5p sponge [31]. miR-181b-5p can target phosphatase and tensin homolog (PTEN), a negative regulator in the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway [31], which promotes HSC activation [5][32]. Therefore, circMTO1 plays an anti-fibrotic role by downregulating miR-181b-5p and enhancing PTEN activity [31]. Additionally, Akt signaling can also lead to the activation of NF-κB [33], protecting activated HSCs against apoptosis and sustaining cell survival [34]. As a consequence, by suppressing PI3K/Akt signaling via PTEN, circMTO1 overexpression potentially enhances HSC apoptosis and diminishes ECM production.
Some circRNAs play a significant role in other liver cell types but can indirectly have an impact on HSC activation. For example, in normal hepatocytes, circBNC2 expression is high but drastically decreased upon liver injury [35]. Interestingly, expression of activation markers (α-SMA and type I collagen) is significantly increased in HSCs incubated with conditional medium from circBNC2 knockout hepatocytes, which appear to contain high levels of the pro-fibrotic cytokines including TGF-β [35]. In contrast, the overexpression of circBNC2 in hepatocytes can reduce expression levels of these cytokines upon liver injury, and conditional medium from these hepatocytes can suppress expression of α-SMA and type I collagen in cultured HSCs, indicating the anti-fibrotic roles of circBNC2 [35]. Mechanistically, circBNC2 contains an open reading frame (ORF) and an IRES, suggesting their function as a protein template [35]. The circBNC2-translated protein (ctBNC2) is a protein product derived from circBNC2 translation [35]. This 681-amino acid protein can bind to CDK1 and cyclin B1 and promote CDK/cyclin complex translocation into the nucleus, a critical step to initiate mitosis and prevent apoptosis [35]. As ctBNC2 levels decrease in a damaged liver, the translocation of the CDK/cyclin complex could be impaired and induce apoptosis, which triggers the secretion of TGF-β and DAMPs from hepatocytes [36][37]. As previously mentioned, these molecules can activate ECM production from HSCs and promote fibrosis progression. Therefore, by protecting hepatocytes from apoptosis upon injury, circBNC2 could play an anti-fibrotic role by suppressing production of inflammatory cytokines [35].
Another key signaling pathway that involves HSC activation is the network of PTEN/PI3K/Akt [5]. PI3K/Akt signaling can activate the serine/threonine kinase p70 ribosomal protein S6 kinase (p70S6K) via the mammalian target of rapamycin complex 1 (mTORC1), whereas PTEN inhibits activation of PI3K/Akt signaling [5][38]. Evidently, p70S6K facilitates HSC proliferation and collagen expression [38], and thus, the PI3K/Akt signaling pathway is considered pro-fibrotic [5]. A recent report shows that circDIDO1 inhibits HSC activation through the miR-141-3p/PTEN axis [39]. The overexpression of circDIDO1 sponges miR-141-3p and increases PTEN expression, which impairs PI3K/Akt signaling and subsequently suppresses HSC activation [39]. Similarly, circCDK13 forestalls liver fibrosis by repressing the activation and proliferation of HSCs via the miR-17-5p/KAT2B/MFGE8/PTEN axis [40]. By sponging miR-17-5p, circCDK13 can promote the expression of lysine acetyltransferase 2B (KAT2B), a protein that can regulate histone protein acetylation [40]. The acetylation of histones can enhance the accessibility of transcriptional factors to DNA templates, thereby increasing transcriptional activity [41]. Specifically, KAT2B facilitates milk fat globulin-epidermal growth factor 8 (MFGE8) transcription by promoting histone H3 acetylation [40]. Because MFGE8 can inhibit PTEN ubiquitination and degradation [42], KAT2B promotes PTEN stability, which in turn suppresses the PI3K/Akt signaling pathway [40]. Inactivation of Akt can also lead to the reduction of NF-κB activity, thus impairing the survival of fibrogenic HSCs [40][43]. Collectively, circDIDO1 and circCDK13 can exert the anti-fibrotic mechanism via suppression of PI3K/Akt signaling.
In addition to TGF-β and PI3K/Akt signaling pathways, Wnt/β-catenin and hippo signaling could be regulated by circRNAs in HSCs. For example, circ608 increases PTEN-induced kinase 1 (PINK1) expression through sponging miR-222 [44]. PINK1 can then phosphorylate Parkin, an E3 ubiquitin-protein ligase, which in turn triggers ubiquitination and degradation of β-catenin, thereby inhibiting Wnt/β-catenin transduction [45][46]. PINK1 can also promote expression of Mps one binder kinase activator 1B (MOB1B) [47], a regulator of large tumor suppressor kinases 1/2 (LATS1/2) [48]. The MOB1/LATS complex can inactivate YAP and TAZ [48], the effectors in the Hippo signaling pathway [49], therefore inhibiting the Hippo signaling cascade and subsequently HSC activation. PINK1/Parkin can promote mitophagy [47], which is suppressed in fibrogenic HSCs [50]. Taken together, circ608 is an anti-fibrotic mediator via PINK1-mediated suppression of Wnt/β-catenin and hippo signaling.
For the Notch signaling pathway, circFBXW4 positively regulates F-box/WD repeat-containing protein 7 (FBXW7) [51], which induces Notch intracellular domain (NICD) degradation [52]. By interacting with miR-18b-3p, circFBXW4 can upregulate FBXW7 expression and inhibit Notch signaling, thereby inhibiting HSC activation and proliferation as well as promoting apoptosis [51].
A mitochondrial circRNA called circSCAR is found to be downregulated in NASH patients [53]. Lipid accumulation can induce endoplasmic reticulum (ER) stress, thus increasing the expression of the ER stress mediator CCAAT-enhancer-binding protein homologous protein (CHOP) [53]. CHOP can inhibit the expression of PGC-1α, which positively regulates circSCAR transcription and thus decreases circSCAR levels [53]. CircSCAR can interact with ATP5B, a regulator of the mitochondrial permeability transition pore (mPTP) [53]. Binding between circSCAR and ATP5B hinders the opening of mPTP and consequently the efflux of reactive oxygen species (ROS) from mitochondria into the cytosol [53]. Previous studies suggest that ROS promotes NF-κB signaling pathway and HSC activation [54][55]. Therefore, circSCAR may play an anti-fibrotic role by preventing leakage of ROS from mitochondria [53].
Some circRNAs are found to suppress HSC activation, but their underlying mechanisms are not fully understood. One example is hsa_circ_0004018 or circSMYD4, which is proposed to suppress HSC activation and proliferation via miR-660-3p [56]. By using bioinformatics tools, telomerase-associated protein 1 (TEP1) is predicted to be a target of miR-660-3p and experimentally confirmed by a luciferase assay [56]. While functions of TEP1 in HSCs have not been reported, higher levels of TEP1 in hepatocytes can indirectly suppress the proliferation and activation of HSCs, potentially because TEP1 prevents formation of critically short telomeres and reduces DNA-damage response, which normally triggers hepatocyte senescence and sends apoptotic signals to activate HSCs [56][57]. Intriguingly, although TEP1 play a role in telomere length regulation in many cell types [58][59], a study shows that TEP1 is not essential for telomere length regulation in murine liver [60]. This finding suggests the roles of TEP1 in other cellular functions that could modulate HSC activation [60]. In addition to being a component of the telomerase complex, TEP1 has been found in vault ribonucleoprotein complexes (VRCs) [61]. Although the function of VRCs in HSC activation is not yet known, major vault protein knock-out mice can intensify hepatic steatosis and induce fibrotic responses [62]. Further investigations are needed to expand the knowledge of how the circSMYD4/miR-660-3p/TEP1 axis inhibits HSC activation. Other examples are hsa_circ_0089761 and hsa_circ_0089763, which are two mitochondrial-encoded circRNAs downregulated in HSCs during LPS stimulation [63]. Their downregulation indicates their potential roles as anti-fibrotic circRNAs, but their mechanisms and targets remain to be further studied. Lastly, in a hepatitis B virus (HBV)-induced activation model of LX-2 cells, circMTM1 is upregulated along with interleukin 7 receptor (IL7R), potentially via absorbing miR-122-5p [64]. It is shown that circMTM1 knockdown expression and miR-122-5p overexpression reduce the expression levels of activated HSC markers, while the upregulation of IL7R attenuates the anti-fibrotic function of miR-122-5p [64]. Normally, IL7R is expressed in T cells and plays a pivotal role in T cell homeostasis [65]. Despite interesting results, the exact roles of circMTM1 and IL7R in HSC functions need a further investigation.

3. Pro-Fibrotic circRNAs

While most reported circRNAs impedes the activation of TGF-β signaling pathway in HSCs, some circRNAs play the opposite roles. These circRNAs include circPWWP2A [66], circUBE2k [67], and circTUBD1 [68][69]. CircPWWP2A can enhance TGF-β signaling by decreasing miR-203 and miR-223 expression and thus increasing expression levels of follistatin-like 1 (Fstl1) and Toll-like receptor 4 (TLR4), respectively [66]. Fstl1 is a glycoprotein ligand and can promote TGF-β signaling by binding to TGF-β1 type II receptors (TβRII) [70][71]. TLR4 can recognize lipopolysaccharide (LPS) and sequentially trigger signaling cascades that produce the NF-κBp50 homodimer to interact with histone deacetylase 1 (HDAC1). This protein complex can transcriptionally suppress BMP and activin membrane-bound inhibitor (BAMBI), a pseudoreceptor of TGF-β [66][72][73]. Since BAMBI can inhibit TGF-β/Smad signaling [72], TLR4-mediated downregulation of BAMBI can induce fibrotic HSCs via amplification of TGF-β signaling [66]. In addition, TLR4 can activate NF-κB to support the survival of the activated HSCs [74][75]. Together, circPWWP2A can promote HSC activation via sponging miRNAs that suppress the expression of Fstl1 and TLR4.
The overexpression of circUBE2K induces liver fibrosis by sponging miR-149-5p, which negatively regulates expression of TGF-β2 [67]. Conversely, inhibiting circUBE2K expression can impair TGF-β signaling and induce cell cycle arrest in HSCs, confirming the pro-fibrotic roles of circUBE2K in liver fibrosis progression [67]. Finally, circTUBD1 can interact with both miR-203a-3p and miR-146a-5p [68][69]. By sponging miR-203a-3p, circTUBD1 can positively regulate TGF-β signaling by increasing Smad3 expression [68]. Moreover, Smad3 is found to positively regulate circTUBD1 via a feedback loop, thus further enhancing Smad3 expression [68]. TLR4 is targeted by miR-146a-5p, and by downregulating miR-146a-5p via the circTUBD1 sponge, expression of TLR4 increases, thus promoting TGF-β and NF-κB signaling pathways, which can help activate and support cell survival of HSCs, respectively [69][72][74][75][76]. Furthermore, circTUBD1 can also promote HSC proliferation and inhibit the apoptosis of HSCs by increasing the expression of the anti-apoptotic protein B-cell lymphoma-2 (BCL-2), thereby amplifying the population of fibrogenic cells [69].
Interleukin-6 (IL-6) can activate HSC through the MAPK and JAK/STAT signaling pathways [3]. CircCHD2 can enhance hepatic leukemia factor (HLF) expression by interacting with miR-200b-3p [77]. HLF can promote the expression of IL-6 that can bind to the IL-6 receptor and activate the JAK/STAT3 pathway [78]. The JAK/STAT pathway is also a part of a non-SMAD pathway of TGF-β signal transduction that is essential for HSC activation [79]. The JAK/STAT3 pathway also promotes HLF expression, thereby regulating signal transduction in a feed-forward circuit manner [78].
Additionally, hsa_circ_0071410 (circPALLD) and hsa-circ-0067835 (circIFT80) are pro-fibrotic circRNAs that promote the PI3K/Akt signaling pathway [80][81][82]. CircPALLD can induce HSC activation and increase cell viability by interacting with miR-9-5p [81], which is reported to target annexin A2 (ANXA2) [82]. ANXA2 has been considered to play a role in HSC activation, proliferation, and apoptosis [82], possibly by activating the FAK/PI3K/Akt signaling pathway [83]. CircIFT80 can activate HSC by regulating the miR-155/Forkhead box O3 (FOXO3)/Akt axis [80][84]. As CircIFT80 alleviates FOXO3 expression by sponging miR-155, this transcription factor can transactivate PI3K/Akt through a positive feedback loop and promote PI3K/Akt signal transduction in fibrogenic HSCs [85][86].
The Hedgehog signaling pathway plays a significant role in HSC activation [8][9]. A recent study shows that circRSF1 sponges miR-146a-5p. Subsequently, this sequestration promotes Ras-related C3 botulinum toxin substrate 1 (RAC1) expression and Hedgehog signal transduction, resulting in HSC activation and proliferation [87]. Rac1 has been shown to be involved in the Hedgehog signaling pathway [88]. Activated Rac1 induces glioma-associated oncogene (Gli) nuclear translocation, which is necessary for the Hedgehog signaling pathway [89]. Rac1 can also influence NF-κB and JNK signaling by promoting their transduction [90][91]. JNK signal transduction can phosphorylate Smad2 at the C-terminal and linker regions [92]. Initial findings reveal that phosphorylation of Smad2 in the linker region hinders its nuclear translocation and cellular signaling, but recent evidence shows that phosphorylation of the Smad linker can stimulate expression of fibrotic genes [92][93]. One study discovers that the phosphorylated Smad2 linker region is associated with increased expression of glycosaminoglycans (GAG) [94], and hyaluronan (HA), a class of GAG, is found to be able to activate HSCs via Notch1 [95], so the phosphorylation of the Smad2 linker region may be associated with HSC activation by increasing the expression of HA and promoting the Notch1 fibrogenic signaling pathway. However, this proposed mechanism of circRSF1/miR-146a-5p/Rac1 with subsequent signal transductions remains to be further explored.
Moreover, the direct regulation of circRNAs on fibrotic genes have been reported. For instance, the circARID1A/miR-185-3p axis post-transcriptionally regulates expression of COL1A1, a key marker of HSC activation [96]. The pro-fibrotic circARID1A can also promote the proliferation and migration of HSCs as well as inhibit their apoptosis [96]. Mechanistically, increased type I collagen expression can lead to a positive feedback loop of HSC activation in which accumulation of collagen further activates HSCs by increasing ECM stiffness [97]. This mechanical tension in turn leads to YAP activation in the Hippo signaling pathway and Akt activation in the PI3K/Akt signaling pathway [97][98].
The above discussion mainly focuses on the intrinsic expression of circRNAs in HSCs as most in vitro studies rely on the single cell type for their analysis. However, apart from HSCs, liver is a complex organ comprising of several cell types including hepatocytes, Kupffer cells, liver sinusoidal endothelial cells, and cholangiocytes, which are known to communicate with one another to maintain liver functions [99]. Some of these cells were reported to modulate liver fibrosis by transferring circRNAs to HSCs such as hepatocyte-derived circBNC2 [35]. Alternatively, circRNAs that regulate the production of inflammatory cytokines in Kupffer cells can have an indirect impact on the state of HSC activation. These circRNAs include circMcph1 [100][101] and circ1639 [102][103][104][105]. Nevertheless, a study of cell-cell interaction in mediating liver fibrosis through circRNAs is still lacking and need to be further investigated.

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Archittapon Nokkeaw
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