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dc.contributor.author
Pirola, Carlos José
dc.contributor.author
Scian, Romina
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Fernández Gianotti, Tomás
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Dopazo, Hernán Javier
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Rohr, Cristian Oscar
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San Martino, Julio
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Castaño, Gustavo Osvaldo
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Sookoian, Silvia Cristina
dc.date.available
2018-03-16T16:12:48Z
dc.date.issued
2015-09
dc.identifier.citation
Pirola, Carlos José; Scian, Romina; Fernández Gianotti, Tomás; Dopazo, Hernán Javier; Rohr, Cristian Oscar; et al.; Epigenetic Modifications in the Biology of Nonalcoholic Fatty Liver Disease: The Role of DNA-Hydroxymethylation and TET Proteins; Lippincott Williams; Medicine; 94; 36; 9-2015; 1480-1490
dc.identifier.issn
0025-7974
dc.identifier.uri
http://hdl.handle.net/11336/39085
dc.description.abstract
The 5-Hydroxymethylcytosine (5-hmC) is an epigenetic modification whose role in the pathogenesis of metabolic-related complex diseases remains unexplored; 5-hmC appears to be prevalent in the mitochondrial genome. The Ten-Eleven-Translocation (TET) family of proteins is responsible for catalyzing the conversion of 5-methylcytosine to 5-hmC. We hypothesized that epigenetic editing by 5-hmC might be a novel mechanism through which nonalcoholic fatty liver disease (NAFLD)-associated molecular traits could be explained. Hence, we performed an observational study to explore global levels of 5-hmC in fresh liver samples of patients with NAFLD and controls (n = 90) using an enzyme-linked-immunosorbent serologic assay and immunohistochemistry. We also screened for genetic variation in TET 1–3 loci by next generation sequencing to explore its contribution to the disease biology. The study was conducted in 2 stages (discovery and replication) and included 476 participants. We observed that the amount of 5-hmC in the liver of both NAFLD patients and controls was relatively low (up to 0.1%); a significant association was found with liver mitochondrial DNA copy number (R = 0.50, P = 0.000382) and PPARGC1A-mRNA levels (R = −0.57, P = 0.04). We did not observe any significant difference in the 5-hmC nuclear immunostaining score between NAFLD patients and controls; nevertheless, we found that patients with NAFLD (0.4 ± 0.5) had significantly lower nonnuclear-5-hmC staining compared with controls (1.8 ± 0.8), means ± standard deviation, P = 0.028. The missense p.Ile1123Met variant (TET1-rs3998860) was significantly associated with serum levels of caspase-generated CK-18 fragment-cell death biomarker in the discovery and replication stage, and the disease severity (odds ratio: 1.47, 95% confidence interval: 1.10–1.97; P = 0.005). The p.Ile1762Val substitution (TET2-rs2454206) was associated with liver PPARGC1A-methylation and transcriptional levels, and Type 2 diabetes. Our results suggest that 5-hmC might be involved in the pathogenesis of NAFLD by regulating liver mitochondrial biogenesis and PPARGC1A expression. Genetic diversity at TET loci suggests an “epigenetic” regulation of programmed liver-cell death and a TET-mediated fine-tuning of the liver PPARGC1A-transcriptional program.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Lippincott Williams
dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
Nafld
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5hydroxymethyl-Citosine
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Epigenetics
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Tets
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Genetics
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Inmunología
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Medicina Básica
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CIENCIAS MÉDICAS Y DE LA SALUD
dc.title
Epigenetic Modifications in the Biology of Nonalcoholic Fatty Liver Disease: The Role of DNA-Hydroxymethylation and TET Proteins
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2018-03-13T13:55:59Z
dc.journal.volume
94
dc.journal.number
36
dc.journal.pagination
1480-1490
dc.journal.pais
Estados Unidos
dc.journal.ciudad
Filadelfia
dc.description.fil
Fil: Pirola, Carlos José. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
dc.description.fil
Fil: Scian, Romina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
dc.description.fil
Fil: Fernández Gianotti, Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
dc.description.fil
Fil: Dopazo, Hernán Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; Argentina
dc.description.fil
Fil: Rohr, Cristian Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Ecología, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Ecología, Genética y Evolución de Buenos Aires; Argentina
dc.description.fil
Fil: San Martino, Julio. Provincia de Buenos Aires. Ministerio de Salud. Hospital Municipal Dr. Diego Thompson; Argentina
dc.description.fil
Fil: Castaño, Gustavo Osvaldo. Gobierno de la Ciudad de Buenos Aires. Hospital "Dr. Abel Zubizarreta"; Argentina
dc.description.fil
Fil: Sookoian, Silvia Cristina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina
dc.journal.title
Medicine
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1097/MD.0000000000001480
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://journals.lww.com/md-journal/Fulltext/2015/09020/Epigenetic_Modifications_in_the_Biology_of.24.aspx


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