期刊
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
卷 295, 期 4, 页码 E884-E894出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.90438.2008
关键词
fatty acid synthase; triiodothyronine; insulin; triiodothyronine response element; phosphoinositide 3-kinase; extracellular signal regulated kinase-1/2 mitogen-activated protein kinase
资金
- National Sciences and Engineering Research Council of Canada
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 T-3 increase FAS activity, whereas glucagon and saturated and polyunsaturated fatty acids decrease it. In the present study we show that, in liver, T-3 and insulin were able to activate FAS enzymatic activity, mRNA expression, and gene transcription. We localized the T-3 response element (TRE) that mediates the T-3 genomic effect, on the FAS promoter between -741 and -696 bp that mediates the T-3 genomic effect. We show that both T-3 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 T-3 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 T-3 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 T-3 and insulin are probably common to several TREs, as we observed similar effects on a classical DR4 consensus sequence.
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