Doctoral Thesis
DOI
https://doi.org/10.11606/T.42.2015.tde-01062015-162513
Document
Author
Full name
Lucas Carminatti Pantaleão
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2015
Supervisor
Committee
Silva, Silvana Auxiliadora Bordin da (President)
Geraldo, Murilo Vieira
Sawaya, Ana Lydia
Torsoni, Adriana Souza
Velloso, Lício Augusto
Title in Portuguese
Reprogramação fenotípica por excesso de glicocorticoides: participação de micro-RNAs no desenvolvimento hepático e possíveis repercussões na vida adulta.
Keywords in Portuguese
Desenvolvimento
Dexametasona
Fígado
MiR-322-5P/424-5P
Neonatos
Proliferação
Abstract in Portuguese
Avaliamos o efeito da RCIU induzida por glicocorticoides sobre a regulação da expressão de miRNAs no fígado de ratos albinos. Animais expostos intrauterinamente à dexametasona apresentaram menor peso ao nascer, fígados relativamente menores dos que os observados em animais controle e menores concentrações hepáticas de PCNA. Em longo prazo, os animais DEX desenvolveram distúrbios metabólicos caracterizados por intolerância à glicose e maior potencial gliconeogênico no desmame e na vida adulta. Ao avaliarmos o perfil de miRNAs no fígado, detectamos aumento da expressão de todo o cluster do miR-322 no período perinatal, com menor conteúdo de alvos preditos desses transcritos (AKT3, CCND1 e INSR). A superexposição ao miR-322-5P reduz a taxa de proliferação em linhagens celulares de hepatocarcinoma e a expressão dos alvos observados no fígado dos animais estudados. Propomos um link entre a expressão aberrante do miR-322-5P e a reduzida taxa de proliferação detectada no tecido hepático em desenvolvimento, contribuindo para o estabelecimento do fenótipo em longo prazo.
Title in English
Programming by glucocorticoid excess: actions of miRNAs on hepatic development and outcome.
Keywords in English
Development
Dexamethasone
Liver
MiR-322-5P/424-5P
Newborn rats
Proliferation
Abstract in English
We evaluated the effects of glucocorticoid induced IUGR on the expression of miRNA on Wistar rat livers. Dexamethasone (DEX) treated animals were lighter and had smaller liver weight:body weight ratio when compared to control animals. Furthermore, liver PCNA expression was downregulated, sugesting a reduction on cell proliferation rate. In the long term, DEX animals developed metabolic disturbances such as glucose intolerance e increased gluconeogenesis rate in a fast state. The analysis of miRNA expression profile showed an upregulation of miR-322 cluster on perinatal period, together with a downregulation of three putative targets: Akt3, CCND1 and INSR. Later, we used in vitro studies to prove that overexpression of miR-322-5P arrests cell cycle and impairs proliferation of HEPG2 cells as well as it downregulates the predicted targets. Based on this data, we suggest a link between overexpression of miR-322-5P and impaired proliferation rate on the developing liver, which affects the phenotype in the long term.
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Publishing Date
2015-06-03