HIF3A gene disruption causes abnormal alveoli structure and early neonatal death.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Apoptosis Regulatory Proteins*/genetics ; Apoptosis Regulatory Proteins*/metabolism ; Pulmonary Alveoli*/metabolism ; Pulmonary Alveoli*/pathology ; Repressor Proteins*/genetics ; Repressor Proteins*/metabolism; Animals ; Female ; Male ; Mice ; Animals, Newborn ; Aryl Hydrocarbon Receptor Nuclear Translocator/genetics ; Aryl Hydrocarbon Receptor Nuclear Translocator/metabolism ; Fatty Acids/metabolism ; Stearoyl-CoA Desaturase/genetics ; Stearoyl-CoA Desaturase/metabolism

Transcriptional response to changes in oxygen concentration is mainly controlled by hypoxia-inducible transcription factors (HIFs). Besides regulation of hypoxia-responsible gene expression, HIF-3α has recently been shown to be involved in lung development and in the metabolic process of fat tissue. However, the precise mechanism for such properties of HIF-3α is still largely unknown. To this end, we generated HIF3A gene-disrupted mice by means of genome editing technology to explore the pleiotropic role of HIF-3α in development and physiology. We obtained adult mice carrying homozygous HIF3A gene mutations with comparable body weight and height to wild-type mice. However, the number of litters and ratio of homozygous mutation carriers born from the mating between homozygous mutant mice was lower than expected due to sporadic deaths on postnatal day 1. HIF3A gene-disrupted mice exhibited abnormal configuration of the lung such as a reduced number of alveoli and thickened alveolar walls. Transcriptome analysis showed, as well as genes associated with lung development, an upregulation of stearoyl-Coenzyme A desaturase 1, a pivotal enzyme for fatty acid metabolism. Analysis of fatty acid composition in the lung employing gas chromatography indicated an elevation in palmitoleic acid and a reduction in oleic acid, suggesting an imbalance in distribution of fatty acid, a constituent of lung surfactant. Accordingly, administration of glucocorticoid injections during pregnancy resulted in a restoration of normal alveolar counts and a decrease in neonatal mortality. In conclusion, these observations provide novel insights into a pivotal role of HIF-3α in the preservation of critically important structure and function of alveoli beyond the regulation of hypoxia-mediated gene expression.
Competing Interests: The authors have declared that no competing interests exist.
(Copyright: © 2024 Kawahata et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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0 (Apoptosis Regulatory Proteins)
138391-32-9 (Aryl Hydrocarbon Receptor Nuclear Translocator)
0 (Fatty Acids)
0 (Hif3a protein, mouse)
0 (Repressor Proteins)
EC 1.14.19.1 (Stearoyl-CoA Desaturase)

Date Created: 20240508 Date Completed: 20240508 Latest Revision: 20240605

20240606

PMC11078382

10.1371/journal.pone.0300751

38717999