Hepatic regulation of fatty acid synthase by insulin and T3: evidence for T3genomic and nongenomic actions

Abstract

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 T3increase FAS activity, whereas glucagon and saturated and polyunsaturated fatty acids decrease it. In the present study we show that, in liver, T3and insulin were able to activate FAS enzymatic activity, mRNA expression, and gene transcription. We localized the T3response element (TRE) that mediates the T3genomic effect, on the FAS promoter between −741 and −696 bp that mediates the T3genomic effect. We show that both T3and 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 T3and/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 T3is 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 T3and insulin are probably common to several TREs, as we observed similar effects on a classical DR4 consensus sequence.