GPIHBP1 expression in gliomas promotes utilization of lipoprotein-derived nutrients

Abstract

GPIHBP1, a GPI-anchored protein of capillary endothelial cells, binds lipoprotein lipase (LPL) within the subendothelial spaces and shuttles it to the capillary lumen. The GPIHBP1-bound LPL is essential for the margination of triglyceride-rich lipoproteins (TRLs) along capillaries, allowing the lipolytic processing of TRLs to proceed. In peripheral tissues, the intravascular processing of TRLs by the GPIHBP1–LPL complex is crucial for generating lipid nutrients for adjacent parenchymal cells. GPIHBP1 is absent in capillaries of the brain, which uses glucose for fuel; however, GPIHBP1 is expressed in capillaries of mouse and human gliomas. Importantly, the GPIHBP1 in glioma capillaries captures locally produced LPL. We document, by NanoSIMS imaging, that TRLs marginate along glioma capillaries and that there is uptake of TRL-derived lipid nutrients by surrounding glioma cells. Thus, GPIHBP1 expression in gliomas facilitates TRL processing and provides a source of lipid nutrients for glioma cells.

Data availability

All data generated during this study are included in the manuscript and supporting files.

The following previously published data sets were used

Article and author information

Author details

  1. Xuchen Hu

    Department of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  2. Ken Matsumoto

    Vascular Patterning Lab, VIB-KU Leuven Center for Cancer Biology (CCB), Leuven, Belgium
    Competing interests
    No competing interests declared.
  3. Rachel S Jung

    Department of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  4. Thomas A Weston

    Department of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  5. Patrick J Heizer

    Department of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  6. Cuiwen He

    Department of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  7. Norma P Sandoval

    Department of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  8. Christopher M Allan

    Department of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  9. Yiping Tu

    Department of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  10. Harry V Vinters

    Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  11. Linda M Liau

    Department of Neurosurgery, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  12. Rochelle M Ellison

    Department of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  13. Jazmin E Morales

    Department of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  14. Lynn J Baufeld

    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  15. Nicholas A Bayley

    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  16. Liqun He

    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
    Competing interests
    No competing interests declared.
  17. Christer Betsholtz

    Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
    Competing interests
    No competing interests declared.
  18. Anne P Beigneux

    Department of Medicine, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  19. David A Nathanson

    Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, United States
    Competing interests
    No competing interests declared.
  20. Holger Gerhardt

    Integrative Vascular Biology, Max Delbrück Center for Molecular Medicine, Berlin, Germany
    Competing interests
    Holger Gerhardt, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3030-0384
  21. Stephen G Young

    Department of Medicine, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    sgyoung@mednet.ucla.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7270-3176
  22. Loren G Fong

    Department of Medicine, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    lfong@mednet.ucla.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4465-5290
  23. Haibo Jiang

    Department of Medicine, University of California, Los Angeles, Los Angeles, United States
    For correspondence
    haibo.jiang@uwa.edu.au
    Competing interests
    No competing interests declared.

Funding

National Heart, Lung, and Blood Institute (HL090553)

  • Stephen G Young

National Heart, Lung, and Blood Institute (HL087228)

  • Stephen G Young

National Heart, Lung, and Blood Institute (HL125335)

  • Stephen G Young

Foundation Leduq (12CVD04)

  • Stephen G Young

Ruth L. Kirschstein National Research Service Award (T32HL69766)

  • Xuchen Hu

National Institute of General Medical Sciences (GM008042)

  • Xuchen Hu

NCI Brain Tumor SPORE (P50-CA211015)

  • Linda M Liau

Stichting Tegen Kanker (2012‐181)

  • Holger Gerhardt

Stichting Tegen Kanker (2018-074)

  • Holger Gerhardt

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal housing and experimental protocols were approved by UCLA's Animal Research Committee (ARC; 2004-125-51, 2016-005) and the Institutional Animal Care and Research Advisory Committee of the KU Leuven (085/2016). The animals were housed in an AAALAC (Association for Assessment and Accreditation of Laboratory Animal Care International)-approved facility and cared for according to guidelines established by UCLA's Animal Research Committee.

Human subjects: All tissue samples from patients were obtained after informed consent and with approval from the UCLA Institutional Review Board (IRB; protocol 10-000655).

Copyright

© 2019, Hu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,642
    views
  • 255
    downloads
  • 9
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Xuchen Hu
  2. Ken Matsumoto
  3. Rachel S Jung
  4. Thomas A Weston
  5. Patrick J Heizer
  6. Cuiwen He
  7. Norma P Sandoval
  8. Christopher M Allan
  9. Yiping Tu
  10. Harry V Vinters
  11. Linda M Liau
  12. Rochelle M Ellison
  13. Jazmin E Morales
  14. Lynn J Baufeld
  15. Nicholas A Bayley
  16. Liqun He
  17. Christer Betsholtz
  18. Anne P Beigneux
  19. David A Nathanson
  20. Holger Gerhardt
  21. Stephen G Young
  22. Loren G Fong
  23. Haibo Jiang
(2019)
GPIHBP1 expression in gliomas promotes utilization of lipoprotein-derived nutrients
eLife 8:e47178.
https://doi.org/10.7554/eLife.47178

Share this article

https://doi.org/10.7554/eLife.47178

Further reading

    1. Biochemistry and Chemical Biology
    Parnian Arafi, Sujan Devkota ... Michael S Wolfe
    Research Article

    Missense mutations in the amyloid precursor protein (APP) and presenilin-1 (PSEN1) cause early-onset familial Alzheimer’s disease (FAD) and alter proteolytic production of secreted 38-to-43-residue amyloid β-peptides (Aβ) by the PSEN1-containing γ-secretase complex, ostensibly supporting the amyloid hypothesis of pathogenesis. However, proteolysis of APP substrate by γ-secretase is processive, involving initial endoproteolysis to produce long Aβ peptides of 48 or 49 residues followed by carboxypeptidase trimming in mostly tripeptide increments. We recently reported evidence that FAD mutations in APP and PSEN1 cause deficiencies in early steps in processive proteolysis of APP substrate C99 and that this results from stalled γ-secretase enzyme-substrate and/or enzyme-intermediate complexes. These stalled complexes triggered synaptic degeneration in a Caenorhabditis elegans model of FAD independently of Aβ production. Here, we conducted full quantitative analysis of all proteolytic events on APP substrate by γ-secretase with six additional PSEN1 FAD mutations and found that all six are deficient in multiple processing steps. However, only one of these (F386S) was deficient in certain trimming steps but not in endoproteolysis. Fluorescence lifetime imaging microscopy in intact cells revealed that all six PSEN1 FAD mutations lead to stalled γ-secretase enzyme-substrate/intermediate complexes. The F386S mutation, however, does so only in Aβ-rich regions of the cells, not in C99-rich regions, consistent with the deficiencies of this mutant enzyme only in trimming of Aβ intermediates. These findings provide further evidence that FAD mutations lead to stalled and stabilized γ-secretase enzyme-substrate and/or enzyme-intermediate complexes and are consistent with the stalled process rather than the products of γ-secretase proteolysis as the pathogenic trigger.

    1. Biochemistry and Chemical Biology
    2. Chromosomes and Gene Expression
    Kira A Cozzolino, Lynn Sanford ... Dylan J Taatjes
    Research Article

    Hyperactive interferon (IFN) signaling is a hallmark of Down syndrome (DS), a condition caused by Trisomy 21 (T21); strategies that normalize IFN signaling could benefit this population. Mediator-associated kinases CDK8 and CDK19 drive inflammatory responses through incompletely understood mechanisms. Using sibling-matched cell lines with/without T21, we investigated Mediator kinase function in the context of hyperactive IFN in DS over a 75 min to 24 hr timeframe. Activation of IFN-response genes was suppressed in cells treated with the CDK8/CDK19 inhibitor cortistatin A (CA), via rapid suppression of IFN-responsive transcription factor (TF) activity. We also discovered that CDK8/CDK19 affect splicing, a novel means by which Mediator kinases control gene expression. To further probe Mediator kinase function, we completed cytokine screens and metabolomics experiments. Cytokines are master regulators of inflammatory responses; by screening 105 different cytokine proteins, we show that Mediator kinases help drive IFN-dependent cytokine responses at least in part through transcriptional regulation of cytokine genes and receptors. Metabolomics revealed that Mediator kinase inhibition altered core metabolic pathways in cell type-specific ways, and broad upregulation of anti-inflammatory lipid mediators occurred specifically in kinase-inhibited cells during hyperactive IFNγ signaling. A subset of these lipids (e.g. oleamide, desmosterol) serve as ligands for nuclear receptors PPAR and LXR, and activation of these receptors occurred specifically during hyperactive IFN signaling in CA-treated cells, revealing mechanistic links between Mediator kinases, lipid metabolism, and nuclear receptor function. Collectively, our results establish CDK8/CDK19 as context-specific metabolic regulators, and reveal that these kinases control gene expression not only via TFs, but also through metabolic changes and splicing. Moreover, we establish that Mediator kinase inhibition antagonizes IFN signaling through transcriptional, metabolic, and cytokine responses, with implications for DS and other chronic inflammatory conditions.