ArticleProceedings of the National Academy of Sciences of the United States of America2018
Modulation of HIF-2α PAS-B domain contributes to physiological responses.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 26 citations in OpenAlex.
- Hepatic HIF2α Modulates Extra-Hepatic Disease-Associated Phenotypes During Metabolic Dysfunction-Associated Steatotic Liver Disease.Comprehensive physiology · 2026Article
- Iron Deficiency Impairs Muscle Stem Cell Proliferation and Skeletal Muscle Regeneration via HIF-2α Stabilization.Journal of cachexia, sarcopenia and muscle · 2025Article
- Hypoxia signaling in the adipose tissue.Journal of molecular cell biology · 2025Review
- PDGFRβ + cell HIF2α is dispensable for white adipose tissue metabolic remodeling and hepatic lipid accumulation in obese mice.Lipids in health and disease · 2024Article
- Sensing the oxygen and temperature in the adipose tissues - who's sensing what?Experimental & molecular medicine · 2023Review
- Hypoxia and Intestinal Inflammation: Common Molecular Mechanisms and Signaling Pathways.International journal of molecular sciences · 2023Review
- A novel HIF-2α targeted inhibitor suppresses hypoxia-induced breast cancer stemness via SOD2-mtROS-PDI/GPR78-UPRCell death and differentiation · 2022Article
- Adipocyte HIF2α functions as a thermostat via PKA Cα regulation in beige adipocytes.Nature communications · 2022Article
- Editorial: Liver Fibrosis and MAFLD: From Molecular Aspects to Novel Pharmacological Strategies.Frontiers in medicine · 2022Article
- Oxygen-sensing mechanisms in development and tissue repair.Development (Cambridge, England) · 2021Review
- Article
- Review
- Hypoxia-Inducible Factors as Key Players in the Pathogenesis of Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatitis.Frontiers in medicine · 2021Review
- Marked and rapid effects of pharmacological HIF-2α antagonism on hypoxic ventilatory control.The Journal of clinical investigation · 2020Article
- miR-3609 Decelerates the Clearance of Sorafenib in Hepatocellular Carcinoma Cells by Targeting EPAS-1 and Reducing the Activation of the Pregnane X Receptor Pathway.OncoTargets and therapy · 2020Article
- Druggability assessment of mammalian Per-Arnt-Sim [PAS] domains using computational approaches.MedChemComm · 2019Article
- The Evolution of Cholesterol-Rich Membrane in Oxygen Adaption: The Respiratory System as a Model.Frontiers in physiology · 2019Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 2 countries.
Funding
Abstract
Hypoxia-inducible factors (HIFs) are transcription factors in the basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) protein family that contain internal hydrophobic cavities within their PAS-A and PAS-B domains. Among HIFs, the HIF-2α PAS-B domain contains a relatively large cavity exploited for the development of specific artificial ligands such as PT2399. Administration of PT2399 could suppress HIF-2α target gene expression without affecting HIF-1 activity in mice under hypoxia conditions. A single mutation (S305M) within the HIF-2α PAS-B domain suppressed HIF-2α activity while conferring resistance to PT2399 in vivo, indicating the vital role of PAS-B domain in HIF-2α hypoxia response. In contrast, the mutant mice did not phenocopy PT2399 intervention in wild-type mice under metabolic stress. Under a high-fat diet (HFD), the mutant mice exert enhanced adipogenesis and obtain larger adipose mass and body weight gain compared to wild type. However, administration of PT2399 along with HFD feeding sufficiently suppressed HFD-induced body weight and adipose mass increase through suppression of adipogenesis and lipogenesis. The accompanying decreased lipid accumulation in the liver and improved glucose tolerance in wild-type mice were not observed in the mutant mice indicating negative regulation of HIF-2α on obesity and a complex role for the PAS-B domain in metabolic regulation. Notably, short-term administration of PT2399 to obese mice decreased adipose mass and improved metabolic condition. These results indicate a regulatory role for HIF-2α in obesity progression and suggest a therapeutic opportunity for PT2399 in obesity and associated metabolic disorders.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.