ArticleeLife2023
Hypoxia truncates and constitutively activates the key cholesterol synthesis enzyme squalene monooxygenase.
Article in eLife, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers, 1 of them a synthesis that pooled it.
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Who cites it
9 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Squalene Epoxidase: Its Regulations and Links with Cancers.International journal of molecular sciences · 2024Pooled it
- Low temperature rather than hypoxia drives cholesterol synthesis and oxygen consumption in plateau zokors.iScience · 2026Article
- Targeted regulation of sterol biosynthesis genes according to perturbations in ergosterol biosynthesis in fungi.Journal of advanced research · 2025Article
- Hypoxic Status in COPD and ARDS Patients: Impact on Lipid Signature.International journal of molecular sciences · 2025Article
- Srebf and Runx3 regulate hepatic HMG-CoA reductase and intracellular cholesterol under hypoxia.Cellular and molecular life sciences : CMLS · 2025Article
- Knockouts ofiScience · 2024Article
- Age-related cholesterol and colorectal cancer progression: Validating squalene epoxidase for high-risk cases.Aging cell · 2024Article
- Paradoxes: Cholesterol and Hypoxia in Preeclampsia.Biomolecules · 2024Review
- A HIF independent oxygen-sensitive pathway for controlling cholesterol synthesis.Nature communications · 2023Article
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Authors and funding
8 authors.
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Abstract
Cholesterol synthesis is both energy- and oxygen-intensive, yet relatively little is known of the regulatory effects of hypoxia on pathway enzymes. We previously showed that the rate-limiting and first oxygen-dependent enzyme of the committed cholesterol synthesis pathway, squalene monooxygenase (SM), can undergo partial proteasomal degradation that renders it constitutively active. Here, we show hypoxia is a physiological trigger for this truncation, which occurs through a two-part mechanism: (1) increased targeting of SM to the proteasome via stabilization of the E3 ubiquitin ligase MARCHF6 and (2) accumulation of the SM substrate, squalene, which impedes the complete degradation of SM and liberates its truncated form. This preserves SM activity and downstream pathway flux during hypoxia. These results uncover a feedforward mechanism that allows SM to accommodate fluctuating substrate levels and may contribute to its widely reported oncogenic properties.
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