ArticleMolecular metabolism2023
Proline hydroxylase 2 (PHD2) promotes brown adipose thermogenesis by enhancing the hydroxylation of UCP1.
Article in Molecular metabolism, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 14 citations in OpenAlex.
- Hydroxylation of HPPD facilitates its PUB11-mediated ubiquitination and degradation in response to oxidative stress in Arabidopsis.Plant communications · 2025Article
- MitoMAMMAL: a genome scale model of mammalian mitochondria predicts cardiac and BAT metabolism.Bioinformatics advances · 2025Article
- Gallic acid prevents obesity in mice on a high-fat diet via the gut microbiota-adipose tissue axis.Current research in food science · 2025Article
- PHD1-3 oxygen sensors in vivo-lessons learned from gene deletions.Pflugers Archiv : European journal of physiology · 2024Review
- The P124A mutation of SRP14 alters its migration on SDS-PAGE without impacting its function.Acta biochimica et biophysica Sinica · 2024Article
- Lactate-induced protein lactylation in cancer: functions, biomarkers and immunotherapy strategies.Frontiers in immunology · 2024Review
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Authors and funding
26 authors at 1 institution in 1 country.
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Abstract
objectiveBrown adipose tissue (BAT) plays a crucial role in regulating non-shivering thermogenesis under cold exposure. Proline hydroxylases (PHDs) were found to be involved in adipocyte differentiation and lipid deposition. However, the effects of PHDs on regulatory mechanisms of BAT thermogenesis are not fully understood.
methodsWe detected the expression of PHDs in different adipose tissues by using immunoblotting and real-time PCR. Further, immunoblotting, real-time PCR, and immunostaining were performed to determine the correlation between proline hydroxylase 2 (PHD2) and UCP1 expression. Inhibitor of PHDs and PHD2-sgRNA viruses were used to construct the PHD2-deficiency model in vivo and in vitro to investigate the impacts of PHD2 on BAT thermogenesis. Afterward, the interaction between UCP1 and PHD2 and the hydroxylation modification level of UCP1 were verified by Co-IP assays and immunoblotting. Finally, the effect of specific proline hydroxylation on the expression/activity of UCP1 was further confirmed by site-directed mutation of UCP1 and mass spectrometry analysis.
resultsPHD2, but not PHD1 and PHD3, was highly enriched in BAT, colocalized, and positively correlated with UCP1. Inhibition or knockdown of PHD2 significantly suppressed BAT thermogenesis under cold exposure and aggravated obesity of mice fed HFD. Mechanistically, mitochondrial PHD2 bound to UCP1 and regulated the hydroxylation level of UCP1, which was enhanced by thermogenic activation and attenuated by PHD2 knockdown. Furthermore, PHD2-dependent hydroxylation of UCP1 promoted the expression and stability of UCP1 protein. Mutation of the specific prolines (Pro-33, 133, and 232) in UCP1 significantly mitigated the PHD2-elevated UCP1 hydroxylation level and reversed the PHD2-increased UCP1 stability.
conclusionsThis study suggested an important role for PHD2 in BAT thermogenesis regulation by enhancing the hydroxylation of UCP1.
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