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

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 (), Cheng Luo () and Dalei Wu ()
Additional contact information
Xiaotong Diao: Shandong University
Fei Ye: Zhejiang Chinese Medical 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
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
Dalei Wu: Shandong University

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30338-z

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