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000279376 041__ $$aEnglish
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000279376 1001_ $$aBoix, Julia$$b0
000279376 245__ $$aConstitutive HIF-1α Expression in the Epidermis Fuels Proliferation and Is Essential for Effective Barrier Formation.
000279376 260__ $$aAmsterdam$$bElsevier$$c2025
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000279376 520__ $$aEpidermis is one of the most rapidly proliferating tissues in the body with high demands for adenosine triphosphate and cellular building blocks. In this study, we show that to meet these requirements, keratinocytes constitutively express HIF-1α, even in the presence of oxygen levels sufficient for HIF-1α hydroxylation. We previously reported that mice with severe epidermal mitochondrial dysfunction actually showed a hyperproliferative epidermis but rapidly died of systemic lactic acidosis and hypoglycemia, indicating excessive glycolysis. In this work, we interrogated HIF-1α function in glycolysis by its epidermal ablation combined with mitochondrial dysfunction, which resulted in decreased proliferation but even earlier lethality due to a severe barrier defect. Our data demonstrate that HIF-1α is indispensable for maintaining a high aerobic glycolytic flux necessary for supplying energy but also for synthetizing cellular building blocks such as lipids, which are both essential for proliferation as well as barrier formation. HIF-1α is stabilized in keratinocytes in the presence of oxygen by high levels of HIF-1α transcripts, low levels of prolyl-4-hydroxylases (PHD2 and PHD3), and a low cellular a-ketoglutarate/lactate ratio, likely inhibiting prolyl-4-hydroxylase activity. Our data suggest a key role for constitutive HIF-1α expression allowing a Warburg-like metabolism in healthy, highly proliferative keratinocytes, similar to that in tumor cells.
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000279376 650_7 $$2Other$$aEpidermal barrier function
000279376 650_7 $$2Other$$aHIF-1α
000279376 650_7 $$2Other$$aLipid synthesis
000279376 650_7 $$2Other$$aMitochondrial DNA
000279376 650_7 $$2Other$$aSkin homeostasis
000279376 650_7 $$2NLM Chemicals$$aHypoxia-Inducible Factor 1, alpha Subunit
000279376 650_7 $$2NLM Chemicals$$aHif1a protein, mouse
000279376 650_2 $$2MeSH$$aHypoxia-Inducible Factor 1, alpha Subunit: metabolism
000279376 650_2 $$2MeSH$$aHypoxia-Inducible Factor 1, alpha Subunit: genetics
000279376 650_2 $$2MeSH$$aAnimals
000279376 650_2 $$2MeSH$$aCell Proliferation
000279376 650_2 $$2MeSH$$aMice
000279376 650_2 $$2MeSH$$aEpidermis: metabolism
000279376 650_2 $$2MeSH$$aEpidermis: pathology
000279376 650_2 $$2MeSH$$aKeratinocytes: metabolism
000279376 650_2 $$2MeSH$$aKeratinocytes: cytology
000279376 650_2 $$2MeSH$$aGlycolysis
000279376 650_2 $$2MeSH$$aMitochondria: metabolism
000279376 7001_ $$aKnuever, Jana$$b1
000279376 7001_ $$aNiehoff, Nadine$$b2
000279376 7001_ $$aSen, Ayesha$$b3
000279376 7001_ $$aPla-Martin, David$$b4
000279376 7001_ $$aBaris, Olivier R$$b5
000279376 7001_ $$aEtich, Julia$$b6
000279376 7001_ $$aBrachvogel, Bent$$b7
000279376 7001_ $$aKaul, Harshita$$b8
000279376 7001_ $$0P:(DE-2719)2810976$$aIsbrandt, Dirk$$b9$$udzne
000279376 7001_ $$aSoroka, Ekaterina$$b10
000279376 7001_ $$aBazzi, Hisham$$b11
000279376 7001_ $$aWenger, Roland H$$b12
000279376 7001_ $$aGiavalisco, Patrick$$b13
000279376 7001_ $$aWiesner, Rudolf J$$b14
000279376 773__ $$0PERI:(DE-600)2006902-9$$a10.1016/j.jid.2024.09.022$$gVol. 145, no. 7, p. 1683 - 1692.e8$$n7$$p1683 - 1692.e8$$tThe journal of investigative dermatology$$v145$$x0022-202X$$y2025
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