Hypoxia Restrains Lipid Utilization via Protein Kinase A and Adipose Triglyceride Lipase Downregulation through Hypoxia-Inducible Factor

ABSTRACT

Oxygen is a key molecule for efficient energy production in living organisms. Although aerobic organisms have adaptive processes to survive in low-oxygen environments, it is poorly understood how lipolysis, the first step of energy production from stored lipid metabolites, would be modulated during hypoxia. Here, we demonstrate that fasting-induced lipolysis is downregulated by hypoxia through the hypoxia-inducible factor (HIF) signaling pathway. In Caenorhabditis elegans and mammalian adipocytes, hypoxia suppressed protein kinase A (PKA)-stimulated lipolysis, which is evolutionarily well conserved. During hypoxia, the levels of PKA activity and adipose triglyceride lipase (ATGL) protein were downregulated, resulting in attenuated fasting-induced lipolysis. In worms, HIF stabilization was sufficient to moderate the suppressive effect of hypoxia on lipolysis through ATGL and PKA inhibition. These data suggest that HIF activation under hypoxia plays key roles in the suppression of lipolysis, which might preserve energy resources in both C. elegans and mammalian adipocytes.

KEYWORDS:

• ATGL
• HIF
• PKA
• hypoxia
• lipolysis

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ACKNOWLEDGMENTS

We thank Jang-Soo Chun (GIST, Gwangju, South Korea) for adenoviruses and Seung-Jae V. Lee (POSTECH, Pohang, South Korea) for iaIs7[nhr-57p::gfp; unc-119(+)] worms. We also thank Jong-Wan Park (Seoul National University, Seoul, South Korea) for HA-HIF1α, HA-HIF1α ΔNAD, and HA-HIF1α ΔCAD constructs.

This study was supported by the National Research Foundation (NRF) funded by the South Korean government (MISP 2011-0018312, to J. B. Kim) and Basic Science Research Program through the NRF (NRF-2018R1A6A3A11043137, to S. S. Choe). J. S. Han, J. Kong, Y. Ji, and J. Kim were supported by the BK21 program.

We declare that we have no conflicts of interest.

J. S. Han and J. H. Lee designed and conducted the study and wrote the paper. J. Kong, Y. Ji, J. Kim, and S. S. Choe analyzed the experiments and wrote the paper. J. B. Kim supervised the whole study and wrote the paper. All authors reviewed the results and approved the final version of the manuscript.