Modulation of HIF-2α PAS-B domain contributes to physiological responses

Zhihui Feng, Xuan Zou, Yaomin Chen, Hanzhi Wang, Yingli Duan, Richard K Bruick

Research output: Contribution to journalArticle

1 Citation (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)13240-13245
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number52
DOIs
StatePublished - Dec 26 2018

Fingerprint

High Fat Diet
Adipogenesis
Obesity
Body Weight
Hypoxia-Inducible Factor 1
Obese Mice
Lipogenesis
Physiological Stress
endothelial PAS domain-containing protein 1
Weight Gain
Transcription Factors
Ligands
Lipids
Gene Expression
Glucose
Mutation
Hypoxia
Liver
Proteins
Therapeutics

Keywords

  • Adipogenesis
  • HIF-2α antagonist
  • Hypoxia
  • Nonalcoholic fatty liver disease
  • Obesity

ASJC Scopus subject areas

  • General

Cite this

Modulation of HIF-2α PAS-B domain contributes to physiological responses. / Feng, Zhihui; Zou, Xuan; Chen, Yaomin; Wang, Hanzhi; Duan, Yingli; Bruick, Richard K.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 52, 26.12.2018, p. 13240-13245.

Research output: Contribution to journalArticle

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AU - Bruick, Richard K

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