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HIF1α is a direct regulator of steroidogenesis in the adrenal gland

Authors
  • Watts, Deepika1
  • Stein, Johanna1
  • Meneses, Ana1
  • Bechmann, Nicole1, 2, 3
  • Neuwirth, Ales1
  • Kaden, Denise1
  • Krüger, Anja1
  • Sinha, Anupam1
  • Alexaki, Vasileia Ismini1
  • Luis Gustavo Perez-Rivas,4
  • Kircher, Stefan5
  • Martinez, Antoine6
  • Theodoropoulou, Marily4
  • Eisenhofer, Graeme1
  • Peitzsch, Mirko1
  • El-Armouche, Ali1
  • Chavakis, Triantafyllos1
  • Wielockx, Ben1
  • 1 Technische Universität Dresden,
  • 2 German Institute of Human Nutrition Potsdam-Rehbruecke,
  • 3 German Center for Diabetes Research (DZD),
  • 4 Ludwig-Maximilians-Universität (LMU) München,
  • 5 University Würzburg,
  • 6 Centre National de la Recherche Scientifique (CNRS), INSERM, Université Clermont-Auvergne,
Type
Published Article
Journal
Cellular and Molecular Life Sciences
Publisher
Springer-Verlag
Publication Date
Jan 19, 2021
Volume
78
Issue
7
Pages
3577–3590
Identifiers
DOI: 10.1007/s00018-020-03750-1
PMID: 33464382
PMCID: PMC8038963
Source
PubMed Central
Keywords
Disciplines
  • Original Article
License
Unknown

Abstract

Endogenous steroid hormones, especially glucocorticoids and mineralocorticoids, derive from the adrenal cortex, and drastic or sustained changes in their circulatory levels affect multiple organ systems. Although hypoxia signaling in steroidogenesis has been suggested, knowledge on the true impact of the HIFs (Hypoxia-Inducible Factors) in the adrenocortical cells of vertebrates is scant. By creating a unique set of transgenic mouse lines, we reveal a prominent role for HIF1α in the synthesis of virtually all steroids in vivo. Specifically, mice deficient in HIF1α in adrenocortical cells displayed enhanced levels of enzymes responsible for steroidogenesis and a cognate increase in circulatory steroid levels. These changes resulted in cytokine alterations and changes in the profile of circulatory mature hematopoietic cells. Conversely, HIF1α overexpression resulted in the opposite phenotype of insufficient steroid production due to impaired transcription of necessary enzymes. Based on these results, we propose HIF1α to be a vital regulator of steroidogenesis as its modulation in adrenocortical cells dramatically impacts hormone synthesis with systemic consequences. In addition, these mice can have potential clinical significances as they may serve as essential tools to understand the pathophysiology of hormone modulations in a number of diseases associated with metabolic syndrome, auto-immunity or even cancer. Supplementary Information The online version contains supplementary material available at 10.1007/s00018-020-03750-1.

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