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

Fonseca T.L.; Fernandes G.W.; McAninch E.A.; Bocco B.M.L.C.; Abdalla S.M.; Ribeiro M.O.; Mohacsik P.; Fekete C.; Li D.; Xing X.; Wang T.; Gereben B.; Bianco A.C.

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

Tipo

Artigo

Data de publicação

2015

Periódico

Proceedings of the National Academy of Sciences of the United States of America

Citações (Scopus)

32

Autores

Fonseca T.L.
Fernandes G.W.
McAninch E.A.
Bocco B.M.L.C.
Abdalla S.M.
Ribeiro M.O.
Mohacsik P.
Fekete C.
Li D.
Xing X.
Wang T.
Gereben B.
Bianco A.C.

Resumo

Thyroid 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.

Assuntos Scopus

Analysis of Variance , Animals , Animals, Newborn , Calorimetry, Indirect , Diet, High-Fat , Disease Susceptibility , DNA Methylation , Fatty Liver , Gene Expression Profiling , Gene Expression Regulation, Developmental , Hepatocytes , In Situ Hybridization , Iodide Peroxidase , Mice , Mice, Knockout , Microarray Analysis , Obesity , Triiodothyronine