The HIF-prolyl hydroxylases have distinct and nonredundant roles in colitis-associated cancer

Kennel, Kilian B; Burmeister, Julius; Radhakrishnan, P.; Giese, Nathalia A.; Giese, Thomas; Salfenmoser, Martin; Gebhardt, Jasper; Strowitzki, Moritz J.; Taylor, Cormac T.; Wielockx, Ben; Schneider, Martin; Harnoss, Jonathan M.

doi:10.1172/jci.insight.153337

Cited by 4 publications

(1 citation statement)

References 62 publications

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“…Studies have indicated that the three PHD family members have different roles in IBD ( Watts and Walmsley, 2019 ; Dvornikova et al, 2023 ). In a DSS-induced colitis animal model, the intestinal inflammation was diminished in Phd1 -deficient ( Phd1 _/_ ) but unaltered in Phd2 -deficient ( Phd2 +/_ ) and Phd3 -deficient ( Phd3 _/_ ) mice, suggesting that loss of Phd1 , but not Phd2 or Phd3 , is protective against DSS-induced colitis ( Tambuwala et al, 2010 ; Kennel et al, 2022 ). We found that deletion of PHD2 in mice intestinal epithelial cells did not lead to spontaneous enteritis or colitis, nor did it confer upon mice higher susceptibility to DSS-induced colitis ( Xie et al, 2018 ).…”

Section: Role Of Phds In Ibdmentioning

confidence: 99%

Hypoxia inducible factor prolyl hydroxylases in inflammatory bowel disease

et al. 2023

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Inflammatory bowel disease (IBD) is a chronic disease that is characterized by intestinal inflammation. Epithelial damage and loss of intestinal barrier function are believed to be the hallmark pathologies of the disease. In IBD, the resident and infiltrating immune cells consume much oxygen, rendering the inflamed intestinal mucosa hypoxic. In hypoxia, the hypoxia-inducible factor (HIF) is induced to cope with the lack of oxygen and protect intestinal barrier. Protein stability of HIF is tightly controlled by prolyl hydroxylases (PHDs). Stabilization of HIF through inhibition of PHDs is appearing as a new strategy of IBD treatment. Studies have shown that PHD-targeting is beneficial to the treatment of IBD. In this Review, we summarize the current understanding of the role of HIF and PHDs in IBD and discuss the therapeutic potential of targeting PHD-HIF pathway for IBD treatment.

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Section: Role Of Phds In Ibdmentioning

confidence: 99%

Hypoxia inducible factor prolyl hydroxylases in inflammatory bowel disease

et al. 2023

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PHD1-3 oxygen sensors in vivo—lessons learned from gene deletions

Jucht,

Scholz

2024

Pflugers Arch - Eur J Physiol

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Oxygen sensors enable cells to adapt to limited oxygen availability (hypoxia), affecting various cellular and tissue responses. Prolyl-4-hydroxylase domain 1–3 (PHD1-3; also called Egln1-3, HIF-P4H 1–3, HIF-PH 1–3) proteins belong to the Fe2+- and 2-oxoglutarate-dependent dioxygenase superfamily and utilise molecular oxygen (O2) alongside 2-oxoglutarate as co-substrate to hydroxylate two proline residues of α subunits of the dimeric hypoxia inducible factor (HIF) transcription factor. PHD1-3-mediated hydroxylation of HIF-α leads to its degradation and inactivation. Recently, various PHD inhibitors (PHI) have entered the clinics for treatment of renal anaemia. Pre-clinical analyses indicate that PHI treatment may also be beneficial in numerous other hypoxia-associated diseases. Nonetheless, the underlying molecular mechanisms of the observed protective effects of PHIs are only partly understood, currently hindering their translation into the clinics. Moreover, the PHI-mediated increase of Epo levels is not beneficial in all hypoxia-associated diseases and PHD-selective inhibition may be advantageous. Here, we summarise the current knowledge about the relevance and function of each of the three PHD isoforms in vivo, based on the deletion or RNA interference-mediated knockdown of each single corresponding gene in rodents. This information is crucial for our understanding of the physiological relevance and function of the PHDs as well as for elucidating their individual impact on hypoxia-associated diseases. Furthermore, this knowledge highlights which diseases may best be targeted by PHD isoform-selective inhibitors in case such pharmacologic substances become available.

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Hypoxia-Induced Signaling in Gut and Liver Pathobiology

Solanki,

Shah

2024

Annu. Rev. Pathol. Mech. Dis.

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Oxygen (O2) is essential for cellular metabolism and biochemical reactions. When the demand for O2 exceeds the supply, hypoxia occurs. Hypoxia-inducible factors (HIFs) are essential to activate adaptive and survival responses following hypoxic stress. In the gut (intestines) and liver, oxygen gradients or physiologic hypoxia are necessary to maintain normal homeostasis. While physiologic hypoxia is beneficial and aids in normal functions, pathological hypoxia is harmful as it exacerbates inflammatory responses and tissue dysfunction and is a hallmark of many cancers. In this review, we discuss the role of gut and liver hypoxia-induced signaling, primarily focusing on HIFs, in the physiology and pathobiology of gut and liver diseases. Additionally, we examine the function of HIFs in various cell types during gut and liver diseases, beyond intestinal epithelial and hepatocyte HIFs. This review highlights the importance of understanding hypoxia-induced signaling in the pathogenesis of gut and liver diseases and emphasizes the potential of HIFs as therapeutic targets. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 19 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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The HIF-prolyl hydroxylases have distinct and nonredundant roles in colitis-associated cancer

Cited by 4 publications

References 62 publications

Hypoxia inducible factor prolyl hydroxylases in inflammatory bowel disease

Hypoxia inducible factor prolyl hydroxylases in inflammatory bowel disease

PHD1-3 oxygen sensors in vivo—lessons learned from gene deletions

Hypoxia-Induced Signaling in Gut and Liver Pathobiology

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