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The DOI matches its Crossref record; 4 of the 4 references it cites were found in a registry or an index.

Three pools of plasma membrane cholesterol and their relation to cholesterol homeostasis

Das, Akash, Brown, Michael S, Anderson, Donald D, Goldstein, Joseph L, Radhakrishnan, Arun·2014·eLife
DOI 10.7554/elife.02882PMC PMC4086274
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Abstract

When human fibroblasts take up plasma low density lipoprotein (LDL), its cholesterol is liberated in lysosomes and eventually reaches the endoplasmic reticulum (ER) where it inhibits cholesterol synthesis by blocking activation of SREBPs. This feedback protects against cholesterol overaccumulation in the plasma membrane (PM). But how does ER know whether PM is saturated with cholesterol? In this study, we define three pools of PM cholesterol: (1) a pool accessible to bind 125I-PFO*, a mutant form of bacterial Perfringolysin O, which binds cholesterol in membranes; (2) a sphingomyelin(SM)-sequestered pool that binds 125I-PFO* only after SM is destroyed by sphingomyelinase; and (3) a residual pool that does not bind 125I-PFO* even after sphingomyelinase treatment. When LDL-derived cholesterol leaves lysosomes, it expands PM's PFO-accessible pool and, after a short lag, it also increases the ER's PFO-accessible regulatory pool. This regulatory mechanism allows cells to ensure optimal cholesterol levels in PM while avoiding cholesterol overaccumulation.

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Crossref · 10.7554/elife.02882

Cites

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  • Sphingomyelin is concentrated in the outer leaflet of the PM and traps cholesterol, preventing its movement to the ER.

    “Sphingomyelin is concentrated in the outer leaflet of the PM and it traps cholesterol, preventing its movement to the ER (7, 30).”

    From Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine (2020) · cites this paper as [7]

    The Results section reports that removing sphingomyelin increases cholesterol transfer from the plasma membrane to the ER, supporting the claim that sphingomyelin sequesters cholesterol and limits that transfer. The Discussion links sphingomyelin loss to increased cholesterol activity in the outer leaflet, but our copy does not establish that sphingomyelin is concentrated there; it also says the physical nature of the sequestered pool is unknown. No page numbers were provided in our copy. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • PM cholesterol exists in three pools: an accessible pool, a sphingomyelin-bound inaccessible pool, and a third inaccessible pool essential for cell viability.

    “PM cholesterol exists in three pools (7). One pool is termed “accessible” because its cholesterol is accessible to the cholesterol-binding toxins PFO* and anthrolysin O (7, 8). A second pool is bound to sphingomyelin and thus is inaccessible to these toxins. The third pool is also inaccessible and is essential for cell viability (7).”

    From Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine (2020) · cites this paper as [7]

    The Introduction and Discussion describe three pools: PFO-accessible, sphingomyelin-sequestered, and a third pool inaccessible even after sphingomyelinase treatment. The Discussion says the third pool is essential for normal plasma-membrane morphology and integrity, based on cells rounding up and detaching when cholesterol was further depleted; it does not establish that the pool is essential for cell viability. It also describes direct cholesterol–sphingomyelin binding as a plausible model, not a demonstrated property. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Treatment with sphingomyelinase releases cholesterol from sphingomyelin, thereby increasing the accessible pool.

    “Treatment with sphingomyelinase releases cholesterol from sphingomyelin, thereby increasing the accessible pool.”

    From Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine (2020) · cites this paper as [7]

  • LDL-derived cholesterol travels from lysosomes to the plasma membrane before moving to the ER.

    “studies with cholesterol-binding toxins have provided evidence that LDL-derived cholesterol travels from lysosomes to the PM before moving to the ER (7, 8).”

    From Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine (2020) · cites this paper as [7]

  • The accessible pool of cholesterol is the only pool that is free to move to the ER to exert regulatory actions.

    “The accessible pool of cholesterol is the only pool that is free to move to the ER to exert regulatory actions (7, 8, 29).”

    From Last step in the path of LDL cholesterol from lysosome to plasma membrane to ER is governed by phosphatidylserine (2020) · cites this paper as [7]

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Citations

Cites

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Research works printed but not linked: 40

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Metadata

Authors
Das, A., Brown, M. S., Anderson, D. D., Goldstein, J. L., & Radhakrishnan, A.
Affiliations
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, United States
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2014-06-11
Volume
3
ISSN
2050-084X
DOI
10.7554/elife.02882
PMC
PMC4086274
Cited by
354
References
4
Language
en
Licence
Funders
  • National Institutes of Health (NIH) (HL20948-37)
  • Welch Foundation (I-1793)
  • American Heart Association (AHA) (12SDG12040267)

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