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    Topic review

    MicroRNA in Liver Fibrosis

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    Submitted by: Asahiro Morishita

    Definition

    Several miRNAs are associated with organ-specific and systemic fibrosis in the liver. Individual expression of miRNAs in plasma or serum is useful for liver fibrosis detection. In addition, some miRNAs can distinguish between early and late fibrosis with high sensitivity and specificity equal to or greater than the APRI and Fib-4 index.

    1. Introduction

    Activation of hepatic stellate cells (HSCs) is a pivotal event in liver fibrosis [1], and various inflammatory and fibrotic pathways are involved [2]. Activated HSCs are precursors of myofibroblasts that produce extracellular matrix (ECM) in the liver. Therefore, the treatment of hepatic fibrosis requires the prevention of hepatocellular damage and control of activated HSCs [3]. If HSC inactivation can be induced by cell- or target-specific pharmacological interventions, then, more effective, less toxic, and more accurate anti-fibrotic treatments than the currently available ones can be developed.

    HSCs, also known as Ito cells, are fat-storing cells containing vitamin A which are found in the space of Disse and account for approximately 10% of the total number of liver cells. HSCs correspond to pericytes that surround the sinusoidal endothelial cells with branch-like projections and contact hepatocytes [4]. HSCs have also been suggested to serve as antigen-presenting cells in the liver, presenting lipid antigens to CD1-restricted T lymphocytes such as natural killer T (NKT) cells and promoting NKT cell proliferation by presenting hepatic NKT cell lipid antigens via interleukin (IL)-15 [5].

    EVs have attracted attention as delivery media for functional RNAs, including miRNAs. Exosomes are a subset of EVs which are secreted from the endoplasmic reticulum in cells with a lipid bilayer membrane with an average diameter of 30–100 nm [6][7]. They contain mRNAs and miRNAs which they transmit between cells [6]. The endoplasmic reticulum-derived EVs, including exosomes, contain RNA, proteins, and other information from the donor (EV–secreting) cell, and transmit this information to the recipient cell. miRNAs are mostly contained in EVs and are transported to recipient cells by intercellular transport, affecting signal transduction in recipient cells and cell phenotype. miRNAs in EVs extracted from patients are useful as disease biomarkers for various diseases [6]. In addition, a new drug delivery system that hijacks exosomes to deliver anti-miR oligonucleotides into the cells that receive them has been developed and is expected to have therapeutic applications [8].

    Furthermore, it is expected to be applied to the diagnosis of liver fibrosis and to the development of novel therapeutic agents using miRNAs.

    2. Epigenetic Changes in Liver Fibrosis/Cirrhosis

    Several miRNAs are associated with organ-specific and systemic fibrosis in the liver [9]. Individual expression of miRNAs in plasma or serum is useful for liver fibrosis detection [10][11]. In addition, some miRNAs can distinguish between early and late fibrosis with high sensitivity and specificity equal to or greater than the APRI and Fib-4 index [12][13]. For example, patients with advanced cirrhosis showed significantly lower levels of miR-29a in their serum compared to healthy controls and patients with early fibrosis [14]. Additionally, serum levels of miR-138 and miR-143 are characteristic of the later stages of liver fibrosis and thus, miR-138 may be useful for detecting fibrosis in its early stages [15]. Furthermore, serum levels of miR-34a and miR-122 correlate with the progression of fibrosis, especially in patients with chronic hepatitis C or nonalcoholic fatty liver disease (NAFLD) [16]. In addition, miR-221 is upregulated in patients with liver cirrhosis [17]. Elucidation of the relationship between miRNAs and liver fibrosis may be useful for detection of fibrosis without invasive liver biopsy, early therapeutic intervention, and identification of high-risk patients. There are various microRNAs that are expected to be biomarkers for liver diseases ( Table 1 ).

    Table 1. miRNA as biomarker of liver fibrosis.
      miRNA Expression Level References
    Liver fibrosis miR-29a Down [14]
    Liver fibrosis miR-138 Up [15]
    Liver fibrosis miR-143 Up [15]
    Liver fibrosis miR-34a Up [16]
    Liver fibrosis miR-122 Up [16]
    Liver fibrosis miR-221 Up [17]
    Portal vein thrombus miR-19a Up [18]
    Portal vein thrombus miR-34a Up [18]
    Portal vein thrombus miR-21 Up [19]
    SBP miR-122 Down [20]
    SBP miR-155 Up [21][22]
    SBP miR-223 Up [23]
    HBV miR-21-5p Up [24]
    HBV miR-125a-5p Up [25]
    HBV miR-27a Up [26]
    HBV miR-181b Up [27]
    HCV miR-222 Up [28]
    HCV miR-221 Up [28][29]
    HCV miR-21 Up [30]
    HCV miR-99a Down [31]
    HCV miR-215-5p Up [32]
    HCV miR-483-5p Up [32]
    HCV miR-193b-3p Up [32]
    HCV miR-34a Up [29][32]
    HCV miR-885-5p Up [32]
    HCV miR-26b-5p Down [32]
    HCV miR-197-3p Down [32]
    HCV miR-122 Down [33]
    HCV miR-16 Up [29]
    HCV miR-200c Up [34]
    HCV miR-20a Up [35]
    NASH/NAFLD miR-34a Up [36][37]
    NASH/NAFLD miR-372-3p Down [38]
    NASH/NAFLD miR-373-3p Down [38]
    AIH miR-133a Up [39][40]
    AIH miR-122 Down [41]
    AIH miR-21 Down [41]
    PBC miR-21 Up [42]
    PBC miR-210 Up [43]
    PBC let-7b Up [44]
    PBC miR-520a-5p Up [44]
    PBC miR-125b Down [44]
    PBC miR-92a Down [45]
    PBC miR-223-3p Down [46]
    PBC miR-21-5p Down [46]
    PBC miR-139-5p Down [47]
    PSC miR-150-5p Down [48]
    PSC miR-122 Down [49]
    PSC miR-200c Down [50]

    Recently, the relationship between liver diseases and various miRNAs has been confirmed ( Table 2 ). Some miRNAs such as miR-21, miR-221/222, and miR-181b, promote liver fibrosis through the TGF-β and NF-κB pathways [51]. In addition, miR-221 regulates multiple targets, including cyclin-dependent kinase inhibitors (CDKN1C or CDKN1B), cytokine signaling 1, E-cadherin, phosphatase and tensin homolog (PTEN), and Bcl-2 modifying factor, which are involved in liver fibrosis [17]. miR-214 also plays an important role in liver fibrosis by regulating the expression of suppressor of fused homolog protein, and knocking down its expression alleviates liver fibrosis in carbon tetrachloride (CCL4)-treated mice [52]. Moreover, the knockdown of the miR-23b miRNA cluster promotes bile duct differentiation and suppresses or restores TGF-β-induced liver fibrosis depending on stellate cell activation [53].

    Table 2. Fibrosis-associated miRNAs.
      miRNA Predicted Target Involvement in Disease Progression References
    Liver fibrosis miR-21 TGF-β pathway, NF-κB pathway promote [51]
    Liver fibrosis miR-221/222 TGF-β pathway, NF-κB pathway promote [51]
    Liver fibrosis miR-181b TGF-β pathway, NF-κB pathway promote [51]
    Liver fibrosis miR-221 CDKN1C, CDKN1B, Socs1, E-cadherin, PTEN, BMF promote [17]
    Liver fibrosis miR-214 Sufu promote [52]
    Liver fibrosis miR-23b TGF-β pathway inhibit [53]
    Liver fibrosis miR-30a Beclin1,α-SMA,TIMP-1,Collagen I inhibit [54]
    Liver fibrosis miR-29b TGF-β pathway inhibit [51]
    Liver fibrosis miR-101 TGF-β pathway inhibit [51]
    Liver fibrosis miR-122 TGF-β pathway inhibit [51]
    Liver fibrosis miR-214-3p TGF-β pathway inhibit [51]
    Liver fibrosis miR-29a BRD4, CD36 inhibit [55][56][57]
    Liver fibrosis miR-34 TGF-β1/Smad3 pathway inhibit [58]
    Liver fibrosis miR-223 NLRP3 inhibit [59]
    Liver fibrosis miR-455-3p HSF1 inhibit [60]
    Liver fibrosis miR-125b Gli3 inhibit [61]
    Liver fibrosis miR-378 Gli3 inhibit [62]
    Liver fibrosis miR-152 Gli3 inhibit [63]
    Portal hypertension miR-29 VEGF inhibit [64]
    Portal hypertension miR-126 family SPRED1, PIK3R2/p85-beta inhibit [65]
    HBV miR-21-5p TGF-β1 promote [24]
    HBV miR-27a PPARγ, FOXO1, APC, P53, RXRα promote [26]
    HBV miR-181b PTEN/Akt pathway promote [27]
    HCV miR-21 Smad7 promote [30]
    HCV miR-99a mTOR inhibit [31]
    HCV miR-200c FAP-1 promote [34]
    ALD miR-122 HIF1α inhibit [66]
    ALD miR-223 IL-6-p47phox pathway inhibit [67]
    ALD miR-155 PPARγ, PPRE promote [68]
    ALD miR181b-3p importin α5 inhibit [69]
    ALD miR-217 SIRT1 promote [70]
    NASH/NAFLD miR-21 STAT3 signaling pathway, TGF-β/Smad3/Smad7 signaling pathway promote [71]
    NASH/NAFLD miR-29a CD36 inhibit [72]
    NASH/NAFLD miR-122 AGPAT1, DGAT1 inhibit [73]
    NASH/NAFLD miR-34a PPARα signaling pathway promote [36][37]
    NASH/NAFLD miR-129-5p PEG3 inhibit [74]
    NASH/NAFLD miR-188-5p PTEN/PI3K/AKT pathway promote [75]
    NASH/NAFLD miR-223 Cxcl10, Nlrp3, Taz inhibit [76]
    NASH/NAFLD miR-27 insulin signaling pathway promote [77]
    NASH/NAFLD miR-372-3p AEBP1 inhibit [38]
    NASH/NAFLD miR-373-3p AEBP1 inhibit [38]
    AIH miR-375 AEG-1 promote [78]
    AIH miR-138 p53 promote [79]
    AIH miR-15a/miR-16-1 aryl hydrocarbon receptor-IL-22 regulatory axis promote [80]
    AIH miR-674-5p 5-LO inhibit [81]
    AIH miRNA-143 phosphorylation of TAK1 inhibit [82]
    AIH miR-223 AIM2 inhibit [83]
    PBC miR-21 CDK2AP1 promote [42]
    PBC miR-210 MLL4 promote [43]
    PBC miR-506 AE 2, InsP3R3 promote [41]
    PBC miR-92a IL-17A inhibit [45]
    PBC miR-223-3p TGFBR2,MEF2C,FOXP1,RBPJ promote [46]
    PBC miR-21-5p TGFBR2,MEF2C,FOXP2,RBPJ promote [24]
    PBC miR-139-5p c-FOS promote [47]
    PSC miR-7a Ngn-3 promote [84]
    PSC miR-873-5p GNMT promote [85]
    PSC miR-24 menin inhibit [86]

    Thus, various miRNAs are involved in the regulation of liver fibrosis ( Figure 1 ). The identification of miRNAs involved in the pathogenesis of liver fibrosis will enable miRNA-based therapies, and even if this is difficult, miRNA-associated mechanisms can be targeted for therapy.

    Figure 1. Schematic diagram of the relationship between miRNAs and liver fibrosis. HSCs are activated in livers damaged by viruses, alcohol, lipid accumulation, and autoimmunity. Various miRNAs are involved in this process and affect molecules such as TGF-β, NF-κB, and PTEN, which are involved in different pathways. This can improve inflammation or, conversely, result in ECM accumulation and cirrhosis. HSC: hepatic stellate cell; TGF-β: transforming growth factor-β; NF-κB: nuclear factor-kappa B; PTEN: phosphatase and tensin homolog; MFB: myofibroblast; ECM: extracellular matrix; miRNA: micro ribonucleic acid; HBV: hepatitis B virus; HCV: hepatitis C virus.

    In contrast to EVs in serum extracted from mice with induced liver fibrosis, miR-34c, miR-151-3p, miR-483-5p, miR-532-5p, and miR-687 were upregulated in serum EVs from mice without fibrosis. When these EVs were administered to mice with CCL4-induced liver injury, hepatocellular damage and liver fibrosis were suppressed in the healthy mouse-derived EV group, and inflammatory cytokines and transaminases in the blood were reduced. Furthermore, in serum EVs from patients with F3/4 hepatic fibrosis and healthy subjects, levels of miR-34c, miR-151-3p, miR-483-5p, and miR-532-5p were upregulated in healthy subjects compared to levels in patients with F3/4 hepatic fibrosis. When EVs from healthy subjects were administered to human-derived HSCs, HSC activation was suppressed. These EV miRNAs suppress HSC activation and contribute to the suppression of liver fibrosis [87].

    3. miRNAs Associated with Complications of Liver Cirrhosis

    In addition to HCC, gastrointestinal bleeding due to portal hypertension, ascites, portal vein thrombosis, and HE are some of the most common complications of cirrhosis.

    Portal hypertension is caused by an increase in portal venous inflow and intrahepatic vascular resistance, leading to esophageal varices, ascites, HE, and hypersplenism, and it is a major cause of death in patients with cirrhosis [88]. TGF-β-mediated HSC activation is involved in ECM production and is a mechanistic factor in regulating vascular resistance and pressure in the liver [89]. Animal studies have shown that inhibition of TGF-β1 synthesis and blockade of TGF-β receptors can significantly reduce portal hypertensive pressure [90]. Intrahepatic angiogenesis by vascular endothelial growth factor (VEGF), an angiogenic growth factor, is also a cause of sinusoidal systemic circulation and portal hypertension [91]. miR-29 acts as an anti-fibrotic mediator by inhibiting angiogenic factors such as VEGF [64]. The miR-126 family is associated with angiogenesis and directly inhibits negative regulators of the VEGF pathway, such as the Sprouty-related, equine herpesvirus-1 domain-containing protein 1 (SPRED1) and phosphoinositol-3 kinase regulatory subunit 2 (PIK3R2) [65]. Thus, these miRNAs, which affect TGF-β and VEGF, may be key to the treatment of portal hypertension.

    A portal vein thrombus in cirrhosis causes worsening of the liver reserve, gastroesophageal varices, and ascites. The pathophysiology of portal vein thrombosis encompasses one or more of the following features: decreased portal blood flow, hypercoagulable state, and damage to the vascular endothelium. As liver function declines, platelets and hepatic-derived coagulation factors are reduced, while hepatic-derived anticoagulation factors are also reduced, and when this balance is disrupted, portal vein thrombi form [92]. Notably, miR-19a and miR-34a levels are correlated with portal vein thrombosis [18], and miR-21 is considered an independent predictor of portal vein thrombosis in patients with HCC [19].

    Patients with ascites, spontaneous bacterial peritonitis (SBP), and hepatorenal syndrome had significantly lower levels of miR-122 than those without these complications. In addition, serum miR-122 levels were associated with survival of patients with cirrhosis, independent of the Model for End-Stage Liver Disease (MELD) score or patient ’s age [20]. One study indicated that miR-155 is an outstanding diagnostic marker for SBP, and detection of both serum CD64 and calprotectin levels also provide a more useful diagnosis when using blood samples from patients with cirrhosis and ascites [21]. Furthermore, miR-155 [22] and miR-223 [23] were elevated in ascites from patients with cirrhosis and SBP, indicating that these miRNAs may be involved in the immune response in ascites upon SBP. Animal models of HE also show changes in miRNAs in the blood and cerebral cortex [93][94]. In the HE model, ammonia-induced changes in miRNA expression regulate the expression of heme oxygenase 1 (HO-1) and induce astrocyte senescence [95].

    4. Association of the Causes of Liver Cirrhosis and miRNAs

    Direct-acting antivirals are highly effective, but HCV elimination is not a cure for liver disease, especially in patients with advanced fibrosis or cirrhosis. However, miRNAs show promise as a treatment for residual liver fibrosis after antiviral treatment.

    Since the incidence of NAFLD/NASH is expected to continue to increase, there is an urgent need to develop early diagnosis and treatment methods using miRNAs.

    Autoimmune liver diseases include autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC), which are characterized by chronic liver and biliary inflammation. These diseases require persistent treatment, but the underlying causes of these diseases are still unknown. To date, numerous susceptible loci for autoimmune liver diseases in the human leukocyte antigen (HLA) and non-HLA regions have been identified by a genome-wide association studies (GWAS) [96][97]. However, genetic analysis alone is inadequate to identify the cause of autoimmune liver diseases, and environmental factors may be involved in the development of these diseases.

    In recent years, the pathological and diagnostic relevance of miRNAs in autoimmune liver diseases have been reported.

    The entry is from 10.3390/ijms22158139

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