AMP-activated protein kinase and its downstream transcriptional pathways

Abstract

The AMP-activated protein kinase (AMPK) is a key regulator of catabolic versus anabolic processes. Its properties as an energy sensor allow it to couple the energy status of the cell to the metabolic environment. These adaptations not only take place through the acute modulation of key metabolic enzymes via direct phosphorylation, but also through a slower transcriptional adaptative response. The question of how AMPK regulates the expression of a number of gene sets, such as those related to mitochondrial biogenesis, energy production and oxidative protection, is only beginning to be elucidated, and still many questions remain to be answered. In this review we will try to integrate our current knowledge on how AMPK regulates transcription in muscle and liver, which will serve as examples to illustrate the major advances in the field and the key challenges ahead.

Fig. 1

AMPK regulates muscle transcriptional events through distinct mechanisms. Activation of AMPK upon energy stress increases mitochondrial and oxidative metabolism gene expression through direct and indirect events. SIRT1 is an example of a transcriptional regulator whose activity is increased by AMPK through an indirect mechanism (i.e., by promoting an increase in NAD+). Direct phosphorylation of AMPK occurs, for example, on the coactivator PGC-1α and the FOXO family of transcription factors, whose subsequent deacetylation by SIRT1 increases their activity. The activation of PGC-1α leads to the coactivation of a myriad of transcription factors, such as PPARα, PPARβ/δ and CREB, which is also phosphorylated and activated by AMPK. Phosphorylation of GEF promotes co-translocation with MEF2 to the nucleus. Furthermore, phosphorylation of HDAC5 by AMPK relieves the inhibition on the MEF2/GEF complex and allows transcriptional activation. These examples illustrate the mechanisms involved when AMPK directly and indirectly regulates transcriptional events

Fig. 2

AMPK anti-gluconeogenic effects are achieved through a combination of different transcriptional mechanisms. A constellation of transcriptional regulators modulates gluconeogenesis, such as CRTC2, FOXO, ChREBP, HNF4α and PGC-1α. AMPK impacts on them all through different strategies. For example, AMPK phosphorylates CRTC2 and promotes its nuclear exclusion, disassembling the coactivator from CREB on gluconeogenic genes (GG). AMPK can also directly phosphorylate transcription factors (TFs), as happens with HNF4α and ChREBP, promoting their nuclear exclusion and/or degradation. In the case of PGC-1α, phosphorylation by AMPK might direct its coactivating actions towards non-gluconeogenic gene (NGG) regulation. Similarly, phosphorylation of FOXOs by AMPK may drive its action from gluconeogenic genes towards other gene sets, such as oxidative protection