Squalene monooxygenase: a journey to the heart of cholesterol synthesis

Chua, Ngee Kiat; Coates, Hudson W.; Brown, Andrew

doi:10.1016/j.plipres.2020.101033

Cited by 64 publications

(54 citation statements)

References 301 publications

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“… 10,41,86 Small increases in plasma membrane cholesterol also promote the rapid and hyper‐sharp proteolytic inactivation of HMGCR, the rate‐determining ER enzyme for sterol biosynthesis 14,42,133,134 . (Figure 1D) The degradation of another key biosynthetic enzyme, squalene monooxygenase, is also stimulated by cholesterol 135,136 . The transcriptional activator, SREBP‐2, drives the expression of diverse sterol‐accretion proteins; for example, HMGCR, squalene monooxygenase and low‐density lipoprotein (LDL) receptors 133 .…”

Section: Cholesterol Homeostasismentioning

confidence: 99%

Active cholesterol 20 years on

Lange

Steck

2020

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This review considers the following hypotheses, some well‐supported and some speculative. Almost all of the sterol molecules in plasma membranes are associated with bilayer phospholipids in complexes of varied strength and stoichiometry. These complexes underlie many of the material properties of the bilayer. The small fraction of cholesterol molecules exceeding the binding capacity of the phospholipids is thermodynamically active and serves diverse functions. It circulates briskly among the cell membranes, particularly through contact sites linking the organelles. Active cholesterol provides the upstream feedback signal to multiple mechanisms governing plasma membrane homeostasis, pegging the sterol level to a threshold set by its phospholipids. Active cholesterol could also be the cargo for various inter‐organelle transporters and the form excreted from cells by reverse transport. Furthermore, it is integral to the function of caveolae; a mediator of Hedgehog regulation; and a ligand for the binding of cytolytic toxins to membranes. Active cholesterol modulates a variety of plasma membrane proteins—receptors, channels and transporters—at least in vitro.

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Section: Cholesterol Homeostasismentioning

confidence: 99%

Active cholesterol 20 years on

Lange

Steck

2020

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“…SM controls flux through the cholesterol synthesis pathway downstream of HMGCR as recently reviewed (68). The regulatory domain of SM, the first 100 amino acids (dubbed N100) is highly responsive to sterols and increased cholesterol or desmosterol levels lead to rapid destruction of the protein, in a feedback loop from cholesterol (33).…”

Section: A Second Control Enzyme -Smmentioning

confidence: 99%

Post-translational control of the long and winding road to cholesterol

Sharpe

Coates

Brown

2020

Journal of Biological Chemistry

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The synthesis of cholesterol requires more than 20 enzymes, many of which are intricately regulated. Post-translational control of these enzymes provides a rapid means for modifying flux through the pathway. So far, several enzymes have been shown to be rapidly degraded through the ubiquitin proteasome pathway in response to cholesterol and other sterol intermediates. Additionally, several enzymes have their activity altered through phosphorylation mechanisms. Most work has focused on the two rate-limiting enzymes: 3-hydroxy-3-methyl-glutaryl coenzyme A reductase and squalene monooxygenase. Here, we review current literature in the area to define some common themes in the regulation of the entire cholesterol synthesis pathway. We highlight the rich variety of inputs controlling each enzyme, discuss the interplay that exists between regulatory mechanisms, and summarize findings that reveal an intricately coordinated network of regulation along the cholesterol synthesis pathway. We provide a roadmap for future research into the post-translational control of cholesterol synthesis, and no doubt the road ahead will reveal further twists and turns for this fascinating pathway crucial for human health and disease.

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“…Several drugs against SQLE have been evaluated in anti-tumor trials (Cirmena et al, 2018;Liu et al, 2018). Recent study has reported that SQLE can be regulated at transcriptional, translational, and post-translational levels (Chua et al, 2020). Here we report that MYC binds to and activates SQLE promoter.…”

Section: Introductionmentioning

confidence: 99%

MYC Enhances Cholesterol Biosynthesis and Supports Cell Proliferation Through SQLE

Yang

Kou

Liu

et al. 2021

Front. Cell Dev. Biol.

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Oncogene c-Myc (referred in this report as MYC) promotes tumorigenesis in multiple human cancers. MYC regulates numerous cellular programs involved in cell growth and cell metabolism. Tumor cells exhibit obligatory dependence on cholesterol metabolism, which provides essential membrane components and metabolites to support cell growth. To date, how cholesterol biosynthesis is delicately regulated to promote tumorigenesis remains unclear. Here, we show that MYC enhances cholesterol biosynthesis and promotes cell proliferation. Through transcriptional upregulation of SQLE, a rate-limiting enzyme in cholesterol synthesis pathway, MYC increases cholesterol production and promotes tumor cell growth. SQLE overexpression restores the cellular cholesterol levels in MYC-knockdown cells. More importantly, in SQLE-depleted cells, enforced expression of MYC has no effect on cholesterol levels. Therefore, our findings reveal that SQLE is critical for MYC-mediated cholesterol synthesis, and further demonstrate that SQLE may be a potential therapeutic target in MYC-amplified cancers.

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Squalene monooxygenase: a journey to the heart of cholesterol synthesis

Cited by 64 publications

References 301 publications

Active cholesterol 20 years on

Active cholesterol 20 years on

Post-translational control of the long and winding road to cholesterol

MYC Enhances Cholesterol Biosynthesis and Supports Cell Proliferation Through SQLE

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