AMP-ACTIVATED PROTEIN-KINASE INHIBITS THE GLUCOSE-ACTIVATED EXPRESSION OF FATTY-ACID SYNTHASE GENE IN RAT HEPATOCYTES

Although it is now clearly established that a number of genes involved in glucose and lipid metabolism are up-regulated by high glucose conc entrations in both liver and adipose tissue, the signaling pathway ari sing from glucose to the transcriptional machinery is still poorly und erstood. We have analyzed the regulation of fatty acid synthase gene e xpression by glucose in cultured rat hepatocytes. Glucose (25 mM) indu ces an activation of the transcription of the fatty acid synthase gene , and this effect is markedly reduced by incubation of the cells with okadaic acid, an inhibitor of protein phosphatases 1 and 2A. A similar reduction in glucose-activated fatty acid synthase gene expression is obtained by incubation with 5-amino-imidazolecarboxamide riboside, a cell-permeable activator of the AMP-activated protein kinase. Taken to gether, these results indicate that the glucose-induced expression of the fatty acid synthase gene involves a phosphorylation/dephosphorylat ion mechanism and suggest that the AMP-activated protein kinase plays an important role in this process. This is the first evidence that imp licates the AMP-activated protein kinase in the regulation of gene exp ression. AMP-activated protein kinase is the mammalian analog of SNF1, a kinase involved in yeast in the transcriptional regulation of genes by glucose.