|Year : 2023 | Volume
| Issue : 1 | Page : 1-8
Nonalcoholic Fatty Liver Disease and MicroRNAs: A Weighty Consideration
Sanjukta Mishra1, RajLaxmi Sarangi1, Swarnalata Das2, Amresh Mishra3
1 Department of Biochemistry, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, Odisha, India
2 Department of Paediatrics, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, Odisha, India
3 Department of General Surgery, Kalinga Institute of Medical Sciences, KIIT University, Bhubaneswar, Odisha, India
|Date of Submission||07-Nov-2022|
|Date of Decision||28-Dec-2022|
|Date of Acceptance||20-Jan-2023|
|Date of Web Publication||14-Mar-2023|
Department of Biochemistry, Kalinga Institute of Medical Sciences, Campus-5, Bhubaneswar - 751 024, Odisha
Source of Support: None, Conflict of Interest: None
MicroRNAs (miRNAs) are small endogenous, noncoding RNA molecules that regulate the expression of their target genes. The biological functions of miRNAs have been explored considerably. Numerous studies have demonstrated that extracellular miRNA could be implemented as a biomarker for several diseases. Nonalcoholic fatty liver disease (NAFLD) has become one of the leading causes of chronic liver disease worldwide. NAFLD embodies an array of defects extending from elementary steatosis to nonalcoholic steatohepatitis, which might advance to fibrosis, cirrhosis, and even hepatocellular carcinoma, which are closely linked to increased activity hepatic morbidity and mortality. Liver biopsy is acknowledged as the most precise practice for diagnosis and staging of NAFLD. Invasive drawbacks have prompted the likelihood of introducing an alternative noninvasive approach for consideration. Several lines of evidence have revealed that miRNAs are emerging as a potentially useful noninvasive marker for the development and progression of NAFLD. In addition, recent studies have identified that miRNAs take part in lipid metabolism linked to NAFLD and its advancement to severity. This article reviews the contemporary corroboration associating miRNAs and NAFLD and emphasizes the potential role of miRNA as a circulatory biomarker that could alert the growing prevalence of NAFLD. Furthermore, it acknowledges the valuable compendium of information regarding biogenesis and the role of circulating miRNA in lipid metabolism, which is intimately linked to NAFLD.
Keywords: Cirrhosis, liver biopsy, microRNAs, nonalcoholic fatty liver disease
|How to cite this article:|
Mishra S, Sarangi R, Das S, Mishra A. Nonalcoholic Fatty Liver Disease and MicroRNAs: A Weighty Consideration. Biomed Biotechnol Res J 2023;7:1-8
|How to cite this URL:|
Mishra S, Sarangi R, Das S, Mishra A. Nonalcoholic Fatty Liver Disease and MicroRNAs: A Weighty Consideration. Biomed Biotechnol Res J [serial online] 2023 [cited 2023 Mar 28];7:1-8. Available from: https://www.bmbtrj.org/text.asp?2023/7/1/1/371693
| Introduction|| |
Nonalcoholic fatty liver disease (NAFLD) is a prevailing cause of chronic liver disease globally. In a facile perspective, it could be defined as an enhancement in liver fat content (beyond 5%–10% by weight) due to sources other than imprudent alcohol intake. The intricacy of the clinical inception of NAFLD scrupulously involves the dysfunctionality of adipose tissues. Benign fatty liver (steatosis) becomes the earliest histological change to set in. This can advance to a severe condition nonalcoholic steatohepatitis (NASH), from which 25% of patients may progress to cirrhosis. Subsequently, variable degrees of fibrosis may advance to hepatocellular carcinoma (HCC). What's more worrisome is that this type of irreversible liver damage might become the leading cause of end-stage liver disease and liver transplantation in near future. Moreover, NAFLD patients are at increased risk of metabolic syndrome and cardiovascular disease, which correlates with the severity of the disease process. Surveillance, screening, and aggressive management are essential for all patients with NAFLD or who develop complications. At present, there is no simple way to diagnose the disease as well as to know the disease progression to NASH. Liver visualizing imaging technologies such as ultrasound, computed tomography scan, and magnetic resonance imaging scan are widely used in clinical practice to evaluate hepatic steatosis. Notably, it has constraints in confirming a milder form of steatosis. Histological analysis and liver needle biopsy are appraised as the recommended standard for diagnosing and staging NAFLD. Woefully, it is hard to execute due to several drawbacks including inconvenient method, chance of specimen inaccuracy, disparity in result interpretation, and more so chance of other consequential impediments. Thus, the establishment of a definitive circulating biomarker that can alert the incidence and growing prevalence and progression of NAFLD is crucial. Recently, microRNAs (miRNAs) come up with a potential value in the dysregulated metabolism connected with NAFLD diagnosis and prognosis.
miRNAs are a family of naturally occurring short, endogenous, nonprotein-coding RNA molecules within 19–25 nucleotides in length. Since its discovery in the early 1990s, an enormous breakthrough has been established regarding its biogenesis and pathophysiological action, which has revolutionized the field of molecular biology. They are presumed to be indispensable for an extensive range of biological activity comprising cell proliferation, differentiation, development metabolism, stress response, apoptosis, and carcinogenesis by regulating gene expression at the posttranscriptional level either by targeting specific cleavage of homologous messenger RNA or by targeting specific inhibition of protein synthesis., In the past several years, miRNAs have been implicated in various liver functions as well as pathological outcomes of the liver., In addition, recent studies have identified the existence of extracellular/circulating miRNAs in biological fluids such as plasma, serum, cerebrospinal fluid, saliva, and urine, which validate the role of this epigenetic factor in a variety of diseases. The existence of circulating miRNA in NAFLD patients and the noninvasive approach of evaluation may collectively account for its role as a novel diagnostic marker. To date, there is a dearth of published evidence concerning the association between miRNA and NAFLD. Appropriate comprehension might confer prompt identification and establishment of targeted treatment for liver protection. This review comes up with a brief update on miRNA biogenesis and miRNA-mediated gene regulation in NAFLD. It also appraises the contributory role of miRNA in lipid metabolism and insulin resistance as a part of the underlying mechanism to the progression of NAFLD.
| MicroRNA Generation Pathway|| |
The recent advances in molecular technology provide new sight of miRNA, which helps to understand the cellular behavior of these molecules. miRNAs are usually generated through either canonical pathway or noncanonical pathway, out of which the former one is the predominant pathway. Recent advances have led to a more detailed understanding of the canonical pathway of miRNA biogenesis, which comprises transcription, nuclear processing, nuclear export, and cytoplasmic processing, as shown in [Figure 1]. Of note, miRNA can be found between the genes (intergenic miRNA) or in the region of an intron in a gene (intronic miRNA). Evidence accumulated over recent years has indicated that canonical miRNA biogenesis commences with the formation of pri-miRNA transcript by RNA polymerase II (RNA Pol II) within the nucleus from its promoter or promoter of the host genes in which it is contained. Pri-miRNA holds a hairpin structure with variable base pairs in length. Moreover, these are 5' capped and 3'polyadenylated. This process is reported to be regulated by RNA pol II-associated transcription factors and epigenetic regulators. Drosha (initially described in Drosophila), a member of RNAse III endonuclease and its cofactor DGCR8 (DiGeorge Syndrome critical region 8), together known as microprocessor complex is involved in nuclear processing. It intervenes in the first cropping step and cleaves the stem of the hair-spin structure of miRNA to liberate 60–70 nucleotide precursors (pre-miRNA). Subsequently, pre-miRNA with a mini hairpin structure is exported from the nucleus to cytoplasm by exportin-5 (member of karyopherin family). This nucleocytoplasmic shuttle is energy dependent via Ras-related nuclear protein guanosine triphosphate. Finally, cytoplasmic processing occurs by removal of the terminal loop of pre-miRNA by Dicer (RNAse III enzyme) and its cofactor transactivation responsive RNA binding protein. This is considered the final step of mature miRNA duplex formation, after which it is untwisted by RNA helicase enzyme to form mature miRNA strand and passenger strand. Subsequently, mature miRNA gets loaded into Argonaute family protein (AGO 1–4 in humans) in an Adenosine Tri Phosphate (ATP)-dependent manner to form RNA-induced silencing complex and the passenger strand is degraded by cellular machinery. It should be noted that the strand with lower 5' stability is preferentially loaded into AGO which is called the guide strand, which forms the mature miRNA.
In addition to the above predominant canonical pathway, numerous noncanonical pathways can also facilitate miRNA generation. In terms of mechanism, these can be categorized into Drosha/DGCR8-independent pathways or Dicer-independent pathways. Intriguingly, Mirtons are the specific group of miRNAs that can be generated from the introns of messenger RNA (mRNA) during splicing by the Drosha-independent pathway. Similarly, 7-methyl guanosine capped pre-miRNA bypass Drosha cleavage and proceed to the cytoplasm by exportin-1. During the process, the 7-methyl guanosine cap inhibits Argonaute loading. Contrastingly, Dicer-independent miRNAs are stepped by Drosha from shRNA (short hairpin) transcript, which requires Argonaute loading.
| Brief Mechanism of Action of MicroRNAs|| |
miRNAs are thought to be a vital and evolutionarily, conserved, single-stranded molecule. Of note, they are contemplated as the master regulator of gene expression. These are noncoding RNAs with uridine residue at 5'-end, which may act complementary to target mRNAs. Consequently, miRNAs are thought to impede translation and downregulate gene expression by deadenylation of said mRNAs. Moreover, recent studies have also expressed that miRNAs may amend the expression of 20%–30% of mammalian protein-encoding genes at the posttranslational level., In a mechanistic term, “seed site” (2–8 nucleotide from 5' end of miRNA) within 3' Untranslated region (UTR) is reviewed as a miRNA recognition element (MRE). This promotes base pairing between the 3'-segment of miRNA and mRNA target. Thus, it could restrain the translation of mRNA. Based on this molecular basis, it could be summarized that miRNA-induced silencing complex plays part in gene regulation either by degradation of mRNA or blocking mRNA translation. The latest techniques furnish the scope to investigate and explore the advancement of genetic revolution at the miRNA level.
| MicroRNA Dysregulation in Nonalcoholic Fatty Liver Disease|| |
It has been highlighted that circulating miRNAs are connected with both physiological processes and several chronic diseases.,, In the last decade, an increasing number of research articles have underlined the prospective role of miRNA in the pathophysiology of metabolic diseases such as NAFLD and type 2 diabetes mellitus (DM)., Of note, a change in miRNA expression has been demonstrated in NAFLD [Table 1]. In addition, the expression of circulating miRNA may vary based on different stages of NAFLD, which suggests the complex pathogenesis with the involvement of diverse miRNAs. [Figure 2] depicts the diagrammatic presentation of mi-RNA dysregulation in hepatic lipid metabolism at different stages of hepatic steatosis.,
|Table 1: MicroRNA up- and downregulation in nonalcoholic fatty liver disease|
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|Figure 2: miRNA dysregulation at NAFLD progression. miRNA: MicroRNA, NAFLD: Nonalcoholic fatty liver disease|
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As described, several miRNAs have been elucidated to promote the development of NAFLD and thereby delineated as a probable biomarker for NAFLD. In this sense, positioning the correct and on-target miRNA will facilitate the assessment of the progress and intensity of NAFLD.
miRNAs have been extensively studied in liver physiological and pathological function. miRNA122 is considered a major miRNA involved in regulating genes related to lipid metabolism in the liver., Jampoka et al. in their case–control study analyzed the correlation between miRNA 122 and the level of liver inflammation in NAFLD. Not only he could find a significantly high level of the said miRNA in patients, but also he could relate it to the severity of NAFLD. Furthermore, a different work reported that miRNA 122 deletion in mice leads to very low-density lipoprotein alteration in a miR122-dependent manner. This could be considered a fundamental process regulating hepatic lipid metabolism in vivo which could insinuate the commencement and advancement of NAFLD. In this sense, it would be reasonable to mention that alteration in lipogenic gene caused by knockdown of miR122 may unfold other mechanisms to activate the AMP-activated protein kinase (AMPK) pathway, which is characterized by further suppression of lipid assembly. It is noteworthy to mention the association between miR122 and sirtuin 1 (Sirt1), which is a nicotinamide adenine dinucleotide-dependent deacetylase that can regulate gene expression and can alter glucose and lipid metabolism. In this sense, miRNA122 promotes hepatic lipogenesis through inhibiting the AMPK pathway by targeting Sirt1 in NAFLD. These in vitro and in vivo experimental evidence encourage the role of miR122 as a potential noninvasive biomarker of NAFLD. Furthermore, it has also been illustrated by Csak et al. that the inhibition of miR122 promotes and strengthens the fibrogenic and carcinogenic signaling pathway in NAFLD. Another mechanistic study revealed augmentation in miR122 in type 2 DM with NAFLD along with other miRNAs like miR17. Taken together, these findings exemplify the crucial role of miR122 in NAFLD diagnosis and prognosis. Moreover, several data suggest controversial findings owing to different suppression techniques used in distinct models. That apart, feasibility becomes narrow by several areas pertinent to NAFLD such as the presence of comorbid conditions like type 2 DM, which is connected to the heterogeneity of miRNAs. However, future animal and clinical research might recommend enlightenment on the increasing number of miRNAs involved in hepatic lipid metabolism and NAFLD.
It is well known that timely intervention is highly essential to limit the increasing prevalence of NAFLD. As told earlier, miRNA plays a pivotal role in controlling metabolic homeostasis relevant to NAFLD. Importantly, various studies have revealed the importance of miR-29 in the experimental model of NAFLD, NASH, and HCC., Of note, the miR-29 family in humans includes miR-29a, miR-29b, and miR-29c. miRNA profiling reveals diagnostic relevance miR-29a in most hepatic disease simulating experiments. Studies by Roderburg et al. showed the significant role of the aforementioned miRNA in liver fibrosis and cirrhosis. Yet another recent study also highlighted the potential role of miR-29a to predict its contribution in drug-induced NAFLD cases. Mounting lines of evidence have revealed the significance of miR-29a as a diagnostic and prognostic biomarker in NAFLD as well as in HCC through several mechanisms like the nuclear factor-kappa B pathway, SIRT1, and Bcl-2 pathway.,, In this context, a recent observational study outlined the close nexus between cluster of differentiation 36 (CD36), fatty acid metabolism, mitochondrial oxidative stress, and hepatic dysfunction in NAFLD. CD36 is a glycoprotein that acts as fatty acid translocase. Downregulation of CD36 turns down lipid accumulation in Hep G2 (human liver cancer cell line) via AMPK-dependent pathway. It is also revealed that miR-29a gets attached to 3'UTR of CD36 to pause its countenance, thus supporting hepatic lipid dysregulation. Moreover, CD36-mediated oxidized LDL cholesterol activates yes-associated protein 1 oncogenic activity which instigates carcinogenic signaling to NAFLD. On this basis, miR-29a can be a promising target for harmonizing and altering hepatic dysfunction in NAFLD. As mentioned previously, miR-29a is intimately implicated in lipid metabolism, which is highlighted by several studies.,,, These reports are consistent with earlier reports suggesting the predictive role of miR-29a in the diagnosis of NAFLD. In addition to the above-mentioned considerations, it is noteworthy to mention the role of miR-29a as an epigenetic transformer to attenuate hepatic fibrogenesis. Of particular note, DNA methylation may be modulated for monitoring the transformation of latent hepatic stellate cells (HSC) into hepatic myofibroblast. In their study, Yang et al. illustrated the subjugating role of miR-29a on DNA methyltransferase 3b in murine primary HSC. Likewise, histone deacetylase 4 has also been linked to exert a beneficial effect on hepatic fibrosis. Based on experimental animal models and in vitro cellular models of liver fibrosis, miR-29a is reported to mitigate fibrosis in the liver by suppressing HDAC4 activity. Nevertheless, additional studies are needed to further define miR-29a function and mechanism in association with NAFLD as a powerful noninvasive diagnostic tool before implementing into clinical settings.
miR-21 is highly expressed in mammalian cells, which can regulate several biological functions such as proliferation, differentiation, migration, and apoptosis. Functionally, it regulates its target via interaction with 3'UTR binding for posttranscriptional gene silencing. MiR-21 has been considerably explored in several liver diseases such as NAFLD and HCC. Increasing evidence has demonstrated increased expression of miR-2 in experimental models with NAFLD., Depending on different types of animal models, controversial findings were reported about the expression of miR-21. A case–control study by Sun et al. documented a decreased level of miR-21, whereas reverse finding was noted by another study by Yamada et al., The intrinsic mechanism may be dependent on a transcription network that commands lipid metabolism in hepatocytes. The involvement of hydroxymethylglutaryl coenzyme A reductase (HMGCR), sterol regulatory element-binding protein 1, and fatty acid-binding protein 7 supports the effect of miR-21 on lipid metabolism. Furthermore, it is noteworthy to mention the role of miR-21 in causing inflammation and fibrosis through repression of peroxisome proliferator-activated receptor alpha (PPARα) signal pathway, thus contributing to the disease in the experimental model. Discerning outcomes from several studies influence the reliability of miR-21 as a biomarker in establishing NAFLD. Based on the study by Becker et al., NASH patients show upregulated circulatory miR-21expression as compared to healthy controls and NAFLD cases, which might be due to the progression of the disease process and development of fibrosis. While the exact mechanism underlying this is not understood, this can be correlated to PPARα, which supports disease progression in an experimental mouse model. Thus, miR-21 also plays a negative role through suppression of PPARα. Recently, research showed that miR-21 is a confirmed survival factor that is remarkably overexpressed in HCC cases.
miR-34a seems to play an important role in the development of NAFLD. A case–control study by Liu et al. documented the presence of circulating miR-34a in NAFLD/NASH patients. This evidence signifies the role of sirtuin 1, which is considered a target of miRNA.
It could lead to hepatocyte induction via p53 acetylation that might cause an aberrant increase in NAFLD. It is noteworthy to mention here about PPAR alpha signaling pathway, which is essential for the transfer of fatty acid into mitochondria. miR-34a can keep PPARα down, resulting in the increased inflammatory response. Thus, miR-34a silencing can be considered a therapeutic approach for NAFLD. That apart, another recent meta-analysis (including 27 trials and 1775 NAFLD patients) by Shongliang et al. to evaluate the diagnostic value of miR-34a in NAFLD/NASH patients, authenticated the accuracy of the above-mentioned miRNA in patients with body mass index (BMI) more than equal to 30 kg/m2. In this study, the author could find a lower heterogeneity in the case of miR-34a after comparison with other miRNAs. It has also been found by Cai et al. that miR-34a has an exorbitant role in diagnosing NASH compared to NAFLD (sensitivity NAFLD vs. NASH: 0.71 vs. 0.74). Based on the above analysis in terms of clinical utility, miR-34a should be considered a real-time, quantitative, and easy-to-conduct diagnostic index for NAFLD. Definitely research to a greater extent on this point is imperative hereafter.
Apart from the above-discussed miRNAs, there are several other miRNAs that are indicated to be upregulated and overexpressed in the liver. One such example is miR-33 which has a crucial role in fatty liver disease by regulating lipid metabolism. Furthermore, it has been described that SREBPs control miR-33 to direct de novo lipogenesis, triglyceride accumulation, and fatty acid oxidation. Data reflect that miR-33a has an important role in liver steatosis in liver transplant patients. The author mentioned the regression analysis of 116 liver transplant recipients and revealed that miR-33a stands out as a regulator of lipid homeostasis in the liver through SREPPs. Taken together, miR-33a could be used as a forecaster for liver steatosis and inflammation. In vivo and in vitro studies demonstrate that miR-33 overexpression could be considered an important factor for NAFLD development. Therefore, its upregulation should be considered an approach to treating the disease. Another miRNA that seems to be important is miR-192. It has been described that its involvement in lipid synthesis mostly occurs by targeting stearoyl-CoA desaturase. This is consistent with a recent study by Kim et al. showing upregulated expression of miR-192 in NASH patients as compared to NAFLD, which might be due to disease progression by activation of pro-inflammatory macrophages. According to Zoibeiri et al. altered expression of miR-192 can be well correlated with hepatic steatosis during the pathophysiological changes to NASH. That apart, miR-451 has been extensively reviewed for its role in carcinogenesis and tumor progression. It has emerged as a regulator of lipid metabolism. In an experimental high-fat diet-induced NASH mouse study, hepatocyte-treated cells with palmitic acid, and NASH patients, the miR-451 expression is downregulated in the liver. This finding comes up with the perception of the negative impact of miR-451 on proinflammatory cytokines and its role in inflammation through the AMP-activated protein kinase (AMPK)/AKT pathway. Another miRNA that is demonstrated to regulate cholesterol metabolism is miR-185. It is reported to lessen liver steatosis in a high-fat diet mouse model of NAFLD in an overexpressed manner. At a molecular level, it is a crucial regulator of HMGCR and SREBP2 genes which can modify lipid metabolism. Overall, this can be considered for molecular targeting in therapeutics. One more miRNA which can also be reviewed for curative approach in the case of NAFLD is miR-155. Studies have shown that its altered expression could downturn lipid metabolism-related genes. miR-375 could be another option for the treatment of NAFLD. Its downregulation could bring to decreased lipid aggregation through the action of adiponectin receptor 2, interleukin-6, and leptin. MiR-335 predictably can be thought of as a biomarker from the reports of an obese mouse study.
| Current Utility, Limitations, and Future Direction|| |
Nowadays, NAFLD is considered the most common hepatic disorder due to its high prevalence. The association of miRNA expression profile with NAFLD and the stable nature of circulating miRNA in body fluid could represent a real-time signal of how NAFLD develops and progresses. Therefore, the exact miRNA signature validates and denotes the development mechanism. Already stated, this serum biomarker enables early diagnosis and severity evaluation of NAFLD. According to a recent systemic review and meta-analysis, miRNA is a more available biomarker to diagnose NAFLD.,, Collectively, it could reflect the entire course of the disease by modulating abnormal lipid metabolism, inflammation, and apoptosis. Further characterization of mechanical roles of these miRNAs in the pathogenesis of IR and NAFLD may assist in targeted pharmacotherapies.
According to reports, serum miRNA shows a moderate diagnostic accuracy for NAFLD. Whereas, a high accuracy is observed in distinguishing NASH from NAFLD. Therefore, it could be used for the early diagnosis of NASH in clinical practice. This disease deterioration could be one reason for exhibiting better accuracy for NASH diagnosis. The diagnostic efficacy of serum miRNA for NAFLD may depend on BMI. Hence, still, there is a need for a better noninvasive method for the diagnosis of NAFLD and the entire course of the disease.
An increase in knowledge of serum miRNAs could be of great interest for early diagnosis. The mechanism involved in the development and progression of NAFLD and the related outcome is still poorly understood. It has been demonstrated that changes in miRNA expression are well correlated with NAFLD progression.,,,
miRNAs play a crucial role in dysregulated metabolism and inflammatory signaling connected to NAFLD and its progression toward a more severe stage. The knowledge that is based on epigenetic activity, mitochondrial homeostasis, and immunomodulation might enhance the perception of NAFLD. Hence, a therapeutic perspective should concentrate more on regulating epigenetic modification, and suppression of metabolic damage is indispensable. However, it is undoubtedly a challenging task. It is likely that NAFLD will have miRNA-based therapeutics in the near future.
| Conclusion|| |
According to epidemiological studies, the prevalence of NAFLD has increased significantly and it has become a considerable burden among chronic liver diseases. Lipid dysregulation in hepatocytes and overaccumulation of triglycerides in the liver is considered one of the major causes. Proper curative intervention might reduce this public health burden. Liver biopsy cannot be extensively practiced due to patients' unwillingness and several drawbacks. Thus, noninvasive tools are important for the assessment of NAFLD severity, especially for the discrimination of NASH or advanced fibrosis among NAFLD.
Mounting line of evidence endorses the identification steady level of serum miRNA in NAFLD patients. Micro RNA are the noncoding RNAs that regulate posttranscriptional gene silencing. The present review summarizes the specific role of miRNAs in the pathogenesis of NAFLD. However, it is difficult to consider all the miRNAs due to the growing number of miRNAs involved in NAFLD. Based on the understanding of this review, it can be accomplished that miRNA could be contemplated as a noninvasive test for diagnosis and clinical monitoring of disease progression. Nevertheless, diligent research and more randomized controlled studies are obligatory to authenticate the above conclusion.
The authors would like to acknowledge the staff of central library for accessing full text of articles for reading and preparing the manuscript.
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Conflicts of interest
The authors declare that none of the authors have any competing interest.
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