The Myeloid-Epithelial-Reproductive Tyrosine Kinase (MERTK) rs4374383 Polymorphism Predicts Progression of Liver Fibrosis in Hepatitis C Virus-Infected Patients: A Longitudinal Study

Jiménez-Sousa, María Ángeles; Gómez-Moreno, Ana Zaida; Pineda‐Tenor, Daniel; Brochado-Kith, Óscar; Sánchez-Ruano, Juan José; Artaza-Varasa, Tomas; Gómez-Sanz, Alicia; Fernández‐Rodríguez, Amanda; Resino, Salvador

doi:10.3390/jcm7120473

Cited by 15 publications

(18 citation statements)

References 29 publications

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“…The involvement of MerTK in chronic liver diseases (CLDs) in humans has been explored by a genome-wide association study, which reported a linkage between the non-coding single nucleotide polymorphism (SNP) rs4374383 G > A of the MERTK gene and the risk of liver fibrosis progression in hepatitis C virus (HCV) patients [39]. This observation was confirmed in a longitudinal study, which agreed in identifying the A/A homozygosity as protective for liver fibrosis progression in HCV-related CLD [40]. Similarly, this genotype is protective in non-alcoholic fatty liver disease (NAFLD): A/A homozygosity was associated to a lower rate of significant fibrosis and to a lower liver expression of MerTK.…”

Section: Gas6/tam and Liver Fibrosismentioning

confidence: 99%

Gas6/TAM System: A Key Modulator of the Interplay between Inflammation and Fibrosis

Bellan

Cittone

Tonello

et al. 2019

IJMS

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Fibrosis is the result of an overly abundant deposition of extracellular matrix (ECM) due to the fact of repetitive tissue injuries and/or dysregulation of the repair process. Fibrogenesis is a pathogenetic phenomenon which is involved in different chronic human diseases, accounting for a high burden of morbidity and mortality. Despite being triggered by different causative factors, fibrogenesis follows common pathways, the knowledge of which is, however, still unsatisfactory. This represents a significant limit for the development of effective antifibrotic drugs. In the present paper, we aimed to review the current evidence regarding the potential role played in fibrogenesis by growth arrest-specific 6 (Gas6) and its receptors Tyro3 protein tyrosine kinase (Tyro3), Axl receptor tyrosine kinase (Axl), and Mer tyrosine kinase protooncogene (MerTK) (TAM). Moreover, we aimed to review data about the pathogenetic role of this system in the development of different human diseases characterized by fibrosis. Finally, we aimed to explore the potential implications of these findings in diagnosis and treatment.

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Section: Gas6/tam and Liver Fibrosismentioning

confidence: 99%

Gas6/TAM System: A Key Modulator of the Interplay between Inflammation and Fibrosis

Bellan

Cittone

Tonello

et al. 2019

IJMS

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“…As shown in other diseases, it is likely that patients carrying the GG/GA genotypes have a significantly higher hepatic MERTK expression, although the underlying mechanism is unknown [104]. This in turn will lead to a dysregulation of the phagocytosis of apoptotic cells by macrophages and, more in general, of various inflammatory responses [103, 107–109]. It has to be noted that, although the rs4374383 SNP is not located in a regulatory MERTK region, a high number of SNPs are in high linkage disequilibrium (LD) with it.…”

Section: Gas6/tam Receptorsmentioning

confidence: 99%

Gas6/TAM Signaling Components as Novel Biomarkers of Liver Fibrosis

et al. 2019

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Liver fibrosis consists in the accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells. This is commonly the result of chronic liver injury repair and represents an important health concern. As liver biopsy is burdened with many drawbacks, not surprisingly there is great interest to find new reliable noninvasive methods. Among the many are new potential fibrosis biomarkers under study, some of the most promising represented by the growth arrest-specific gene 6 (Gas6) serum protein and its family of tyrosine kinase receptors, namely, Tyro3, Axl, and MERTK (TAM). Gas6/TAM system (mainly, Axl and MERTK) has in fact recently emerged as an important player in the progression of liver fibrosis. This review is aimed at giving an overall perspective of the roles played by these molecules in major chronic liver diseases. The most promising findings up to date acknowledge that both Gas6 and its receptor serum levels (such as sAxl and, probably, sMERTK) have been shown to potentially allow for easy and accurate measurement of hepatic fibrosis progression, also providing indicative parameters of hepatic dysfunction. Although most of the current scientific evidence is still preliminary and there are no in vivo validation studies on large patient series, it still looks very promising to imagine a possible future prognostic role for these biomarkers in the multidimensional assessment of a liver patient. One may also speculate on a potential role for this system targeting (e.g., with small molecule inhibitors against Axl) as a therapeutic strategy for liver fibrosis management, always bearing in mind that any such therapeutic approach might face toxicity.

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“…We have shown that the TAM receptor tyrosine kinases (RTKs)—Tyro3, Axl, and Mer ( Lemke, 2013 )—are pivotal modulators of tissue macrophage function generally ( Lu & Lemke, 2001 ; Rothlin et al, 2007 ; Zagórska et al, 2014 ; Dransfield et al, 2015 ; Fourgeaud et al, 2016 ; Lemke, 2019 ). Over the last several years, genome-wide association studies have tied polymorphisms in the human MERTK gene—encoding Mer—to altered risk for both (a) fibrosis in patients with chronic hepatitis C virus infection ( Patin et al, 2012 ; Rueger et al, 2014 ; Matsuura & Tanaka, 2016 ; Jimenez-Sousa et al, 2018 ) and (b) NAFLD, in which two intronic single-nucleotide MERTK polymorphisms are protective ( Petta et al, 2016 ; Musso et al, 2017 ). In the progression from NAFLD to nonalcoholic steatohepatitis (NASH), these polymorphisms, which are associated with reduced Mer expression, are linked to reduced risk for liver fibrosis ( Cavalli et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of hepatic physiology and injury by the TAM receptors Axl and Mer

et al. 2020

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Genome-wide association studies have implicated the TAM receptor tyrosine kinase (RTK) Mer in liver disease, yet our understanding of the role that Mer and its related RTKs Tyro3 and Axl play in liver homeostasis and the response to acute injury is limited. We find that Mer and Axl are most prominently expressed in hepatic Kupffer and endothelial cells and that as mice lacking these RTKs age, they develop profound liver disease characterized by apoptotic cell accumulation and immune activation. We further find that Mer is critical to the phagocytosis of apoptotic hepatocytes generated in settings of acute hepatic injury, and that Mer and Axl act in concert to inhibit cytokine production in these settings. In contrast, we find that Axl is uniquely important in mitigating liver damage during acetaminophen intoxication. Although Mer and Axl are protective in acute injury models, we find that Axl exacerbates fibrosis in a model of chronic injury. These divergent effects have important implications for the design and implementation of TAM-directed therapeutics that might target these RTKs in the liver.

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The Myeloid-Epithelial-Reproductive Tyrosine Kinase (MERTK) rs4374383 Polymorphism Predicts Progression of Liver Fibrosis in Hepatitis C Virus-Infected Patients: A Longitudinal Study

Cited by 15 publications

References 29 publications

Gas6/TAM System: A Key Modulator of the Interplay between Inflammation and Fibrosis

Gas6/TAM System: A Key Modulator of the Interplay between Inflammation and Fibrosis

Gas6/TAM Signaling Components as Novel Biomarkers of Liver Fibrosis

Differential regulation of hepatic physiology and injury by the TAM receptors Axl and Mer

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