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Squalene and cholesterol in the balance at the ER membrane.

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Targeting the cholesterol biosynthetic pathway has become a mainstay for the treatment of ischaemic heart disease (1). However, the importance of cholesterol metabolism is not just confined to atherosclerosis, as cholesterol is an essential component of membranes, a precursor for other metabolic pathways, and can fuel tumour growth (2). Understanding how the cholesterol synthetic pathway is regulated is therefore of broad biological interest. Cellular cholesterol abundance is tightly regulated through a combination of uptake through LDL receptors and synthesis, with cholesterol sensing occurring at the ER membrane (3, 4). Cholesterol is detected by ER-resident proteins with sterol sensing domains, which both govern the stability of cholesterol synthetic enzymes and control the release of the SREBP2 transcription factor, regulating the transcription of genes required for cholesterol synthesis and uptake (4). This process is classically exemplified by the sterol sensitive degradation of HMG-CoA reductase (HMGCR), a rate limiting step in cholesterol synthesis, and the target of statins (1) (Figure 1). In PNAS, Yoshioka et al. present findings relating to squalene monooxygenase (SM, also known as squalene epoxidase, SQLE), a further rate limiting step in the cholesterol synthetic pathway, identifying a previously unappreciated role for squalene in regulating SM stability (5) (Figure 1).



Animals, Cholesterol, Endoplasmic Reticulum, Mammals, Squalene, Squalene Monooxygenase

Journal Title

Proc Natl Acad Sci U S A

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Proceedings of the National Academy of Sciences


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Lister Institute of Preventive Medicine (unknown)
Wellcome Trust (215477/Z/19/Z)
Wellcome Trust Lister Institute