Methylthioadenosine (MTA) Regulates Liver Cells Proteome and Methylproteome: Implications in Liver Biology and Disease

Bigaud, Emilie; Corrales, Fernando J.

doi:10.1074/mcp.m115.055772

Cited by 35 publications

(21 citation statements)

References 84 publications

(79 reference statements)

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“…Indeed, polyamine catabolism and the production of ROS has been implicated in disease progression (e.g., ischemic reperfusion injury [ 53 ]). Moreover, MTA is a byproduct of S-adenosylmethionine (SAMe) metabolism and, like SAMe, it can act as a primary methyl donor for DNA and protein methylation [ 54 , 55 ]. MTA also has anti-inflammatory and antiproliferative effects [ 54 , 55 ].…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, MTA is a byproduct of S-adenosylmethionine (SAMe) metabolism and, like SAMe, it can act as a primary methyl donor for DNA and protein methylation [ 54 , 55 ]. MTA also has anti-inflammatory and antiproliferative effects [ 54 , 55 ]. Whether polyamine catabolism is involved in the pathophysiology of PSC remains to be explored, but is testable in in vitro and in vivo models of disease.…”

Section: Discussionmentioning

confidence: 99%

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Metabolomic Profiling of Portal Blood and Bile Reveals Metabolic Signatures of Primary Sclerosing Cholangitis

Tietz-Bogert

Kim

Cheung

et al. 2018

IJMS

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Primary sclerosing cholangitis (PSC) is a pathogenically complex, chronic, fibroinflammatory disorder of the bile ducts without known etiology or effective pharmacotherapy. Emerging in vitro and in vivo evidence support fundamental pathophysiologic mechanisms in PSC centered on enterohepatic circulation. To date, no studies have specifically interrogated the chemical footprint of enterohepatic circulation in PSC. Herein, we evaluated the metabolome and lipidome of portal venous blood and bile obtained at the time of liver transplantation in patients with PSC (n = 7) as compared to individuals with noncholestatic, end-stage liver disease (viral, metabolic, etc. (disease control, DC, n = 19)) and to nondisease controls (NC, living donors, n = 12). Global metabolomic and lipidomic profiling was performed on serum derived from portal venous blood (portal serum) and bile using ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and differential mobility spectroscopy-mass spectroscopy (DMS-MS; complex lipid platform). The Mann–Whitney U test was used to identify metabolites that significantly differed between groups. Principal-component analysis (PCA) showed significant separation of both PSC and DC from NC for both portal serum and bile. Metabolite set enrichment analysis of portal serum and bile demonstrated that the liver-disease cohorts (PSC and DC) exhibited similar enrichment in several metabolite categories compared to NC. Interestingly, the bile in PSC was uniquely enriched for dipeptide and polyamine metabolites. Finally, analysis of patient-matched portal serum and biliary metabolome revealed that these biological fluids were more homogeneous in PSC than in DC or NC, suggesting aberrant bile formation and enterohepatic circulation. In summary, PSC and DC patients exhibited alterations in several metabolites in portal serum and bile, while PSC patients exhibited a unique bile metabolome. These specific alterations in PSC are amenable to hypothesis testing and, potentially, therapeutic pharmacologic manipulation.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Metabolomic Profiling of Portal Blood and Bile Reveals Metabolic Signatures of Primary Sclerosing Cholangitis

Tietz-Bogert

Kim

Cheung

et al. 2018

IJMS

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“…In prokaryotic and eukaryotic systems, SAM provides methyl for a variety of protein, DNA, and RNA methylation reactions ( 56 – 61 ). In eukaryotic systems, modulation of methionine metabolism resulting in changes to the cellular MTA and SAM pools can have important consequences on protein, DNA, and RNA methylation ( 62 – 65 ). Therefore, we hypothesize that increased MTA alters methylation to repress the expression or function of critical virulence factors.…”

Section: Discussionmentioning

confidence: 99%

Methylthioadenosine Suppresses Salmonella Virulence

et al. 2018

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“…Further research involving in vivo, using orthotopic GBM models will be necessary to illuminate the functional interplay between MTAP loss and the function of innate immune cells in GBM, and how they collectively influence the adaptive immune characteristics within the tumor. One question raised by this study is what might be the long term impact of the uptake/accumulation of MTA (i.e., via nucleoside transporters) on the epigenomes and epiproteomes of immune cells, an aspect awaiting further investigation, though previous studies indicate this might play an important role (68)(69)(70). Furthermore, we note that the experimental results represent a limited view of the complex time scale of the signaling mechanisms and responses involved.…”

Section: Discussionmentioning

confidence: 86%

MTAP loss correlates with an immunosuppressive profile in GBM and its substrate MTA stimulates alternative macrophage polarization

Yang

Woroniecka

et al. 2018

Preprint

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Glioblastoma (GBM) is a lethal brain cancer known for its potent immunosuppressive effects. Loss of Methylthioadenosine Phosphorylase (MTAP) expression, via gene deletion or epigenetic silencing, is one of the most common alterations in GBM. Here, we show that MTAP loss in GBM cells is correlated with differential expression of immune regulatory genes. In silico analysis of gene expression profiles in GBM samples revealed that low MTAP expression is correlated with reduced proportions of γδT cells, fewer activated CD4 cells, and an increased proportion of M2 macrophages. Using in vitro macrophage models, we found that methylthioadenosine (MTA), the metabolite that accumulates as a result of MTAP loss in GBM cells, promotes the immunosuppressive alternative activation (M2) of macrophages. We show that this effect of MTA on macrophages is independent of IL4/IL3 signaling, is mediated by the adenosine A 2B receptor, and can be pharmacologically reversed. This study suggests that MTAP loss in GBM cells contributes to the immunosuppressive microenvironment, and that MTAP status should be a factor for consideration in understanding GBM immune states and devising immunotherapy-based approaches for treating MTAPnull GBM. laboratory for the LC-MS/MS metabolite analysis, and Heather Hemric, Laura-Leigh Rowlette, and Holly Dressman of the Duke Sequencing and Genomic Technologies Shared Resource for the Affymetrix array processing service.

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Methylthioadenosine (MTA) Regulates Liver Cells Proteome and Methylproteome: Implications in Liver Biology and Disease

Cited by 35 publications

References 84 publications

Metabolomic Profiling of Portal Blood and Bile Reveals Metabolic Signatures of Primary Sclerosing Cholangitis

Metabolomic Profiling of Portal Blood and Bile Reveals Metabolic Signatures of Primary Sclerosing Cholangitis

Methylthioadenosine Suppresses Salmonella Virulence

MTAP loss correlates with an immunosuppressive profile in GBM and its substrate MTA stimulates alternative macrophage polarization

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