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Mechanisms of Epigenetic Regulation in the Fibrogenic Activation of Hepatic Stellate Cells in Non-alcoholic Fatty Liver Disease

  • Dmitry Victorovich Garbuzenko* 
Gene Expression   2024;23(1):31-43

doi: 10.14218/GE.2023.00090

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Citation: Garbuzenko DV. Mechanisms of Epigenetic Regulation in the Fibrogenic Activation of Hepatic Stellate Cells in Non-alcoholic Fatty Liver Disease. Gene Expr. 2024;23(1):31-43. doi: 10.14218/GE.2023.00090.

Abstract

Non-alcoholic fatty liver disease (NAFLD) is an extremely prevalent disease, and the presence and severity of liver fibrosis are considered one of the most important factors determining its prognosis. Hepatic stellate cells (HSCs) are essential in hepatic fibrogenesis associated with NAFLD. A number of factors underlying NAFLD pathogenesis may promote HSCs activation, leading to the development of profibrotic and proinflammatory signs. In addition, for the fibrogenic transdifferentiation of quiescent HSCs, alterations in multiple genes are necessary, where epigenetic regulation plays a defining role. Epigenetic regulation induces changes in gene activity without altering the coding sequence, and these changes are stably inherited after the factor causing the alteration has disappeared. Epigenetic modifications comprise several regulatory mechanisms, including DNA methylation, covalent histone modification, chromatin remodeling, and non-coding RNAs. Since the mechanisms underlying epigenetic regulation of HSCs fibrogenic activation are reversible and dynamic, molecular targeted therapies aimed at correcting these mechanisms provide promising prospects for novel therapeutic approaches for treating liver fibrosis associated with NAFLD.

Keywords

Hepatic stellate cells, Activation, Epigenetic regulation, Nonalcoholic fatty liver disease, Liver fibrosis

Introduction

Non-alcoholic fatty liver disease (NAFLD) occupies a leading position among liver diseases worldwide. The prevalence of NAFLD increased from 25.26% between 1990 and 2006 to 38.00% from 2016 to 2019.1 The total mortality associated with NAFLD across all causes is 0.17%.2

NAFLD is defined as a condition where a minimum of 5% of hepatocytes accumulate fat, excluding excessive alcohol consumption. It presents as simple steatosis or nonalcoholic fatty liver without liver fibrosis (LF) and nonalcoholic steatohepatitis (NASH), which in addition to steatosis, is characterized by lobular inflammation, hepatocyte ballooning, and various stages of LF.3 LF, an undesirable occasion in NAFLD, can progress to cirrhosis. Most complications of liver cirrhosis are primarily due to liver failure and portal hypertension, resulting in an unfavorable outcome.4

Inflammation and cell death are the main triggers of hepatic fibrogenesis in NAFLD, which are regulated by cellular cooperatives consisting of various resident and non-resident cells. Among these, the most important is the hepatocyte-macrophage-hepatic stellate cells (HSCs) network.5 Thus, HSCs are directly involved in hepatic fibrogenesis in NAFLD. These cells remain quiescent under physiological conditions and actively participate in the regulation of retinoid homeostasis.6 Several factors, such as lipid metabolites, free cholesterol buildup, oxidized low-density lipoprotein, palmitic acid, lipopolysaccharide, immune cell-associated profibrotic molecules and growth factors, induce HSCs activation in NAFLD with the acquisition of profibrotic and proinflammatory properties.7 For the fibrogenic transdifferentiation of quiescent HSCs, a change in the expression of multiple genes is required, where epigenetic regulation plays a defining role (Fig. 1).8

The epigenetic regulation of fibrogenic activation of hepatic stellate cells (HSCs).
Fig. 1  The epigenetic regulation of fibrogenic activation of hepatic stellate cells (HSCs).

ASH1, Absent, small, or homeotic discs 1; CpG, 5′-Cyto- sine-phosphate-Guanine-3′ EZH, Enhancer of Zeste Homolog; GAS5, growth arrest-specific transcript 5; IFT80, Intraflagellar Transport 80; lnc-LFAR1, liver fibrosis-associated lncRNA 1; MALAT1, metastasis-associated lung adenocarcinoma transcript 1; NEAT1, nuclear enriched abundant transcript 1; PVT1, plasmacytoma variant translocation 1; RSF1 Repressor splicing factor 1; TUBD1, Tubulin Delta 1; TUG1, Taurine Upregulated Gene 1.

During hepatic fibrogenesis, HSCs undergo the initiation phase of activation, transitioning into the perpetuation phase of activation (Fig. 2).9 The activated HSCs excessively secrete type I and III collagen, fibronectin, and other extracellular matrix proteins. They also release a large number of tissue inhibitors of matrix metalloproteinases to prevent collagen destruction by matrix metalloproteinases. Among the paracrine and autocrine factors released by activated HSCs, the most potent profibrogenic cytokine is the transforming growth factor (TGF)-β, in particular TGF-β1. Low expression of peroxisome proliferator-activated receptor (PPAR)γ also promotes hepatic fibrogenesis. Osteopontin, connective tissue growth factor (CTGF) and basic fibroblast growth factor are other cytokines contributing to extracellular matrix synthesis by HSCs. In addition, oxidative stress promotes HSCs activation, type I collagen synthesis, and is essential in hepatic fibrogenesis.10

The pathophysiological mechanisms of fibrogenic activation of hepatic stellate cells (HSCs) in non-alcoholic fatty liver disease (NAFLD).
Fig. 2  The pathophysiological mechanisms of fibrogenic activation of hepatic stellate cells (HSCs) in non-alcoholic fatty liver disease (NAFLD).

This review discusses the mechanisms underlying the epigenetic regulation of HSCs fibrogenic activation in NAFLD. Epigenetic regulation induces alterations in gene activity without modifying its coding sequence, which remains stable even after the factor causing this alteration disappears. Epigenetic modifications comprise several regulatory mechanisms, such as DNA methylation, covalent histone modification, chromatin remodeling, and non-coding RNAs (ncRNAs).11

DNA methylation

DNA methylation is the most extensively studied mechanism of epigenetic regulation, during which a methyl group is added to the cytosine bases of DNA. The methyl group of methylcytosine is positioned within the large groove of the DNA helix, interacting with numerous DNA-binding proteins. Studies have demonstrated that changes in DNA methylation status within genes’ promoter regions affect their transcriptional levels. Currently, two mechanisms of gene repression during methylation have been described. In the first instance, specific proteins bind to methylated CpG dinucleotides, subsequently recruiting proteins involved in chromatin remodeling, thereby rendering the region transcriptionally inactive. With an alternative mechanism, methylation prevents DNA binding to regulatory proteins necessary for gene expression. While DNA methylation is commonly observed on CpG islands, it is also possible to modify the methyl status of individual Cytosine-Guanine dinucleotides.12 Methyl-CpG-binding protein 2 (MeCP2) is one of the primary regulators of HSCs activation. MeCP2 controls the gene expression during HSCs transdifferentiation, which is important for DNA replication and repair. It was reported that phosphorylation of MeCP2 leads to HSCs proliferation and hepatic fibrogenesis.13

DNA methyltransferases (DNMTs) promote DNA methylation by regulating gene expression.14 The DNMTs family mainly comprises DNMT1, DNMT3A, DNMT3B and DNMT3L. Notably, DNMT3L lacks inherent enzymatic activity unlike other DNMTs.15 DNMT1 is involved in maintaining DNA methylation during cell division or regeneration, while DNMT3A and DNMT3B are involved in de novo methylation in the absence of cell division. Ten-eleven translocation family of methylcytosine dioxygenases carries out DNA demethylation by oxidizing methylcytosine to hydroxymethylcytosine, which is a key step in cytosine restoration.16 LF is accompanied with an increase in DNMTs activity, and a reduction in the activity of ten-eleven translocation methylcytosine dioxygenases, which leads to activation (or elongation) of transcription.17

DNA methylation is essential in NAFLD,18 particularly in the transition from nonalcoholic fatty liver to NASH.19 It was shown that hypermethylation at the MT-ND6 gene is associated with the histological severity of NAFLD, and the ratio of methylated MT-ND6 DNA to unmethylated DNA consistently correlates with the NAFLD activity scale.20 In a study by Zeybel et al.,21 NAFLD patients without LF had stronger methylation of genes involved in hepatic fibrogenesis, whereas in NAFLD patients with LF, antifibrotic genes were involved in methylation, particularly PPARA and PPARD. PPARG was found to negatively affect HSCs activation and hepatic fibrogenesis.22 Differences in DNA methylation within the promoter region of the PPARG gene in circulating cell-free DNA enabled the stratification of NAFLD patients based on the severity of LF.23 Further studies have indicated a significant correlation between cell-free DNA plasma concentration and non-invasive markers of NAFLD activity and severity.24

DNA methylation is also involved in fibrogenic transdifferentiation of quiescent HSCs. Mann et al.25 were the first to demonstrate that suppression of DNA methylation interferes with fibrogenic transdifferentiation of primary rat HSCs activated in culture. Subsequent research revealed total hypomethylation of DNA during the transdifferentiation or activation of HSCs.26 Significant alterations in the DNA methylation profile were revealed at the beginning of HSCs activation in vitro. HSCs activation leads to a complete cessation of DNA methylation. However, at CpG-rich sites, there was gene-specific hyper- and hypomethylation of DNA, resulting in changes in gene expression in activated HSCs.27 An established association exists between gene-specific hyper- and hypomethylation of DNA at promoter and CpG-rich sites, with changed gene expression in activated HSCs.28Ptch1 gene hypermethylation was found to correlate with the preservation of HSCs activation and hepatic fibrogenesis.29 Silencing of the Sun2 gene via DNA hypermethylation was accompanied by HSCs activation and hepatic fibrogenesis in vitro.30Pten gene hypermethylation influenced by DNMT1 led to the disappearance of its expression, thereby activating the PI3K/Akt and ERK signaling pathways, and contributing to HSCs activation.31Ctgf gene promoter methylation in HSCs led to hepatic fibrogenesis.32 DNA methylation of Ptgis (prostaglandin I2 synthase) gene enhanced HSCs activation and hepatic fibrogenesis.33 DNA methylation of Sept9 (septin 9) gene mediated by DNMT3a enhanced HSCs activation and hepatic fibrogenesis.34 Methylation of angiotensin II type I receptor (AT1aR) gene (Agtr1a) is potentially associated with NASH-related LF and HSCs activation.35

Genes involved in DNA methylation during HSCs fibrogenic activation are presented in Table 1.27–36

Table 1

Genes involved in DNA methylation during hepatic stellate cells fibrogenic activation

First author, year, ref.Target genesExpressionRegulatory mechanism
Götze, 201527Apc2Increased expressionPromoter-DNA hypomethylation
El Taghdouini, 201528Actg2, Loxl1, Loxl2, Col4a1/2Increased expressionPromoter-DNA hypomethylation
Adamts9, Mmp15Decreased expressionPromoter DNA-hypermethylation
Yang, 201329Ptch1Decreased expressionPromoter DNA-hypermethylation
Chen, 201830Sun2Decreased expressionPromoter DNA-hypermethylation
Bian, 201231PtenDecreased expressionPromoter DNA-hypermethylation
Bian, 201432Smad7Decreased expressionPromoter DNA-hypermethylation
Shi, 201633CtgfDecreased expressionPromoter DNA-hypermethylation
Pan, 201834PtgisDecreased expressionPromoter DNA-hypermethylation
Wu, 201735Sept9Decreased expressionPromoter DNA-hypermethylation
Asada, 201636Agtr1aIncreased expressionPromoter DNA-hypermethylation

Histone modifications and chromatin remodeling

Posttranslational histone modifications include acetylation, methylation, phosphorylation, ubiquitination and sumoylation. These modifications target specific residues, such as lysine, arginine, serine and threonine. Depending on the timing, type, location, and sequence, posttranslational histone modifications can either enhance or weaken gene expression, suggesting the presence of a histone code. Specific histone codes affect chromatin density and DNA availability for transcription factors, ultimately regulating gene expression.37

Acetylation and methylation of histones are well-investigated post-translational modifications. Two enzyme families regulate histone acetylation: histone acetyltransferases, which attach an acyl group and thus open access to transcription factors to genes, and histone deacetylases (HDACs), which detach it and, accordingly, close access to genes.38 An imbalance in the activity of these enzymes affects gene expression in NAFLD, which contributes to impaired liver metabolism.39 p300 histone acetyltransferase, a transcription regulator, is involved in nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB)-dependent inflammatory pathways. Its participation in NAFLD pathogenesis involves activating glycolytic and lipogenic genes through histone acetylation.40 In addition, p300 histone acetyltransferase induces TGF-β1-stimulated HSCs activation by both canonical (histone acetylation) and non-canonical (cytoplasm-to-nucleus shuttle for SMAD2/3 and TAZ) mechanisms.41 Eighteen HDACs are categorized into four classes based on structure and mechanism of action. The class I HDACs include HDAC 1, -2, -3 and -8. The class II HDACs are subdivided into class IIa (HDAC4, -5, -7, -9) and class IIb (HDAC 6, -10). The class III HDACs form a unique group known as sirtuins (SIRT1-7) and possess distinctive properties, thus considered separately from the “classic” HDACs. The class IV HDACs are represented by a single protein -HDAC 11.42 During HSCs transdifferentiation, changes in the expression of these HDACs may occur, mainly due to temporal differences in HDACs gene expression. In a study by Mannaerts et al.,43 HDAC 1, -2 were detected in quiescent HSCs, with their protein expression decreasing in activated HSCs. In contrast, HDAC 3 maintained constant levels, while HDAC 8 was induced upon HSCs transdifferentiation. No significant changes in HDAC1, -2, -3 expression were observed during HSCs transdifferentiation, while HDAC4 expression significantly increased.44 HDAC4 contributes to HSCs activation and promotes hepatic fibrogenesis by differentially regulating the expression of multiple microRNAs (miRNAs), thereby simultaneously amplifying a number of pro-fibrotic pathways.45 Class IIa HDACs are overexpressed in activated HSCs.46 The class III HDACs (sirtuins) are involved in NAFLD pathogenesis due to their involvement in lipid metabolism, oxidative stress and insulin resistance.47

Histone H3 lysine 27 (H3K27) is an extensively studied histone modification with a complex biological role. The H3K27 acetylation is essential in hepatic fibrogenesis by elevating the expression of Col1a1 and Col1a2 genes through the engagement of epidermal growth factor receptor and TGF-β signaling pathways.48 Histone H4 is one of the main histone proteins participating in the chromatin structure in eukaryotic cells. The acetylation of histone H4 at the antifibrogenic factor Pparg gene was impaired in rats with a model of CCl4-induced liver cirrhosis.49

Histone methylation/demethylation also plays an important regulatory role in NAFLD. Methylation of lysine and arginine residues of histone N-terminal tails induces chromatin silencing and transcription inactivation. However, in specific scenarios, histone methylation can activate gene transcription and initiate chromatin remodeling.50 Histone methylation is regulated by the action of proteins with opposite properties-histone methyltransferases and histone demethylases.51 Similar to the HDACs, these enzymes can regulate gene expression during the fibrogenic transdifferentiation of quiescent HSCs, and participate in hepatic fibrogenesis. Histone H3-lysine 36 methyltransferase absent, small, or homeotic discs 1 (ASH1) binds to regulatory regions of genes like smooth muscle α-actin (α-SMA), type I collagen [α1(I) collagen] (Col1a1), Timp1 and Tgfb1 during HSCs activation. ASH1 depletion contributes to the decrease in fibrogenic gene expression.52 H3K27 methyltransferase enhancer of zeste homolog 2 (EZH2) is well represented in activated HSCs, and its expression is directly associated with LF severity. It is one of the primary epigenetic regulators of HSCs fibrogenic activation.53 EZH2 upregulation in activated HSCs is associated with H3K27 methylation in the exons of the Pparg gene, resulting in reduced transcription.54 The histone lysine demethylase 3A activates HSCs, promoting hepatic fibrogenesis through H3K9me2 demethylation at Pparg promoter, thereby positively regulating its expression.55 Moreover, the upregulation of Kdm4d in activated HSCs induces hepatic fibrogenesis by influencing the signaling pathway of Toll-like receptor 4 in the CCl4-treated mouse model, while Kdm4d knockdown decelerates LF progression.56

Genes involved in histone modifications during HSCs fibrogenic activation are presented in Table 2.44,52,55–59

Table 2

Genes involved in histone modifications during hepatic stellate cells fibrogenic activation

First author, year, ref.Target genesExpressionRegulatory mechanism
Qin, 201044Mmp9Decreased expressionHDAC4-mediated histone deacetylation
Perugorria, 201252α-SMAIncreased expressionp300 histone acetyltransferases-dependent transcription
Col1a1, Timp1, Tgfb1Increased expressionASH1-mediated H3K4 methylation
PpargDecreased expressionG9a-mediated H3K9 methylation
Jiang, 201555Kdm3aIncreased expressionJMJD1A-mediated H3K9 demethylation
Dong, 201956Kdm4dIncreased expressionKDM4D-mediated H3K9 demethylation
Dou, 201857α-SMAIncreased expressionp300 histone acetyltransferases-dependent transcription
Page, 201558ElastinIncreased expressionMixed lineage leukemia 1-mediated H3K4 methylation
Pannem, 201459HgfDecreased expressionHDAC7-mediated histone deacetylation

ASH1, Absent, small, or homeotic discs 1; H3K4, histone H3 lysine 4; H3K9, histone H3 lysine 9; HDAC, histone deacetylase; JMJD1A, Jumonji Domain-Containing 1A; KDM4D, lysine demethylase 4D.

Crosstalk between DNA methylation and histone modifications

Chromatin remodeling coordinates gene expression under the control of epigenetic modifications. The crosstalk between DNA methylation and post-translational histone modifications is a functional regulatory mechanism affecting the structure of chromatin. DNA modifications provide binding sites for most transcriptional regulatory proteins involved in gene expression.60

MECP2, a protein with a specific affinity for methylated DNA, plays a crucial role in regulating transcription and chromatin organization.61 It is essential for the coordinated epigenetic regulation of HSCs transdifferentiation and hepatic fibrogenesis. Through the histone-lysine-N-methyltransferases EZH2 and ASH 1, MeCP2 can regulate the fibrogenic transdifferentiation of quiescent HSCs. While EZH2 is recruited to the Pparg gene, contributing to HSCs fibrogenic activation, ASH1 is simultaneously recruited to genes such as α-SMA, Col1a1, Timp1 and Tgfb1, inducing an active transcriptional state54 MeCP2 has a favorable effect on ASH 1 expression, which makes it possible to identify ASH1 as an important component within the transcriptional activator of the MeCP2 epigenetic relay pathway.52 Other epigenetic complexes are also involved in crosstalk during HSCs transdifferentiation. In particular, the interaction between the histone H3 lysine 9 (H3K9) methyltransferase G9a and DNMT1 may suppress Pparg gene expression during TGF-β-mediated HSCs activation.62 Thus, the crosstalk among DNA methylation, histone modifications, and epigenetic enzymes contributes to both stimulation and suppression of transcription, depending on specific molecular interactions in addition to the promoters of target genes.

Non-coding RNAs

The epigenetic landscape in LF is also influenced by numerous non-coding RNAs (ncRNAs). They have a profibrotic effect by regulating genes in various signaling pathways involved in HSCs activation.63 ncRNAs are a group of transcripts that do not undergo protein translation. They participate in the regulation of gene expression, including chromatin remodeling, transcriptional and post-transcriptional processes, and gene methylation. ncRNAs are classified into small ncRNAs and long ncRNAs (lncRNAs), depending on the length of the nucleotide chain. Small ncRNAs demonstrate considerable heterogeneity and comprise various types, including microRNAs (miRNAs), transfer RNAs, small nucleolar RNAs, short interfering RNAs, ribosomal RNAs, and small RNAs interacting with PIWI proteins. The most extensively studied ncRNAs are representatives of the miRNAs and long ncRNA (lncRNA) families.64

miRNAs are short, highly conserved single-stranded endogenous ncRNAs, with a length of 18 to 24 nucleotides. They are transcribed by RNA polymerase II and III, generating precursors that undergo cleavage to form mature miRNAs.65 miRNAs act as gene repressors by binding to a complementary site of the 3′- or 5′-untranslated region of the target mRNAs, leading to mRNA degradation or inhibition of its translation into a protein.66 lncRNAs are a large group of ncRNAs, containing more than 200 nucleotides, with limited or no ability to encode proteins. Circular RNAs (circRNAs) represent a form of competitive endogenous single-stranded ncRNAs with a closed structure, which participate in the regulation of transcriptional and post-transcriptional gene expression. CircRNAs can serve as RNA-binding proteins, miRNA sponges, and participate in the regulation of transcription, translation, and splicing processes.63 A large number of ncRNAs are found in the liver, exhibiting altered expression profiles in various diseases, including NAFLD. Moreover, the expression patterns of ncRNAs may vary among different morphological forms of NAFLD.67

MicroRNAs

miRNAs carry out post-transcriptional regulation by controlling the gene expression of other RNAs, particularly mRNAs, either by promoting mRNA degradation or suppressing their translation. miRNAs are the primary regulators influencing the expression of numerous coding and non-coding genes.68 Currently, accumulating evidence indicates that dysregulation in miRNAs gene expression is associated with pathological processes in different morphological forms of NAFLD.69 miRNAs are involved in insulin resistance, adipocyte differentiation, lipid and glucose metabolism, as well as immune response. The disruption of these mechanisms in NAFLD leads to changes in miRNA expression, contributing to disease progression.70 Extensive evidence supports the involvement of miRNAs in hepatic fibrogenesis, highlighting the isolation of both profibrotic and antifibrotic liver miRNAs.71 Besides, specific miRNAs have been identified for their modulatory effects on HSCs activation in hepatic fibrogenesis.72 Notably, in this pathophysiological situation, some miRNAs can be upregulated, while other miRNAs are downregulated.73 In addition, integrative gene expression and miRNA profiling have been reported in quiescent human HSCs.74

miR-21

There is a lot of evidence indicating the involvement of miR-21 in NAFLD pathogenesis.75 miR-21 deficiency diminishes the expression of genes affecting lipogenesis and cell cycle transition via the p53 pathway.76 Hepatic miR-21 overexpression has been observed in both NASH patients and mice with NASH caused by a diet deficient in methionine and choline. A decreased hepatic level of miR-21 can restore PPARα expression, contributing to a favorable outcome in NASH.77 Simultaneously, PPARα inhibition caused by miR-21 contributes to the development of NASH by inducing liver inflammation, fibrosis and steatosis.78 miR-21 upregulation can cause hepatic fibrogenesis in NASH through the inhibition of SMAD7.79 TGF-β promotes miR-21 overexpression, which acquires profibrotic properties by suppressing the TGF-β inhibitory SMAD7 protein.80 miR-21 can activate HSCs by binding to specific transcripts, particularly PDCD4, SMAD7 and PTEN.81 Additionally, miR-21 interacting with 3′-UTR Spry2 and Hnf4a leads to enhanced ERK1 signaling in HSCs.82

miR-103-3p

miR-103-3p plays a crucial role in NAFLD pathogenesis.83 Hepatic miR-103-3p overexpression was observed in mouse models of NAFLD. miR-103-3p inhibition improved pathophysiological disorders and liver morphology in NAFLD.83 miR103-3p expression correlated with histological activity of steatosis and LF severity in patients with NAFLD.84 miR 103-3p can promote the activation and proliferation of HSCs by suppressing Kruppel-like factor 4 suppression.85

miR-125b

The role of miR-125b in NAFLD pathogenesis has not been definitively established. High upregulation of miR-125b was detected in animal models of NAFLD. miR-125b induces an inflammatory response in NAFLD via the NF-kB signaling pathway by directly targeting tumor necrosis factor-α-induced protein 3.86 miR-125b-2 knockout in mice increased high-fat diet-induced insulin resistance and fat accumulation.87 miR-125b upregulation in HSCs was demonstrated in hepatic fibrogenesis, which promoted α-SMA and type I collagen expression and HSCs contractility.88

miRNA-181a

miR-181a is involved in lipidosis and promotes lipid peroxidation in NAFLD. miR-181a can also influence NAFLD pathogenesis and progression by inhibiting SIRT1 expression.89 Besides, miR-181a might act as a positive regulator of TGF-β-induced LF.90

miR-200a

miR-200a-3p promotes the development of liver steatosis induced by free fatty acid in vitro.72 Upregulation of miR-200a is associated with hepatic fibrogenesis in NAFLD.91 It is also established that miR-200a is a key regulator in HSCs fibrogenic activation, particularly via the SIRT1/Notch1 signaling pathway.92

miR-221/222

Hepatic miR-221/222 overexpression was detected in NASH, which contributed to the progression of liver inflammation, fibrosis and steatosis.93 In addition, the expression levels of miR-221/222 increased with LF progression and correlated with the mRNA expression levels of COL1A1 and α-SMA.94 miR-221/222 promotes LF by activating profibrotic signaling pathways of TGF-β and NF-kB.95 miR-221 also regulates some targets involved in hepatic fibrogenesis, including E-cadherin, cyclin-dependent kinase inhibitors, cytokine signaling 1, PTEN, and Bcl-2 modifying factor.96

Long non-coding RNAs

lncRNAs participate in many complex cellular processes, such as cell growth and differentiation, cell cycle control, maintenance of cellular structure integrity, intracellular transport, apoptosis and cell death. They are also involved in basic processes, including transcription, splicing, translation and epigenetic regulation. lncRNAs exert their effects at both the transcriptional and post-transcriptional levels. At the transcriptional level, lncRNAs recruit transcription factors or epigenetic modification complexes. At the post-transcriptional level, lncRNAs can regulate mRNA translation, and modulate alternative splicing and mRNA degradation.97 Although information regarding the role of lncRNAs in NAFLD pathogenesis is limited, recent studies have indicated their involvement in all stages of NAFLD, including the development of LF and cirrhosis. Based on their influence mechanisms on NAFLD, lncRNAs are categorized into those inducing only liver steatosis, those involved in both steatosis and inflammation and/or LF, and those exclusively impacting hepatic fibrogenesis.98 Furthermore, lncRNAs can also regulate HSCs fibrogenic activation.99

Metastasis-associated lung adenocarcinoma transcript 1

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is located on human chromosome 11q13.1 and is involved in various physiological processes, including alternative splicing, epigenetic modification of gene expression, synapse formation and myogenesis.100 MALAT1 is also involved in insulin resistance and liver steatosis due to the overexpression of SREBP-1c and target genes in liver.101 Moreover, MALAT1 induces hepatic lipogenesis in NAFLD by modulating the miR-206/ARNT axis.102 MALAT1 overexpression has been observed in activated HSCs, suggesting a potential role in hepatic fibrogenesis through mechanisms associated with the inflammatory chemokine CXCL5.103 Simultaneously, MALAT1 suppression led to a decrease in HSCs activation, α-SMA and COL1A1 levels, and inhibited collagen accumulation in liver tissue.104 Exosomal MALAT1 derived from liver cells has also been shown to participate in HSCs activation via miR-26b in the arsenite-induced LF mouse model.105 In addition, the MALAT1/miR-181a-5p axis contributes to HSCs activation by transmitting TLR4/NF-kB signals, thereby regulating collagen production and promoting LF in vitro.106 These findings indicate that MALAT1 can induce hepatic lipogenesis, cause hepatic inflammation, and also promote hepatic fibrogenesis by directly affecting HSCs.

Nuclear enriched abundant transcript 1

In recent years, the role of nuclear enriched abundant transcript 1 (NEAT1) in various liver diseases has garnered increasing attention.107 NEAT1 overexpression has been observed in animal models of NAFLD, while its suppression beneficially effects NAFLD through the mTOR/S6K1 signaling pathway.108 NEAT1 promoted liver steatosis by enhancing estrogen receptor alpha-mediated aquaporin-7 expression upon treatment with 17b-estradiol (E2) and oleic acids in HepG2 cells.109 NEAT1 contributed to NAFLD by targeting miR-146a-5p, which in turn regulates ROCK1, and additionally influences the AMPK/SREBP pathway.110 NEAT1 was involved in hepatic fibrogenesis and inflammatory response in NAFLD by influencing the miR-506/GLI3 axis.111 NEAT1 also activated HSCs by influencing the miR-129-5p/PEG3 axis in mouse model of NASH.112 Inhibition of NEAT1 expression improved experimental LF, while its stimulation led to HSCs activation by influencing the miR-122-KLF6 axis, thereby contributing to their proliferation and collagen production.113 The involvement of the NEAT1/miR-29b/Atg9a regulatory axis in autophagy and HSCs activation was discovered in an adenovirus-mediated IGFBPrP1-induced LF mouse model.114 NEAT1 overexpression was also detected in fibrous liver tissues of CCl4-treated mice. Knockdown of NEAT1 attenuated LF and inhibited HSCs activation by sponging miR-148a-3p and miR-22-3p, thereby regulating Cyth3 expression.115

Plasmacytoma variant translocation 1

Plasmacytoma variant translocation 1 (PVT1) is a lncRNA related to cell invasion, proliferation, and metastasis.116 PVT1 is abundantly expressed in adipose tissue in a mouse model of obesity compared to the non-obese mice.117 In addition, increased PVT1 level has been observed in NAFLD patients.118 Increased PVT1 expression was also found in activated HSCs and fibrous liver tissues, whereas its suppression reduced collagen deposition. PVT1 promotes HSCs activation through the Hedgehog (Hh) signaling pathway and stimulates epithelial-mesenchymal transition.119

HOX transcript antisense intergenic RNA

HOX transcript antisense intergenic RNA (HOTAIR) is a well-studied lncRNA, known for its essential role in oncogenesis.120 HOTAIR overexpression was found in animal models of NAFLD, whereas its suppression significantly reduced NAFLD progression via the miR-130b-3p/ROCK1 axis.121 The HOTAIR level was significantly increased in mice with CCl4-induced LF, in humans with LF, and in activated HSCs following stimulation with TGF-β1.122 It has been demonstrated that HOTAIR enhances PTEN methylation by suppressing miR-29b expression, which leads to HSCs activation and LF progression.123

Alu-mediated transcriptional regulator

lncRNA Alu-mediated p21 transcriptional regulator (APTR) is involved in cell proliferation.124 APTR was overexpressed in fibrous liver tissues and activated HSCs. Inhibition of APTR suppressed HSCs activation and reduced collagen accumulation in mice with CCL4-induced LF, and also abrogated TGF-β1-induced α-SMA upregulation in activated HSCs.125

LF-associated lncRNA1

LF- -associated lncRNA1 promotes hepatic fibrogenesis and HSCs activation by activating the TGF-β and Notch signaling pathways. Conversely, suppressing LF-associated lncRNA1 inhibits HSCs activation, reduces TGF-β-induced hepatocyte apoptosis, and improves LF.126

Taurine upregulated gene 1

lncRNA taurine upregulated gene 1, also known as LIN00080 or TI-227H, regulates gene expression at the transcriptional and post-transcriptional levels by interacting with miRNAs or proteins. lncRNA TAG 1 expression was increased in fibrous liver tissues and activated HSCs, but not in injured hepatocytes. In addition, lncRNA taurine upregulated gene 1 induces the expression of profibrogenic genes such as α-SMA, COL1A1, TIMP1 and MMP2/9/10 by suppressing miR-29b, thereby accelerating LF progression.127

Circular RNAs

CircRNAs include transcripts wherein the 5′ and 3′ ends of the molecule form a ring structure connected by a phosphodiester bond, thus rendering them resistant to exonuclease-mediated degradation. They originate from precursor RNAs through backsplicing.128 CircRNAs are associated with the fundamental processes underlying the occurrence and progression of NAFLD, such as steatosis, autophagy, fibrosis, inflammation, and oxidative stress. Notably, studies on mice with CCl4-induced LF have predominantly explored the association between circRNAs and HSCs fibrogenic activation.129 It has been demonstrated that some circRNAs contribute to HSCs activation by upregulating the expressions of the fibrogenic marker gene in response to the various pro-fibrotic signaling pathways, like TGF-β, JAK/STAT, PI3K/Akt, Hedgehog (Hh), etc.130

CircPWWP2A increases the expression level of follistatin-like receptor 1 and Toll-like receptor 4 by suppressing miR-203 and miR-223, respectively, thereby activating the TGF-β signaling pathway.131circUBE2K overexpression promotes LF by sponging miR-149-5p/TGF-β2 axis, whereas its suppression disrupts TGF-β signaling and inhibits HSCs fibrogenic activation.132CircTUBD1 acts as a miR-146a-5p sponge and promotes the production of proinflammatory cytokines in activated human HSCs line LX-2 via the Toll-like receptor 4 signaling pathway.133CircIFT80 (CircBase ID: hsa_circ_0067835) is involved in LF pathogenesis by acting as a miR-155 sponge, promoting FOXO3a expression.134CircRSF1 participates in LF pathogenesis by acting as a miR-146a-5p sponge. It promotes profibrotic and proinflammatory phenotypes of irradiated human HSCs line LX2 by modulating miR-146a-5p.135CircARID1A (CircBase identifier: hsa_circ_0008494) overexpression was detected in fibrous liver tissues and HSCs cytoplasm. A study by Li et al.136 revealed the influence of the circ_0008494/miR-185 axis on the proliferation, migration, apoptosis of HSCs, as well as the activation of HSCs via the Col1a1 gene. CircPALLD (CircBase identifier: hsa_circ_0071410) is capable of activating HSCs and improving cell survivability by interacting with miR-9-5p targeting annexin A2.137CircASPH was upregulated in LF, and downregulation of circASPH suppressed HSCs activation and hepatic fibrogenesis via the circASPH/miR-139-5p/Notch1 axis.138

ncRNAs that regulate genes in signaling pathways involved in histone modifications during HSCs fibrogenic activation are presented in Table 3.80,82,88,92,106,112,119,126,127,133-135,139-146

Table 3

ncRNAs regulating genes in signaling pathways involved in hepatic stellate cells fibrogenic activation

First author, year, ref.ncRNAsTarget genesSignaling pathways
Noetel, 201280miR-21Smad2/3/7TGF-β/Smad
Zhao, 201482miR-21Spry2, Hnf4αERK1
You, 201888miR-125bStard13RhoA/Mrtf-A/Srf
Yang, 201792miR-200aSirt1SIRT1/Notch1
Wang, 2021106MALAT1/miR-181a-5pα-SMA, COL1, TIMP1TLR4/NF-κB
Zhang, 2021112NEAT1/miR-129-5pPeg3NF-κB
Zheng, 2016119PVT1/miR-152Ptch1Hedgehog
Zhang, 2017126lnc-LFAR1Smad2/3TGF-β, Notch
Han, 2018127TUG1/miR-29ba-SMA, Col1a1, Mmp2/9/10, Timp1NF-kB, JAK/STAT
Niu, 2020133circTUBD1/ miR-146a-5pTlr4, Irak1, Traf6TLR4/NF-κB
Zhu, 2018134circIFT80/miR-155Foxo3aAKT/FOXO3a
Chen, 2020135circRSF1/miR-146a-5pRac1NF-κB, JNK
Lv, 2023139miR-20b-5pStat3STAT3
Ning, 2017140miR-21Spry1, Smad7Spry1/ERK/NF-κB, Smad7/Smad2/3/NOX4
Sun, 2021141miR-21VegfHIF-1α/VEGF
Yang, 2020142miR-199a-3pCav2TGF-β/Smad
Zhou, 2021143miR-497Smad7TGF-β/Smad
Luo, 2021144miR-1297PtenPI3K/AKT
Wang, 2021145NEAT1/miR-139-5pβ-cateninβ-catenin/SOX9/TGF-β1
Su, 2022146GAS5/miR-433-3pTLR10NF-κB

AKT, protein kinase B; ERK, extracellular-signal-regulated kinase; GAS5, growth arrest-specific transcript 5; HIF, Hypoxia-Inducible Factor; HIF-1α, hypoxia-induced factor-1α; IFT80, Intraflagellar Transport 80; JAK/STAT, Janus kinase/Signal Transducer and Activator of Transcription; JNK, c-Jun NH2-terminal kinase; lnc-LFAR1, liver fibrosis-associated lncRNA 1; MALAT1, metastasis-associated lung adenocarcinoma transcript 1; miR, micro RNA; ncRNAs, non-coding RNAs; NEAT1, nuclear enriched abundant transcript 1; NF, Nuclear Factor; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NOX4, NADPH oxidase 4; PI3K, phosphoinositide 3-kinase; PVT1, plasmacytoma variant translocation 1; RSF1, Repressor splicing factor 1; SOX9, SRY-box transcription factor 9; TGF, transforming growth factor; TLR4, Toll-like receptor 4; TUBD1, Tubulin Delta 1; TUG1, Taurine Upregulated Gene 1; VEGF, vascular endothelial growth factor.

Epigenetic mechanisms of HSCs fibrogenic activation as a new therapeutic target for LF

Current guidelines for the management of NAFLD recommend lifestyle changes, normalization of body weight, specific pharmacotherapy for LF, and treatment of metabolic syndrome-related diseases.147 Epigenetic mechanisms underlying HSCs fibrogenic activation may be a new therapeutic target for LF.148

DNA methylation inhibitors may ameliorate LF by upregulating the expression of genes, whose expression in HSCs decreases due to hypermethylation.149 For example, curcumin reversed LF in a CCl4-treated mouse model and inhibited HSCs activation through downregulation of Dnmt1, a-SMA, and Col1a1, and by demethylation of the key genes.150

Various histone modifications present potential therapeutic targets for LF treatment.48 In particular, chronic administration of valproic acid, a class I and IIa HDAC inhibitor, in a mouse model of CCl4-induced LF, enhanced histone H4 acetylation, resulting in reduced collagen deposition and inhibited HSCs activation. In addition, it has been suggested that valproic acid can prevent further progression of LF.43 Suberoylanilide hydroxamic acid, another HDAC inhibitor, alleviated LF in CCl4-treated rat model by suppressing TGF-β1/Smad signaling pathway, which is a pivotal for HSCs activation.151 Suppression of H3K27 methyltransferase EZH2 by 3-Deazaneplanocin A weakens the TGF-β1/Smad signaling, inhibiting HSCs activation, reducing the accumulation of extracellular matrix in the liver and ultimately attenuating LF.53

Antifibrotic therapy targeting ncRNAs involves various signaling pathways. It is based on the gene-suppressing effect of miRNAs and the sponging action of lncRNAs and circRNAs on miRNAs.63 For example, treatment with human umbilical cord mesenchymal stem cells inhibited HSCs activation, protected hepatocytes, and improved LF by up-regulating miR-148-5p expression and attenuating the Notch signaling pathway.152 miR-150, a typical antifibrotic microRNA, suppresses HSCs activation and prevents collagen types I and IV synthesis by activating HSCs via attenuation of the TGF-β signaling pathway.153 The synthetic miR-223 analog miR-223-3p considerably slowed the development of LF, inhibited HSCs and caspase-1 p10 activation, as well as NLRP3 inflammasome activation in a mouse model of NASH.154 In addition, administration of miR-223 ameliorated LF in a CCl4-treated mouse model, and miR-223 overexpression downregulated the expression of Gli2 and platelet-derived growth factor receptor α/β (Pdgfrα/β) genes in HSCs, thus inhibiting HSCs activation and proliferation.155 Exosomes derived from natural killer cells mitigated HSCs activation by miR-223 transfer.156 miR-338-3p overexpression suppressed HSCs activation and proliferation via the miR-338-3p/CDK4 signaling pathway.157 miR-690 directly inhibited HSCs fibrogenic activation, mitigated inflammation in recruited hepatic macrophages, and reduced de novo lipogenesis in hepatocytes in a mouse model of NASH.158 In a CCl4-treated mouse model, 3D human embryonic stem cell exosomes enriched with miR-6766-3p ameliorated LF by weakening activated HSCs via the TGFβRII-SMADS signaling pathway.159 microRNA-23b/27b/24-1 overexpression through intravenous delivery of miR-23b/27b/24-1 lentivirus improved LF in a CCl4-treated mouse model. Increasing the miR-23b/27b/24-1 cluster level inhibited HSCs activation by directly targeting the mRNAs of five profibrotic genes, namely, Tgfb2, Gremlin 1, LOX, Itga2 and Itga5.160 Bone marrow mesenchymal stem cells inhibited LF by downregulating the lnc-BIHAA1/rno-miR-667-5p signaling pathway in HSCs.161 CircDIDO1 transfer mediated by exosomes isolated from mesenchymal stem cells inhibited HSCs activation via the miR-141-3p/PTEN/AKT signaling pathway.162

Conclusions

The presence and severity of LF are considered crucial factors determining NAFLD prognosis. HSCs are the precursors for the majority of profibrogenic myofibroblasts, which produce extracellular matrix in NAFLD. A number of factors underlying NAFLD pathogenesis may promote HSCs activation. One of them is the epigenetic regulatory mechanism, including DNA methylation, covalent histone modification, chromatin remodeling, and ncRNAs. Since these mechanisms are reversible and dynamic, targeted molecular therapies that aim to correct them present promising avenues for novel therapeutic approaches in managing LF associated with NAFLD.

Abbreviations

AKT: 

protein kinase B

APTR: 

Alu-mediated p21 transcriptional regulator

ASH1: 

Absent, small, or homeotic discs 1

circRNAs: 

circular RNAs

CpG: 

5′-Cyto- sine-phosphate-Guanine-3′

CTGF: 

connective tissue growth factor

DNMTs: 

DNA methyltransferases

ERK: 

extracellular-signal-regulated kinase

EZH2: 

Enhancer of Zeste Homolog 2

GAS5: 

growth arrest-specific transcript 5

H3K27: 

histone H3 lysine 27

H3K4: 

histone H3 lysine 4

H3K9: 

histone H3 lysine 9

HDACs: 

histone deacetylases

HIF: 

hypoxia-inducible factor

HOTAIR: 

HOX transcript anti- sense intergenic RNA

HSCs: 

hepatic stellate cells

IFT80: 

Intraflagellar Transport 80

JAK/STAT: 

janus kinase/signal transducer and activator of transcription

JMJD1A: 

Jumonji Domain-Containing 1A

JNK: 

c-Jun NH2-terminal kinase

KDM4D: 

lysine demethylase 4D

LF: 

liver fibrosis

lnc-LFAR1: 

liver fibrosis-associated lncRNA 1

lncRNAs: 

long ncRNAs

MALAT1: 

metastasis-associated lung adenocarcino- ma transcript 1

MeCP2: 

methyl-CpG-binding protein 2

miRNAs: 

microRNAs

NAFLD: 

non-alcoholic fatty liver disease

NASH: 

nonalcoholic steatohepatitis

ncRNAs: 

non-coding RNAs

NEAT1: 

nuclear enriched abundant transcript 1

NF: 

Nuclear Factor

NF-kB: 

nuclear factor kappa-light-chain-enhancer of activated B cells

NOX4: 

NADPH oxidase 4

PI3K: 

phosphoinositide 3-kinase

PPAR: 

peroxisome proliferator-activated receptor

PVT1: 

plasmacytoma variant translocation 1

RSF1: 

Repressor splicing factor 1

SOX9: 

SRY-box transcription factor 9

TGF: 

transforming growth factor

TLR4: 

Toll-like receptor 4

TUBD1: 

Tubulin Delta 1

TUG1: 

Taurine Upregulated Gene 1

VEGF: 

vascular endothelial growth factor

Declarations

Acknowledgement

None.

Funding

This is a non-funded work.

Conflict of interest

There are no conflicts relevant to this work.

References

  1. Younossi ZM, Golabi P, Paik JM, Henry A, Van Dongen C, Henry L. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): A systematic review. Hepatology 2023;77(4):1335-1347 View Article PubMed/NCBI
  2. Devarbhavi H, Asrani SK, Arab JP, Nartey YA, Pose E, Kamath PS. Global burden of liver disease: 2023 update. J Hepatol 2023;79(2):516-537 View Article PubMed/NCBI
  3. Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, Abdelmalek MF, Caldwell S, Barb D, et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology 2023;77(5):1797-1835 View Article PubMed/NCBI
  4. Noureddin M, Harrison SA. NASH cirrhosis trials and major adverse liver outcomes: Big data needed. J Hepatol 2023;78(1):5-7 View Article PubMed/NCBI
  5. Schwabe RF, Tabas I, Pajvani UB. Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis. Gastroenterology 2020;158(7):1913-1928 View Article PubMed/NCBI
  6. Luo N, Li J, Wei Y, Lu J, Dong R. Hepatic Stellate Cell: A Double-Edged Sword in the Liver. Physiol Res 2021;70(6):821-829 View Article PubMed/NCBI
  7. Wiering L, Subramanian P, Hammerich L. Hepatic Stellate Cells: Dictating Outcome in Nonalcoholic Fatty Liver Disease. Cell Mol Gastroenterol Hepatol 2023;15(6):1277-1292 View Article PubMed/NCBI
  8. Barcena-Varela M, Colyn L, Fernandez-Barrena MG. Epigenetic Mechanisms in Hepatic Stellate Cell Activation During Liver Fibrosis and Carcinogenesis. Int J Mol Sci 2019;20(10):2507 View Article PubMed/NCBI
  9. Garbuzenko DV. Pathophysiological mechanisms of hepatic stellate cells activation in liver fibrosis. World J Clin Cases 2022;10(12):3662-3676 View Article PubMed/NCBI
  10. Gandhi CR. Hepatic stellate cell activation and pro-fibrogenic signals. J Hepatol 2017;67(5):1104-1105 View Article PubMed/NCBI
  11. Chen L, Huang W, Wang L, Zhang Z, Zhang F, Zheng S, et al. The effects of epigenetic modification on the occurrence and progression of liver diseases and the involved mechanism. Expert Rev Gastroenterol Hepatol 2020;14(4):259-270 View Article PubMed/NCBI
  12. Klose RJ, Bird AP. Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 2006;31(2):89-97 View Article PubMed/NCBI
  13. Moran-Salvador E, Garcia-Macia M, Sivaharan A, Sabater L, Zaki MYW, Oakley F, et al. Fibrogenic Activity of MECP2 Is Regulated by Phosphorylation in Hepatic Stellate Cells. Gastroenterology 2019;157(5):1398-1412.e9 View Article PubMed/NCBI
  14. Mattei AL, Bailly N, Meissner A. DNA methylation: a historical perspective. Trends Genet 2022;38(7):676-707 View Article PubMed/NCBI
  15. Jin B, Robertson KD. DNA methyltransferases, DNA damage repair, and cancer. Adv Exp Med Biol 2013;754:3-29 View Article PubMed/NCBI
  16. Liu H, Li S, Wang X, Zhu J, Wei Y, Wang Y, et al. DNA methylation dynamics: identification and functional annotation. Brief Funct Genomics 2016;15(6):470-484 View Article PubMed/NCBI
  17. Page A, Paoli P, Moran Salvador E, White S, French J, Mann J. Hepatic stellate cell transdifferentiation involves genome-wide remodeling of the DNA methylation landscape. J Hepatol 2016;64(3):661-673 View Article PubMed/NCBI
  18. Hyun J, Jung Y. DNA Methylation in Nonalcoholic Fatty Liver Disease. Int J Mol Sci 2020;21(21):8138 View Article PubMed/NCBI
  19. Vachher M, Bansal S, Kumar B, Yadav S, Burman A. Deciphering the role of aberrant DNA methylation in NAFLD and NASH. Heliyon 2022;8(10):e11119 View Article PubMed/NCBI
  20. Pirola CJ, Gianotti TF, Burgueño AL, Rey-Funes M, Loidl CF, Mallardi P, et al. Epigenetic modification of liver mitochondrial DNA is associated with histological severity of nonalcoholic fatty liver disease. Gut 2013;62(9):1356-1363 View Article PubMed/NCBI
  21. Zeybel M, Hardy T, Robinson SM, Fox C, Anstee QM, Ness T, et al. Differential DNA methylation of genes involved in fibrosis progression in non-alcoholic fatty liver disease and alcoholic liver disease. Clin Epigenetics 2015;7(1):25 View Article PubMed/NCBI
  22. Liu X, Xu J, Rosenthal S, Zhang LJ, McCubbin R, Meshgin N, et al. Identification of Lineage-Specific Transcription Factors That Prevent Activation of Hepatic Stellate Cells and Promote Fibrosis Resolution. Gastroenterology 2020;158(6):1728-1744.e14 View Article PubMed/NCBI
  23. Hardy T, Zeybel M, Day CP, Dipper C, Masson S, McPherson S, et al. Plasma DNA methylation: a potential biomarker for stratification of liver fibrosis in non-alcoholic fatty liver disease. Gut 2017;66(7):1321-1328 View Article PubMed/NCBI
  24. Karlas T, Weise L, Kuhn S, Krenzien F, Mehdorn M, Petroff D, et al. Correlation of cell-free DNA plasma concentration with severity of non-alcoholic fatty liver disease. J Transl Med 2017;15(1):106 View Article PubMed/NCBI
  25. Mann J, Oakley F, Akiboye F, Elsharkawy A, Thorne AW, Mann DA. Regulation of myofibroblast transdifferentiation by DNA methylation and MeCP2: implications for wound healing and fibrogenesis. Cell Death Differ 2007;14(2):275-285 View Article PubMed/NCBI
  26. Komatsu Y, Waku T, Iwasaki N, Ono W, Yamaguchi C, Yanagisawa J. Global analysis of DNA methylation in early-stage liver fibrosis. BMC Med Genomics 2012;5:5 View Article PubMed/NCBI
  27. Götze S, Schumacher EC, Kordes C, Häussinger D. Epigenetic Changes during Hepatic Stellate Cell Activation. PLoS One 2015;10(6):e0128745 View Article PubMed/NCBI
  28. El Taghdouini A, Sørensen AL, Reiner AH, Coll M, Verhulst S, Mannaerts I, et al. Genome-wide analysis of DNA methylation and gene expression patterns in purified, uncultured human liver cells and activated hepatic stellate cells. Oncotarget 2015;6(29):26729-26745 View Article PubMed/NCBI
  29. Yang JJ, Tao H, Huang C, Shi KH, Ma TT, Bian EB, et al. DNA methylation and MeCP2 regulation of PTCH1 expression during rats hepatic fibrosis. Cell Signal 2013;25(5):1202-1211 View Article PubMed/NCBI
  30. Chen X, Li WX, Chen Y, Li XF, Li HD, Huang HM, et al. Suppression of SUN2 by DNA methylation is associated with HSCs activation and hepatic fibrosis. Cell Death Dis 2018;9(10):1021 View Article PubMed/NCBI
  31. Bian EB, Huang C, Ma TT, Tao H, Zhang H, Cheng C, et al. DNMT1-mediated PTEN hypermethylation confers hepatic stellate cell activation and liver fibrogenesis in rats. Toxicol Appl Pharmacol 2012;264(1):13-22 View Article PubMed/NCBI
  32. Bian EB, Huang C, Wang H, Chen XX, Zhang L, Lv XW, et al. Repression of Smad7 mediated by DNMT1 determines hepatic stellate cell activation and liver fibrosis in rats. Toxicol Lett 2014;224(2):175-185 View Article PubMed/NCBI
  33. Shi C, Li G, Tong Y, Deng Y, Fan J. Role of CTGF gene promoter methylation in the development of hepatic fibrosis. Am J Transl Res 2016;8(1):125-132 View Article PubMed/NCBI
  34. Pan XY, Yang Y, Meng HW, Li HD, Chen X, Huang HM, et al. DNA Methylation of PTGIS Enhances Hepatic Stellate Cells Activation and Liver Fibrogenesis. Front Pharmacol 2018;9:553 View Article PubMed/NCBI
  35. Wu Y, Bu F, Yu H, Li W, Huang C, Meng X, et al. Methylation of Septin9 mediated by DNMT3a enhances hepatic stellate cells activation and liver fibrogenesis. Toxicol Appl Pharmacol 2017;315:35-49 View Article PubMed/NCBI
  36. Asada K, Aihara Y, Takaya H, Noguchi R, Namisaki T, Moriya K, et al. DNA methylation of angiotensin II receptor gene in nonalcoholic steatohepatitis-related liver fibrosis. World J Hepatol 2016;8(28):1194-1199 View Article PubMed/NCBI
  37. Zhang Y, Sun Z, Jia J, Du T, Zhang N, Tang Y, et al. Overview of Histone Modification. Adv Exp Med Biol 2021;1283:1-16 View Article PubMed/NCBI
  38. Zhang T, Cooper S, Brockdorff N. The interplay of histone modifications - writers that read. EMBO Rep 2015;16(11):1467-1481 View Article PubMed/NCBI
  39. Lee JH, Friso S, Choi SW. Epigenetic mechanisms underlying the link between non-alcoholic fatty liver diseases and nutrition. Nutrients 2014;6(8):3303-3325 View Article PubMed/NCBI
  40. Botello-Manilla AE, Chávez-Tapia NC, Uribe M, Nuño-Lámbarri N. Genetics and epigenetics purpose in nonalcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 2020;14(8):733-748 View Article PubMed/NCBI
  41. Wang Y, Tu K, Liu D, Guo L, Chen Y, Li Q, et al. p300 Acetyltransferase Is a Cytoplasm-to-Nucleus Shuttle for SMAD2/3 and TAZ Nuclear Transport in Transforming Growth Factor β-Stimulated Hepatic Stellate Cells. Hepatology 2019;70(4):1409-1423 View Article PubMed/NCBI
  42. Hammond CM, Strømme CB, Huang H, Patel DJ, Groth A. Histone chaperone networks shaping chromatin function. Nat Rev Mol Cell Biol 2017;18(3):141-158 View Article PubMed/NCBI
  43. Mannaerts I, Nuytten NR, Rogiers V, Vanderkerken K, van Grunsven LA, Geerts A. Chronic administration of valproic acid inhibits activation of mouse hepatic stellate cells in vitro and in vivo. Hepatology 2010;51(2):603-614 View Article PubMed/NCBI
  44. Qin L, Han YP. Epigenetic repression of matrix metalloproteinases in myofibroblastic hepatic stellate cells through histone deacetylases 4: implication in tissue fibrosis. Am J Pathol 2010;177(4):1915-1928 View Article PubMed/NCBI
  45. Han X, Hao C, Li L, Li J, Fang M, Zheng Y, et al. HDAC4 stimulates MRTF-A expression and drives fibrogenesis in hepatic stellate cells by targeting miR-206. Oncotarget 2017;8(29):47586-47594 View Article PubMed/NCBI
  46. Yang Z, Liu Y, Qin L, Wu P, Xia Z, Luo M, et al. Cathepsin H-Mediated Degradation of HDAC4 for Matrix Metalloproteinase Expression in Hepatic Stellate Cells: Implications of Epigenetic Suppression of Matrix Metalloproteinases in Fibrosis through Stabilization of Class IIa Histone Deacetylases. Am J Pathol 2017;187(4):781-797 View Article PubMed/NCBI
  47. Nassir F, Ibdah JA. Sirtuins and nonalcoholic fatty liver disease. World J Gastroenterol 2016;22(46):10084-10092 View Article PubMed/NCBI
  48. Cai Q, Gan C, Tang C, Wu H, Gao J. Mechanism and Therapeutic Opportunities of Histone Modifications in Chronic Liver Disease. Front Pharmacol 2021;12:784591 View Article PubMed/NCBI
  49. Rodríguez-Aguilera JR, Guerrero-Hernández C, Pérez-Molina R, Cadena-Del-Castillo CE, Pérez-Cabeza de Vaca R, Guerrero-Celis N, et al. Epigenetic Effects of an Adenosine Derivative in a Wistar Rat Model of Liver Cirrhosis. J Cell Biochem 2018;119(1):401-413 View Article PubMed/NCBI
  50. Bannister AJ, Kouzarides T. Regulation of chromatin by histone modifications. Cell Res 2011;21(3):381-395 View Article PubMed/NCBI
  51. Yuan GC. Linking genome to epigenome. Wiley Interdiscip Rev Syst Biol Med 2012;4(3):297-309 View Article PubMed/NCBI
  52. Perugorria MJ, Wilson CL, Zeybel M, Walsh M, Amin S, Robinson S, et al. Histone methyltransferase ASH1 orchestrates fibrogenic gene transcription during myofibroblast transdifferentiation. Hepatology 2012;56(3):1129-1139 View Article PubMed/NCBI
  53. Jiang Y, Xiang C, Zhong F, Zhang Y, Wang L, Zhao Y, et al. Histone H3K27 methyltransferase EZH2 and demethylase JMJD3 regulate hepatic stellate cells activation and liver fibrosis. Theranostics 2021;11(1):361-378 View Article PubMed/NCBI
  54. Mann J, Chu DC, Maxwell A, Oakley F, Zhu NL, Tsukamoto H, et al. MeCP2 controls an epigenetic pathway that promotes myofibroblast transdifferentiation and fibrosis. Gastroenterology 2010;138(2):705-714 View Article PubMed/NCBI
  55. Jiang Y, Wang S, Zhao Y, Lin C, Zhong F, Jin L, et al. Histone H3K9 demethylase JMJD1A modulates hepatic stellate cells activation and liver fibrosis by epigenetically regulating peroxisome proliferator-activated receptor γ. FASEB J 2015;29(5):1830-1841 View Article PubMed/NCBI
  56. Dong F, Jiang S, Li J, Wang Y, Zhu L, Huang Y, et al. The histone demethylase KDM4D promotes hepatic fibrogenesis by modulating Toll-like receptor 4 signaling pathway. EBioMedicine 2019;39:472-483 View Article PubMed/NCBI
  57. Dou C, Liu Z, Tu K, Zhang H, Chen C, Yaqoob U, et al. P300 Acetyltransferase Mediates Stiffness-Induced Activation of Hepatic Stellate Cells Into Tumor-Promoting Myofibroblasts. Gastroenterology 2018;154(8):2209-2221 View Article PubMed/NCBI
  58. Page A, Paoli PP, Hill SJ, Howarth R, Wu R, Kweon SM, et al. Alcohol directly stimulates epigenetic modifications in hepatic stellate cells. J Hepatol 2015;62(2):388-397 View Article PubMed/NCBI
  59. Pannem RR, Dorn C, Hellerbrand C, Massoumi R. Cylindromatosis gene CYLD regulates hepatocyte growth factor expression in hepatic stellate cells through interaction with histone deacetylase 7. Hepatology 2014;60(3):1066-1081 View Article PubMed/NCBI
  60. Lempiäinen JK, Garcia BA. Characterizing crosstalk in epigenetic signaling to understand disease physiology. Biochem J 2023;480(1):57-85 View Article PubMed/NCBI
  61. Song C, Feodorova Y, Guy J, Peichl L, Jost KL, Kimura H, et al. DNA methylation reader MECP2: cell type- and differentiation stage-specific protein distribution. Epigenetics Chromatin 2014;7:17 View Article PubMed/NCBI
  62. Bárcena-Varela M, Caruso S, Llerena S, Álvarez-Sola G, Uriarte I, Latasa MU, et al. Dual Targeting of Histone Methyltransferase G9a and DNA-Methyltransferase 1 for the Treatment of Experimental Hepatocellular Carcinoma. Hepatology 2019;69(2):587-603 View Article PubMed/NCBI
  63. Li QY, Gong T, Huang YK, Kang L, Warner CA, Xie H, et al. Role of noncoding RNAs in liver fibrosis. World J Gastroenterol 2023;29(9):1446-1459 View Article PubMed/NCBI
  64. Esteller M. Non-coding RNAs in human disease. Nat Rev Genet 2011;12(12):861-874 View Article PubMed/NCBI
  65. López-Sánchez GN, Dóminguez-Pérez M, Uribe M, Chávez-Tapia NC, Nuño-Lámbarri N. Non-alcoholic fatty liver disease and microRNAs expression, how it affects the development and progression of the disease. Ann Hepatol 2021;21:100212 View Article PubMed/NCBI
  66. Schueller F, Roy S, Vucur M, Trautwein C, Luedde T, Roderburg C. The Role of miRNAs in the Pathophysiology of Liver Diseases and Toxicity. Int J Mol Sci 2018;19(1):261 View Article PubMed/NCBI
  67. Zaiou M. Noncoding RNAs as additional mediators of epigenetic regulation in nonalcoholic fatty liver disease. World J Gastroenterol 2022;28(35):5111-5128 View Article PubMed/NCBI
  68. O’Brien J, Hayder H, Zayed Y, Peng C. Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Front Endocrinol (Lausanne) 2018;9:402 View Article PubMed/NCBI
  69. Mahmoudi A, Butler AE, Jamialahmadi T, Sahebkar A. The role of exosomal miRNA in nonalcoholic fatty liver disease. J Cell Physiol 2022;237(4):2078-2094 View Article PubMed/NCBI
  70. Panera N, Gnani D, Crudele A, Ceccarelli S, Nobili V, Alisi A. MicroRNAs as controlled systems and controllers in non-alcoholic fatty liver disease. World J Gastroenterol 2014;20(41):15079-86 View Article PubMed/NCBI
  71. Teng KY, Ghoshal K. Role of Noncoding RNAs as Biomarker and Therapeutic Targets for Liver Fibrosis. Gene Expr 2015;16(4):155-162 View Article PubMed/NCBI
  72. Ezhilarasan D. Role of MicroRNAs in Hepatic Fibrosis Progression. J App Pharm Sci 2018;8(5):174-178 View Article PubMed/NCBI
  73. Guo CJ, Pan Q, Cheng T, Jiang B, Chen GY, Li DG. Changes in microRNAs associated with hepatic stellate cell activation status identify signaling pathways. FEBS J 2009;276(18):5163-5176 View Article PubMed/NCBI
  74. Coll M, El Taghdouini A, Perea L, Mannaerts I, Vila-Casadesús M, Blaya D, et al. Integrative miRNA and Gene Expression Profiling Analysis of Human Quiescent Hepatic Stellate Cells. Sci Rep 2015;5:11549 View Article PubMed/NCBI
  75. Liu M, Lu T, Bai Y, Han X, Zhang W, Zhang L, et al. The Critical Role of microRNA-21 in Non-alcoholic Fatty Liver Disease Pathogenesis. Curr Pharm Des 2023;29(12):904-913 View Article PubMed/NCBI
  76. Sun C, Huang F, Liu X, Xiao X, Yang M, Hu G, Liu H, Liao L. miR-21 regulates triglyceride and cholesterol metabolism in non-alcoholic fatty liver disease by targeting HMGCR. Int J Mol Med 2015;35(3):847-853 View Article PubMed/NCBI
  77. Loyer X, Paradis V, Hénique C, Vion AC, Colnot N, Guerin CL, et al. Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARα expression. Gut 2016;65(11):1882-1894 View Article PubMed/NCBI
  78. Rodrigues PM, Afonso MB, Simão AL, Carvalho CC, Trindade A, Duarte A, et al. miR-21 ablation and obeticholic acid ameliorate nonalcoholic steatohepatitis in mice. Cell Death Dis 2017;8(4):e2748 View Article PubMed/NCBI
  79. Dattaroy D, Pourhoseini S, Das S, Alhasson F, Seth RK, Nagarkatti M, et al. Micro-RNA 21 inhibition of SMAD7 enhances fibrogenesis via leptin-mediated NADPH oxidase in experimental and human nonalcoholic steatohepatitis. Am J Physiol Gastrointest Liver Physiol 2015;308(4):G298-312 View Article PubMed/NCBI
  80. Noetel A, Kwiecinski M, Elfimova N, Huang J, Odenthal M. microRNA are Central Players in Anti- and Profibrotic Gene Regulation during Liver Fibrosis. Front Physiol 2012;3:49 View Article PubMed/NCBI
  81. Szabo G, Bala S. MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol 2013;10(9):542-552 View Article PubMed/NCBI
  82. Zhao J, Tang N, Wu K, Dai W, Ye C, Shi J, et al. MiR-21 simultaneously regulates ERK1 signaling in HSCs activation and hepatocyte EMT in hepatic fibrosis. PLoS One 2014;9(10):e108005 View Article PubMed/NCBI
  83. Kim JH, Lee BR, Choi ES, Lee KM, Choi SK, Cho JH, et al. Reverse Expression of Aging-Associated Molecules through Transfection of miRNAs to Aged Mice. Mol Ther Nucleic Acids 2017;6:106-115 View Article PubMed/NCBI
  84. Ding J, Xia C, Cen P, Li S, Yu L, Zhu J, et al. MiR-103-3p promotes hepatic steatosis to aggravate nonalcoholic fatty liver disease by targeting of ACOX1. Mol Biol Rep 2022;49(8):7297-7305 View Article PubMed/NCBI
  85. Chen L, Yao X, Yao H, Ji Q, Ding G, Liu X. Exosomal miR-103-3p from LPS-activated THP-1 macrophage contributes to the activation of hepatic stellate cells. FASEB J 2020;34(4):5178-5192 View Article PubMed/NCBI
  86. Zhang Q, Yu K, Cao Y, Luo Y, Liu Y, Zhao C. miR-125b promotes the NF-κB-mediated inflammatory response in NAFLD via directly targeting TNFAIP3. Life Sci 2021;270:119071 View Article PubMed/NCBI
  87. Wei LM, Sun RP, Dong T, Liu J, Chen T, Zeng B, et al. MiR-125b-2 knockout increases high-fat diet-induced fat accumulation and insulin resistance. Sci Rep 2020;10(1):21969 View Article PubMed/NCBI
  88. You K, Li SY, Gong J, Fang JH, Zhang C, Zhang M, et al. MicroRNA-125b Promotes Hepatic Stellate Cell Activation and Liver Fibrosis by Activating RhoA Signaling. Mol Ther Nucleic Acids 2018;12:57-66 View Article PubMed/NCBI
  89. Huang RX, Duan XY, Liu XL, Cao HX, Wang YQ, Fan JG, et al. Role and mechanism of miRNA-181a in nonalcoholic fatty liver disease. Zhonghua Gan Zang Bing Za Zhi 2021;29(12):1177-1181 View Article PubMed/NCBI
  90. Gupta P, Sata TN, Yadav AK, Mishra A, Vats N, Hossain MM, et al. TGF-β induces liver fibrosis via miRNA-181a-mediated down regulation of augmenter of liver regeneration in hepatic stellate cells. PLoS One 2019;14(6):e0214534 View Article PubMed/NCBI
  91. Hochreuter MY, Dall M, Treebak JT, Barrès R. MicroRNAs in non-alcoholic fatty liver disease: Progress and perspectives. Mol Metab 2022;65:101581 View Article PubMed/NCBI
  92. Yang JJ, Tao H, Liu LP, Hu W, Deng ZY, Li J. miR-200a controls hepatic stellate cell activation and fibrosis via SIRT1/Notch1 signal pathway. Inflamm Res 2017;66(4):341-352 View Article PubMed/NCBI
  93. Jiang X, Jiang L, Shan A, Su Y, Cheng Y, Song D, et al. Targeting hepatic miR-221/222 for therapeutic intervention of nonalcoholic steatohepatitis in mice. EBioMedicine 2018;37:307-321 View Article PubMed/NCBI
  94. Ogawa T, Enomoto M, Fujii H, Sekiya Y, Yoshizato K, Ikeda K, et al. MicroRNA-221/222 upregulation indicates the activation of stellate cells and the progression of liver fibrosis. Gut 2012;61(11):1600-1609 View Article PubMed/NCBI
  95. Hayes CN, Chayama K. MicroRNAs as Biomarkers for Liver Disease and Hepatocellular Carcinoma. Int J Mol Sci 2016;17(3):280 View Article PubMed/NCBI
  96. Markovic J, Sharma AD, Balakrishnan A. MicroRNA-221: A Fine Tuner and Potential Biomarker of Chronic Liver Injury. Cells 2020;9(8):1767 View Article PubMed/NCBI
  97. Dhanoa JK, Sethi RS, Verma R, Arora JS, Mukhopadhyay CS. Long non-coding RNA: its evolutionary relics and biological implications in mammals: a review. J Anim Sci Technol 2018;60:25 View Article PubMed/NCBI
  98. De Vincentis A, Rahmani Z, Muley M, Vespasiani-Gentilucci U, Ruggiero S, Zamani P, et al. Long noncoding RNAs in nonalcoholic fatty liver disease and liver fibrosis: state-of-the-art and perspectives in diagnosis and treatment. Drug Discov Today 2020;25(7):1277-1286 View Article PubMed/NCBI
  99. Shi CX, Wang Y, Jiao FZ, Chen Q, Cao P, Pei MH, et al. Epigenetic Regulation of Hepatic Stellate Cell Activation and Macrophage in Chronic Liver Inflammation. Front Physiol 2021;12:683526 View Article PubMed/NCBI
  100. Lu J, Guo J, Liu J, Mao X, Xu K. Long Non-coding RNA MALAT1: A Key Player in Liver Diseases. Front Med (Lausanne) 2022;8:734643 View Article PubMed/NCBI
  101. Yan C, Chen J, Chen N. Long noncoding RNA MALAT1 promotes hepatic steatosis and insulin resistance by increasing nuclear SREBP-1c protein stability. Sci Rep 2016;6:22640 View Article PubMed/NCBI
  102. Xiang J, Deng YY, Liu HX, Pu Y. LncRNA MALAT1 Promotes PPARα/CD36-Mediated Hepatic Lipogenesis in Nonalcoholic Fatty Liver Disease by Modulating miR-206/ARNT Axis. Front Bioeng Biotechnol 2022;10:858558 View Article PubMed/NCBI
  103. Leti F, Legendre C, Still CD, Chu X, Petrick A, Gerhard GS, et al. Altered expression of MALAT1 lncRNA in nonalcoholic steatohepatitis fibrosis regulates CXCL5 in hepatic stellate cells. Transl Res 2017;190:25-39 View Article PubMed/NCBI
  104. Yu F, Lu Z, Cai J, Huang K, Chen B, Li G, et al. MALAT1 functions as a competing endogenous RNA to mediate Rac1 expression by sequestering miR-101b in liver fibrosis. Cell Cycle 2015;14(24):3885-3896 View Article PubMed/NCBI
  105. Dai X, Chen C, Xue J, Xiao T, Mostofa G, Wang D, et al. Exosomal MALAT1 derived from hepatic cells is involved in the activation of hepatic stellate cells via miRNA-26b in fibrosis induced by arsenite. Toxicol Lett 2019;316:73-84 View Article PubMed/NCBI
  106. Wang Y, Mou Q, Zhu Z, Zhao L, Zhu L. MALAT1 promotes liver fibrosis by sponging miR-181a and activating TLR4-NF-κB signaling. Int J Mol Med 2021;48(6):215 View Article PubMed/NCBI
  107. Bu FT, Wang A, Zhu Y, You HM, Zhang YF, Meng XM, et al. LncRNA NEAT1: Shedding light on mechanisms and opportunities in liver diseases. Liver Int 2020;40(11):2612-2626 View Article PubMed/NCBI
  108. Wang X. Down-regulation of lncRNA-NEAT1 alleviated the non-alcoholic fatty liver disease via mTOR/S6K1 signaling pathway. J Cell Biochem 2018;119(2):1567-1574 View Article PubMed/NCBI
  109. Fu X, Zhu J, Zhang L, Shu J. Long non-coding RNA NEAT1 promotes steatosis via enhancement of estrogen receptor alpha-mediated AQP7 expression in HepG2 cells. Artif Cells Nanomed Biotechnol 2019;47(1):1782-1787 View Article PubMed/NCBI
  110. Chen X, Tan XR, Li SJ, Zhang XX. LncRNA NEAT1 promotes hepatic lipid accumulation via regulating miR-146a-5p/ROCK1 in nonalcoholic fatty liver disease. Life Sci 2019;235:116829 View Article PubMed/NCBI
  111. Jin SS, Lin XF, Zheng JZ, Wang Q, Guan HQ. lncRNA NEAT1 regulates fibrosis and inflammatory response induced by nonalcoholic fatty liver by regulating miR-506/GLI3. Eur Cytokine Netw 2019;30(3):98-106 View Article PubMed/NCBI
  112. Zhang Z, Wen H, Peng B, Weng J, Zeng F. Downregulated microRNA-129-5p by Long Non-coding RNA NEAT1 Upregulates PEG3 Expression to Aggravate Non-alcoholic Steatohepatitis. Front Genet 2021;11:563265 View Article PubMed/NCBI
  113. Yu F, Jiang Z, Chen B, Dong P, Zheng J. NEAT1 accelerates the progression of liver fibrosis via regulation of microRNA-122 and Kruppel-like factor 6. J Mol Med (Berl) 2017;95(11):1191-1202 View Article PubMed/NCBI
  114. Kong Y, Huang T, Zhang H, Zhang Q, Ren J, Guo X, et al. The lncRNA NEAT1/miR-29b/Atg9a axis regulates IGFBPrP1-induced autophagy and activation of mouse hepatic stellate cells. Life Sci 2019;237:116902 View Article PubMed/NCBI
  115. Huang W, Huang F, Zhang R, Luo H. LncRNA Neat1 expedites the progression of liver fibrosis in mice through targeting miR-148a-3p and miR-22-3p to upregulate Cyth3. Cell Cycle 2021;20(5-6):490-507 View Article PubMed/NCBI
  116. Xia X, Huang L, Zhou S, Han R, Li P, Wang E, et al. Hypoxia-induced long non-coding RNA plasmacytoma variant translocation 1 upregulation aggravates pulmonary arterial smooth muscle cell proliferation by regulating autophagy via miR-186/Srf/Ctgf and miR-26b/Ctgf signaling pathways. Int J Cardiol 2023;370:368-377 View Article PubMed/NCBI
  117. Zhang L, Zhang D, Qin ZY, Li J, Shen ZY. The role and possible mechanism of long noncoding RNA PVT1 in modulating 3T3-L1 preadipocyte proliferation and differentiation. IUBMB Life 2020;72(7):1460-1467 View Article PubMed/NCBI
  118. Zhang H, Niu Q, Liang K, Li X, Jiang J, Bian C. Effect of LncPVT1/miR-20a-5p on Lipid Metabolism and Insulin Resistance in NAFLD. Diabetes Metab Syndr Obes 2021;14:4599-4608 View Article PubMed/NCBI
  119. Zheng J, Yu F, Dong P, Wu L, Zhang Y, Hu Y, et al. Long non-coding RNA PVT1 activates hepatic stellate cells through competitively binding microRNA-152. Oncotarget 2016;7(39):62886-62897 View Article PubMed/NCBI
  120. Angelopoulou E, Paudel YN, Piperi C. Critical role of HOX transcript antisense intergenic RNA (HOTAIR) in gliomas. J Mol Med (Berl) 2020;98(11):1525-1546 View Article PubMed/NCBI
  121. Guo B, Cheng Y, Yao L, Zhang J, Lu J, Qi H, et al. LncRNA HOTAIR regulates the lipid accumulation in non-alcoholic fatty liver disease via miR-130b-3p/ROCK1 axis. Cell Signal 2022;90:110190 View Article PubMed/NCBI
  122. Bian EB, Wang YY, Yang Y, Wu BM, Xu T, Meng XM, et al. Hotair facilitates hepatic stellate cells activation and fibrogenesis in the liver. Biochim Biophys Acta Mol Basis Dis 2017;1863(3):674-686 View Article PubMed/NCBI
  123. Yu F, Chen B, Dong P, Zheng J. HOTAIR Epigenetically Modulates PTEN Expression via MicroRNA-29b: A Novel Mechanism in Regulation of Liver Fibrosis. Mol Ther 2017;25(1):205-217 View Article PubMed/NCBI
  124. Negishi M, Wongpalee SP, Sarkar S, Park J, Lee KY, Shibata Y, et al. A new lncRNA, APTR, associates with and represses the CDKN1A/p21 promoter by recruiting polycomb proteins. PLoS One 2014;9(4):e95216 View Article PubMed/NCBI
  125. Yu F, Zheng J, Mao Y, Dong P, Li G, Lu Z, et al. Long non-coding RNA APTR promotes the activation of hepatic stellate cells and the progression of liver fibrosis. Biochem Biophys Res Commun 2015;463(4):679-685 View Article PubMed/NCBI
  126. Zhang K, Han X, Zhang Z, Zheng L, Hu Z, Yao Q, et al. The liver-enriched lnc-LFAR1 promotes liver fibrosis by activating TGFβ and Notch pathways. Nat Commun 2017;8(1):144 View Article PubMed/NCBI
  127. Han X, Hong Y, Zhang K. TUG1 is involved in liver fibrosis and activation of HSCs by regulating miR-29b. Biochem Biophys Res Commun 2018;503(3):1394-1400 View Article PubMed/NCBI
  128. Chen X, Lu Y. Circular RNA: Biosynthesis in vitro. Front Bioeng Biotechnol 2021;9:787881 View Article PubMed/NCBI
  129. Yepmo M, Potier JB, Pinget M, Grabarz A, Bouzakri K, Dumond Bourie A. Discussing the role of circular RNA in the pathogenesis of non-alcoholic fatty liver disease and its complications. Front Endocrinol (Lausanne) 2022;13:1035159 View Article PubMed/NCBI
  130. Nokkeaw A, Thamjamrassri P, Tangkijvanich P, Ariyachet C. Regulatory Functions and Mechanisms of Circular RNAs in Hepatic Stellate Cell Activation and Liver Fibrosis. Cells 2023;12(3):378 View Article PubMed/NCBI
  131. Liu W, Feng R, Li X, Li D, Zhai W. TGF-β- and lipopolysaccharide-induced upregulation of circular RNA PWWP2A promotes hepatic fibrosis via sponging miR-203 and miR-223. Aging (Albany NY) 2019;11(21):9569-9580 View Article PubMed/NCBI
  132. Zhu S, Chen X, Wang JN, Xu JJ, Wang A, Li JJ, et al. Circular RNA circUbe2k promotes hepatic fibrosis via sponging miR-149-5p/TGF-β2 axis. FASEB J 2021;35(6):e21622 View Article PubMed/NCBI
  133. Niu H, Zhang L, Chen YH, Yuan BY, Wu ZF, Cheng JC, et al. Circular RNA TUBD1 Acts as the miR-146a-5p Sponge to Affect the Viability and Pro-Inflammatory Cytokine Production of LX-2 Cells through the TLR4 Pathway. Radiat Res 2020;193(4):383-393 View Article PubMed/NCBI
  134. Zhu L, Ren T, Zhu Z, Cheng M, Mou Q, Mu M, et al. Thymosin-β4 Mediates Hepatic Stellate Cell Activation by Interfering with CircRNA-0067835/miR-155/FoxO3 Signaling Pathway. Cell Physiol Biochem 2018;51(3):1389-1398 View Article PubMed/NCBI
  135. Chen Y, Yuan B, Chen G, Zhang L, Zhuang Y, Niu H, et al. Circular RNA RSF1 promotes inflammatory and fibrotic phenotypes of irradiated hepatic stellate cell by modulating miR-146a-5p. J Cell Physiol 2020;235(11):8270-8282 View Article PubMed/NCBI
  136. Li B, Zhou J, Luo Y, Tao K, Zhang L, Zhao Y, et al. Suppressing circ_0008494 inhibits HSCs activation by regulating the miR-185-3p/Col1a1 axis. Front Pharmacol 2022;13:1050093 View Article PubMed/NCBI
  137. Chen Y, Yuan B, Wu Z, Dong Y, Zhang L, Zeng Z. Microarray profiling of circular RNAs and the potential regulatory role of hsa_circ_0071410 in the activated human hepatic stellate cell induced by irradiation. Gene 2017;629:35-42 View Article PubMed/NCBI
  138. Meng H, Jiang L, Jia P, Niu R, Bu F, Zhu Y, et al. Inhibition of circular RNA ASPH reduces the proliferation and promotes the apoptosis of hepatic stellate cells in hepatic fibrosis. Biochem Pharmacol 2023;210:115451 View Article PubMed/NCBI
  139. Lv L, Wang D, Yin J, Yang T, Huang B, Cao Y, et al. Downregulation of miR-20b-5p Contributes to the Progression of Liver Fibrosis via the STAT3 Signaling Pathway In Vivo and In Vitro. Dig Dis Sci 2023;68(2):487-496 View Article PubMed/NCBI
  140. Ning ZW, Luo XY, Wang GZ, Li Y, Pan MX, Yang RQ, et al. MicroRNA-21 Mediates Angiotensin II-Induced Liver Fibrosis by Activating NLRP3 Inflammasome/IL-1β Axis via Targeting Smad7 and Spry1. Antioxid Redox Signal 2017;27(1):1-20 View Article PubMed/NCBI
  141. Sun J, Shi L, Xiao T, Xue J, Li J, Wang P, et al. microRNA-21, via the HIF-1α/VEGF signaling pathway, is involved in arsenite-induced hepatic fibrosis through aberrant cross-talk of hepatocytes and hepatic stellate cells. Chemosphere 2021;266:129177 View Article PubMed/NCBI
  142. Yang X, Ma L, Wei R, Ye T, Zhou J, Wen M, et al. Twist1-induced miR-199a-3p promotes liver fibrosis by suppressing caveolin-2 and activating TGF-β pathway. Signal Transduct Target Ther 2020;5(1):75 View Article PubMed/NCBI
  143. Zhou QY, Yang HM, Liu JX, Xu N, Li J, Shen LP, et al. MicroRNA-497 induced by Clonorchis sinensis enhances the TGF-β/Smad signaling pathway to promote hepatic fibrosis by targeting Smad7. Parasit Vectors 2021;14(1):472 View Article PubMed/NCBI
  144. Luo X, Luo SZ, Xu ZX, Zhou C, Li ZH, Zhou XY, et al. Lipotoxic hepatocyte-derived exosomal miR-1297 promotes hepatic stellate cell activation through the PTEN signaling pathway in metabolic-associated fatty liver disease. World J Gastroenterol 2021;27(14):1419-1434 View Article PubMed/NCBI
  145. Wang Q, Wei S, Li L, Bu Q, Zhou H, Su W, Liu Z, et al. miR-139-5p sponged by LncRNA NEAT1 regulates liver fibrosis via targeting β-catenin/SOX9/TGF-β1 pathway. Cell Death Discov 2021;7(1):243 View Article PubMed/NCBI
  146. Su SB, Tao L, Liang XL, Chen W. Long noncoding RNA GAS5 inhibits LX-2 cells activation by suppressing NF-κB signalling through regulation of the miR-433-3p/TLR10 axis. Dig Liver Dis 2022;54(8):1066-1075 View Article PubMed/NCBI
  147. Garbuzenko DV. Drug Therapy for Non-Alcoholic Steatohepatitis-Induced Liver Fibrosis. Rus J Gastroenterol Hepatol Coloproctol 2021;31(5):16-24 View Article PubMed/NCBI
  148. Zhang J, Liu Q, He J, Li Y. Novel Therapeutic Targets in Liver Fibrosis. Front Mol Biosci 2021;8:766855 View Article PubMed/NCBI
  149. Lyu SY, Xiao W, Cui GZ, Yu C, Liu H, Lyu M, et al. Role and mechanism of DNA methylation and its inhibitors in hepatic fibrosis. Front Genet 2023;14:1124330 View Article PubMed/NCBI
  150. Wu P, Huang R, Xiong YL, Wu C. Protective effects of curcumin against liver fibrosis through modulating DNA methylation. Chin J Nat Med 2016;14(4):255-264 View Article PubMed/NCBI
  151. Wang Y, Zhao L, Jiao FZ, Zhang WB, Chen Q, Gong ZJ. Histone deacetylase inhibitor suberoylanilide hydroxamic acid alleviates liver fibrosis by suppressing the transforming growth factor-β1 signal pathway. Hepatobiliary Pancreat Dis Int 2018;17(5):423-429 View Article PubMed/NCBI
  152. Zhou Q, Rong C, Gu T, Li H, Wu L, Zhuansun X, et al. Mesenchymal stem cells improve liver fibrosis and protect hepatocytes by promoting microRNA-148a-5p-mediated inhibition of Notch signaling pathway. Stem Cell Res Ther 2022;13(1):354 View Article PubMed/NCBI
  153. Paik KY, Kim KH, Park JH, Lee JI, Kim OH, Hong HE, et al. A novel antifibrotic strategy utilizing conditioned media obtained from miR-150-transfected adipose-derived stem cells: validation of an animal model of liver fibrosis. Exp Mol Med 2020;52(3):438-449 View Article PubMed/NCBI
  154. Jimenez Calvente C, Del Pilar H, Tameda M, Johnson CD, Feldstein AE. MicroRNA 223 3p Negatively Regulates the NLRP3 Inflammasome in Acute and Chronic Liver Injury. Mol Ther 2020;28(2):653-663 View Article PubMed/NCBI
  155. Wang X, Seo W, Park SH, Fu Y, Hwang S, Rodrigues RM, et al. MicroRNA-223 restricts liver fibrosis by inhibiting the TAZ-IHH-GLI2 and PDGF signaling pathways via the crosstalk of multiple liver cell types. Int J Biol Sci 2021;17(4):1153-1167 View Article PubMed/NCBI
  156. Wang L, Wang Y, Quan J. Exosomal miR-223 derived from natural killer cells inhibits hepatic stellate cell activation by suppressing autophagy. Mol Med 2020;26(1):81 View Article PubMed/NCBI
  157. Duan B, Hu J, Zhang T, Luo X, Zhou Y, Liu S, et al. miRNA-338-3p/CDK4 signaling pathway suppressed hepatic stellate cell activation and proliferation. BMC Gastroenterol 2017;17(1):12 View Article PubMed/NCBI
  158. Gao H, Jin Z, Bandyopadhyay G, Cunha E, Rocha K, Liu X, et al. MiR-690 treatment causes decreased fibrosis and steatosis and restores specific Kupffer cell functions in NASH. Cell Metab 2022;34(7):978-990 View Article PubMed/NCBI
  159. Wang N, Li X, Zhong Z, Qiu Y, Liu S, Wu H, et al. 3D hESC exosomes enriched with miR-6766-3p ameliorates liver fibrosis by attenuating activated stellate cells through targeting the TGFβRII-SMADS pathway. J Nanobiotechnology 2021;19(1):437 View Article PubMed/NCBI
  160. Wan LY, Peng H, Ni YR, Jiang XP, Wang JJ, Zhang YQ, et al. The miR-23b/27b/24-1 Cluster Inhibits Hepatic Fibrosis by Inactivating Hepatic Stellate Cells. Cell Mol Gastroenterol Hepatol 2022;13(5):1393-1412 View Article PubMed/NCBI
  161. Feng Y, Li Y, Xu M, Meng H, Dai C, Yao Z, et al. Bone marrow mesenchymal stem cells inhibit hepatic fibrosis via the AABR07028795.2/rno-miR-667-5p axis. Stem Cell Res Ther 2022;13(1):375 View Article PubMed/NCBI
  162. Ma L, Wei J, Zeng Y, Liu J, Xiao E, Kang Y, et al. Mesenchymal stem cell-originated exosomal circDIDO1 suppresses hepatic stellate cell activation by miR-141-3p/PTEN/AKT pathway in human liver fibrosis. Drug Deliv 2022;29(1):440-453 View Article PubMed/NCBI

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