Activating cardiac E2F1 induces up-regulation of pyruvate dehydrogenase kinase 4 in mice on a short term of high fat feeding

A high fat diet (HFD) induces substantial cardiac metabolic alteration(s), but the initiating molecular events remain unclear. We assessed the early cardiac energy metabolic changes in C57/BJ mice fed a HFD for 10 days. Carbohydrate oxidation was markedly decreased in mice on a HFD, in which up-regulation of pyruvate dehydrogenase kinase 4 (PDK4) was evident. Concurrently, E2F1, a transcription factor controlling PDK4 expression, was activated, as was cyclin D1, an upstream-molecule of E2F1, and eukaryotic initiation factor 4E (eIF4E), a modulator of cyclinD1 translation. Hence, HFD may initiate early cardiac metabolic alterations through the eIF4E/cyclin D1/E2F1/PDK4 axis.

► High fat diet induces an early suppression of cardiac carbohydrate oxidation rates.
► Cardiac E2F1 accumulates in the nucleus following 10 days of a high fat diet.
► Activation of E2F1 is a result of nuclear translocation of cyclinD1 and CDK4.
► Activation of E2F1 up-regulates pyruvate dehydrogenase kinase 4.
► High fat diet activates eukaryotic initiation factors to initiate the cardiac events.