Hepatic regulation of fatty acid synthase by insulin and T_3: evidence for T_3 genomic and nongenomic actions

摘要

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 phos-phorylation 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-ERKl/2-MAPK-dependent pathway. Insulin also targets the TRE sequence, probably via the activation of two parallel pathways: Ras/ERKl/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