Perinatal deiodinase 2 expression in hepatocytes defines epigenetic susceptibility to liver steatosis and obesity

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dc.contributor.authorFonseca T.L.
dc.contributor.authorFernandes G.W.
dc.contributor.authorMcAninch E.A.
dc.contributor.authorBocco B.M.L.C.
dc.contributor.authorAbdalla S.M.
dc.contributor.authorRibeiro M.O.
dc.contributor.authorMohacsik P.
dc.contributor.authorFekete C.
dc.contributor.authorLi D.
dc.contributor.authorXing X.
dc.contributor.authorWang T.
dc.contributor.authorGereben B.
dc.contributor.authorBianco A.C.
dc.date.accessioned2024-03-13T00:55:58Z
dc.date.available2024-03-13T00:55:58Z
dc.date.issued2015
dc.description.abstractThyroid hormone binds to nuclear receptors and regulates gene transcription. Here we report that in mice, at around the first day of life, there is a transient surge in hepatocyte type 2 deiodinase (D2) that activates the prohormone thyroxine to the active hormone triiodothyronine, modifying the expression of 165 genes involved in broad aspects of hepatocyte function, including lipid metabolism. Hepatocyte-specific D2 inactivation (ALB-D2KO) is followed by a delay in neonatal expression of key lipid-related genes and a persistent reduction in peroxisome proliferator-Activated receptor-γ expression. Notably, the absence of a neonatal D2 peak significantly modifies the baseline and long-Term hepatic transcriptional response to a high-fat diet (HFD). Overall, changes in the expression of approximately 400 genes represent the HFD response in control animals toward the synthesis of fatty acids and triglycerides, whereas in ALB-D2KO animals, the response is limited to a very different set of only approximately 200 genes associated with reverse cholesterol transport and lipase activity. A whole genome methylation profile coupled to multiple analytical platforms indicate that 10-20% of these differences can be related to the presence of differentially methylated local regions mapped to sites of active/suppressed chromatin, thus qualifying as epigenetic modifications occurring as a result of neonatal D2 inactivation. The resulting phenotype of the adult ALB-D2KO mouse is dramatic, with greatly reduced susceptibility to diet-induced steatosis, hypertriglyceridemia, and obesity.
dc.description.firstpage14018
dc.description.issuenumber45
dc.description.lastpage14023
dc.description.volume112
dc.identifier.doi10.1073/pnas.1508943112
dc.identifier.issn1091-6490
dc.identifier.urihttps://dspace.mackenzie.br/handle/10899/36129
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of America
dc.rightsAcesso Aberto
dc.titlePerinatal deiodinase 2 expression in hepatocytes defines epigenetic susceptibility to liver steatosis and obesity
dc.typeArtigo
local.scopus.citations32
local.scopus.eid2-s2.0-84946771655
local.scopus.subjectAnalysis of Variance
local.scopus.subjectAnimals
local.scopus.subjectAnimals, Newborn
local.scopus.subjectCalorimetry, Indirect
local.scopus.subjectDiet, High-Fat
local.scopus.subjectDisease Susceptibility
local.scopus.subjectDNA Methylation
local.scopus.subjectFatty Liver
local.scopus.subjectGene Expression Profiling
local.scopus.subjectGene Expression Regulation, Developmental
local.scopus.subjectHepatocytes
local.scopus.subjectIn Situ Hybridization
local.scopus.subjectIodide Peroxidase
local.scopus.subjectMice
local.scopus.subjectMice, Knockout
local.scopus.subjectMicroarray Analysis
local.scopus.subjectObesity
local.scopus.subjectTriiodothyronine
local.scopus.updated2024-05-01
local.scopus.urlhttps://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=84946771655&origin=inward
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