Details

Autor(en) / Beteiligte

• Fonseca, Tatiana L.
• Fernandes, Gustavo W.
• McAninch, Elizabeth A.
• Bocco, Barbara M. L. C.
• Abdalla, Sherine M.
• Ribeiro, Miriam O.
• Mohácsik, Petra
• Fekete, Csaba
• Li, Daofeng
• Xing, Xiaoyun
• Wang, Ting
• Gereben, Balázs
• Bianco, Antonio C.

Titel

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

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2015-11, Vol.112 (45), p.14018-14023

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2015

Quelle

Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals

Beschreibungen/Notizen

• 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.