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A HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis.

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Pauzaite, Tekle 
Arnaiz, Esther 
Ortmann, Brian M 
West, James A 


Cholesterol biosynthesis is a highly regulated, oxygen-dependent pathway, vital for cell membrane integrity and growth. In fungi, the dependency on oxygen for sterol production has resulted in a shared transcriptional response, resembling prolyl hydroxylation of Hypoxia Inducible Factors (HIFs) in metazoans. Whether an analogous metazoan pathway exists is unknown. Here, we identify Sterol Regulatory Element Binding Protein 2 (SREBP2), the key transcription factor driving sterol production in mammals, as an oxygen-sensitive regulator of cholesterol synthesis. SREBP2 degradation in hypoxia overrides the normal sterol-sensing response, and is HIF independent. We identify MARCHF6, through its NADPH-mediated activation in hypoxia, as the main ubiquitin ligase controlling SREBP2 stability. Hypoxia-mediated degradation of SREBP2 protects cells from statin-induced cell death by forcing cells to rely on exogenous cholesterol uptake, explaining why many solid organ tumours become auxotrophic for cholesterol. Our findings therefore uncover an oxygen-sensitive pathway for governing cholesterol synthesis through regulated SREBP2-dependent protein degradation.



3101 Biochemistry and Cell Biology, 31 Biological Sciences, Genetics, 1 Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Animals, Humans, Oxygen, Transcription Factors, Hypoxia, Cholesterol, Sterols, Sterol Regulatory Element Binding Protein 2, Hypoxia-Inducible Factor 1, alpha Subunit, Mammals

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Nat Commun

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Springer Science and Business Media LLC
Wellcome Trust (215477/Z/19/Z)
Lister Institute of Preventive Medicine (unknown)
Wellcome Trust (210688/Z/18/Z)
MRC (MR/V011561/1)
Wellcome Trust (222497/Z/21/Z)
Lister Institute of Preventative Medicine National Institutes of Health (NIH) grant Pfizer ITEN Award