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Metabolic disorders

New avenue to AMPK activation

Nature Reviews Drug Discovery volume 11, pages 830–831 (2012)Cite this article

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AMPK is a ternary complex composed of a catalytic α-subunit and regulatory β- and γ-subunits. Activation of AMPK occurs via several independent mechanisms, one of which involves Thr172 phosphorylation of AMPKα by various kinases, including liver kinase B1 (LKB1). Although the regulation of LKB1 function is poorly understood, various nuclear receptors have been shown to affect the activity of this kinase. With this in mind, the authors set out to investigate the potential involvement of nuclear hormone receptor 77 (NUR77; also known as NR4A1; a nuclear receptor shown to have important roles in metabolism and energy balance) in the control of LKB1-mediated AMPK activation, with the aim of identifying novel strategies to therapeutically target AMPK.

First, they found that small interfering RNA (siRNA)-mediated depletion of NUR77 in cells increased Thr172 phosphorylation and activation of AMPK, whereas overexpression of NUR77 had the opposite effect. Similar results were observed in mice, in which an inverse relationship between AMPKα phosphorylation and NUR77 expression was seen. Interestingly, when NUR77 was overexpressed in cells deficient in LKB1, AMPKα phosphorylation was not suppressed. However, introduction of LKB1 into these cells increased AMPKα phosphorylation, an effect that was repressed upon co-transfection with NUR77. Further studies revealed that the ligand binding domain (LBD) of NUR77 was interacting directly with LKB1, sequestering LKB1 in the nucleus where it was unable to phosphorylate AMPK.

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ORIGINAL RESEARCH PAPER

  1. Zhan, Y.-Y. et al. The orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPK. Nature Chem. Biol. 16 Sep 2012 (doi:10.1038/nchembio.1069)

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  1. Sarah Crunkhorn
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Crunkhorn, S. New avenue to AMPK activation. Nat Rev Drug Discov 11, 830–831 (2012). https://doi.org/10.1038/nrd3872

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