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Identification of oleoylethanolamide as an endogenous ligand for HIF-3α

Author

Listed:
  • Xiaotong Diao

    (Shandong University)

  • Fei Ye

    (Zhejiang Chinese Medical University
    Zhejiang Sci-Tech University)

  • Meina Zhang

    (Shandong University)

  • Xintong Ren

    (Shandong University)

  • Xiaoxu Tian

    (Chinese Academy of Science)

  • Jingping Lu

    (NDM Research Building, University of Oxford)

  • Xiangnan Sun

    (Shandong University)

  • Zeng Hou

    (University of Chinese Academy of Sciences
    Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

  • Xiaoyu Chen

    (Shandong University)

  • Fengwei Li

    (Shandong University)

  • Jingjing Zhuang

    (Shandong University)

  • Hong Ding

    (Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

  • Chao Peng

    (Chinese Academy of Science)

  • Fraydoon Rastinejad

    (NDM Research Building, University of Oxford)

  • Cheng Luo

    (Zhejiang Chinese Medical University
    University of Chinese Academy of Sciences
    Shanghai Institute of Materia Medica, Chinese Academy of Sciences)

  • Dalei Wu

    (Shandong University)

Abstract

Hypoxia-inducible factors (HIFs) are α/β heterodimeric transcription factors modulating cellular responses to the low oxygen condition. Among three HIF-α isoforms, HIF-3α is the least studied to date. Here we show that oleoylethanolamide (OEA), a physiological lipid known to regulate food intake and metabolism, binds selectively to HIF-3α. Through crystallographic analysis of HIF-3 α/β heterodimer in both apo and OEA-bound forms, hydrogen-deuterium exchange mass spectrometry (HDX-MS), molecular dynamics (MD) simulations, and biochemical and cell-based assays, we unveil the molecular mechanism of OEA entry and binding to the PAS-B pocket of HIF-3α, and show that it leads to enhanced heterodimer stability and functional modulation of HIF-3. The identification of HIF-3α as a selective lipid sensor is consistent with recent human genetic findings linking HIF-3α with obesity, and demonstrates that endogenous metabolites can directly interact with HIF-α proteins to modulate their activities, potentially as a regulatory mechanism supplementary to the well-known oxygen-dependent HIF-α hydroxylation.

Suggested Citation

  • Xiaotong Diao & Fei Ye & Meina Zhang & Xintong Ren & Xiaoxu Tian & Jingping Lu & Xiangnan Sun & Zeng Hou & Xiaoyu Chen & Fengwei Li & Jingjing Zhuang & Hong Ding & Chao Peng & Fraydoon Rastinejad & Ch, 2022. "Identification of oleoylethanolamide as an endogenous ligand for HIF-3α," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-30338-z
    DOI: 10.1038/s41467-022-30338-z
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    References listed on IDEAS

    as
    1. Dalei Wu & Nalini Potluri & Jingping Lu & Youngchang Kim & Fraydoon Rastinejad, 2015. "Structural integration in hypoxia-inducible factors," Nature, Nature, vol. 524(7565), pages 303-308, August.
    2. Yuichi Makino & Renhai Cao & Kristian Svensson & Göran Bertilsson & Mikael Asman & Hirotoshi Tanaka & Yihai Cao & Anders Berkenstam & Lorenz Poellinger, 2001. "Inhibitory PAS domain protein is a negative regulator of hypoxia-inducible gene expression," Nature, Nature, vol. 414(6863), pages 550-554, November.
    3. Jin Fu & Silvana Gaetani & Fariba Oveisi & Jesse Lo Verme & Antonia Serrano & Fernando Rodríguez de Fonseca & Anja Rosengarth & Hartmut Luecke & Barbara Di Giacomo & Giorgio Tarzia & Daniele Piomelli, 2003. "Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-α," Nature, Nature, vol. 425(6953), pages 90-93, September.
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