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This Article Full Text Full Text (PDF) All Versions of this Article: 295/4/E884    most recent 90438.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Radenne, A. Articles by Mounier, C. PubMed PubMed Citation Articles by Radenne, A. Articles by Mounier, C.

Hepatic regulation of fatty acid synthase by insulin and T₃: evidence for T₃ genomic and nongenomic actions

Département des Sciences Biologiques, Centre de recherche BioMed, Université du Québec, Montreal, Quebec, Canada

Submitted 13 May 2008 ; accepted in final form 18 July 2008

Fatty acid synthase (FAS) is a key enzyme of hepatic lipogenesis responsible for the synthesis of long-chain saturated fatty acids. This enzyme is mainly regulated at the transcriptional level by nutrients and hormones. In particular, glucose, insulin, and T₃ increase FAS activity, whereas glucagon and saturated and polyunsaturated fatty acids decrease it. In the present study we show that, in liver, T₃ and insulin were able to activate FAS enzymatic activity, mRNA expression, and gene transcription. We localized the T₃ response element (TRE) that mediates the T₃ genomic effect, on the FAS promoter between –741 and –696 bp that mediates the T₃ genomic effect. We show that both T₃ and insulin regulate FAS transcription via this sequence. The TRE binds a TR/RXR heterodimer even in the absence of hormone, and this binding is increased in response to T₃ and/or insulin treatment. The use of H7, a serine/threonine kinase inhibitor, reveals that a phosphorylation mechanism is implicated in the transcriptional regulation of FAS in response to both hormones. Specifically, we show that T₃ is able to modulate FAS transcription via a nongenomic action targeting the TRE through the activation of a PI 3-kinase-ERK1/2-MAPK-dependent pathway. Insulin also targets the TRE sequence, probably via the activation of two parallel pathways: Ras/ERK1/2 MAPK and PI 3-kinase/Akt. Finally, our data suggest that the nongenomic actions of T₃ and insulin are probably common to several TREs, as we observed similar effects on a classical DR4 consensus sequence.

fatty acid synthase; triiodothyronine; insulin; triiodothyronine response element; phosphoinositide 3-kinase; extracellular signal-regulated kinase-1/2 mitogen-activated protein kinase