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Cited by 23Cholesterol and Lipid MetabolismLipoproteins and Cardiovascular HealthLipid metabolism and disorders

A neuronal VLDLR variant lacking the third complement-type repeat exhibits high capacity binding of apoE containing lipoproteins

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Sakai, Keiko, Tiebel, Oliver, Ljungberg, M. Cecilia, Sullivan, Merry, Lee, Hye-Jeong, Terashima, Tomoya, Li, Rongying, Kobayashi, Kunihisa +3 more·2009·Brain Research
DOI 10.1016/j.brainres.2009.04.030PMC PMC2733343
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Abstract

Very-low-density lipoprotein receptor (VLDLR) is a multi ligand apolipoprotein E (apoE) receptor and is involved in brain development through Reelin signaling. Different forms of VLDLR can be generated by alternative splicing. VLDLR-I contains all exons. VLDLR-II lacks an O-linked sugar domain encoded by exon 16, while VLDLR-III lacks the third complement-type repeat in the ligand binding domain encoded by exon 4. We quantitatively compared lipoprotein binding to human VLDLR variants and analyzed their mRNA expression in both human cerebellum and mouse brain. VLDLR-III exhibited the highest capacity in binding to apoE enriched beta-VLDL in vitro and was more effective in removing apoE containing lipoproteins from the circulation than other variants in vivo. In human cerebellum, the major species was VLDLR-II, while the second most abundant species was a newly identified VLDLR-IV which lacks both exon 4 and 16. VLDLR-I was present at low levels. In adult mice, exon 4 skipping varied between 30 and 47% in different brain regions, while exon 16 skipping ranged by 51-76%. Significantly higher levels of VLDLR proteins were found in mouse cerebellum and cerebral cortex than other regions. The deletions of exon 4 and exon 16 frequently occurred in primary neurons, indicating that newly identified variant VLDLR-IV is abundant in neurons. In contrast, VLDLR mRNA lacking exon 4 was not detectable in primary astrocytes. Such cell type-specific splicing patterns were found in both mouse cerebellum and cerebral cortex. These results suggest that a VLDLR variant lacking the third complement-type repeat is generated by neuron-specific alternative splicing. Such differential splicing may result in different lipid uptake in neurons and astrocytes.

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  • Several isoforms of the VLDLR have been observed in neurons.

    “Several isoforms of the VLDLR have been observed in neurons (26, 29).”

    From The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2 (2010) · cites this paper as [29]

  • In HL60 cells, AD heritability showed significant enrichment for SPI1 (PU.1) that was much stronger than for POLR2AphosphoS5.

    “We observed a significant enrichment for SPI1 (PU.1) (34.58 fold enrichment, P=1.31×10−3 in first replicate; 58.12 fold enrichment, P=4.95×10−3 in second replicate) much stronger than that for POLR2AphosphoS5 (15.78 fold enrichment, P=1.71×10−2 in first replicate; 16.34 fold enrichment, P=1.25×10−1 in second replicate)”

    From A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease (2017) · cites this paper as [37]

    The Results (§2.5) concern VLDLR splicing in mouse neurons and astrocytes, not AD heritability enrichment in HL60 cells. Searches for SPI1/PU.1, POLR2AphosphoS5, and the reported fold-enrichment values found no passage addressing the claim; no page numbers were available in our copy. (LLM, conf=0.78)

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Authors
Sakai, K., Tiebel, O., Ljungberg, M. C., Sullivan, M., Lee, H.-J., Terashima, T., Li, R., Kobayashi, K., Lu, H.-C., Chan, L., & Oka, K.
Affiliations
Baylor College of Medicine (US)
ORCID
Venue
Brain Research
Publisher
Elsevier BV
Published
2009-06
Volume
1276
Pages
11-21
ISSN
0006-8993 (ISSN-L)
DOI
10.1016/j.brainres.2009.04.030
PMC
PMC2733343
OpenAlex
W1992879613
Cited by
23
References
59
Citations by year
2026: 2 · 2024: 2 · 2023: 1 · 2021: 3 · 2020: 1 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 1 · 2013: 1 · 2012: 2
FWCI
2.67
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Brain Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Heart, Lung, and Blood Institute (HL73144, P50HL059314, R01HL073144)
  • National Institute of Diabetes and Digestive and Kidney Diseases (P30DK079638)
  • National Institute of Neurological Disorders and Stroke (R01NS048884, NS04884)
Topics
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
VLDLR, apolipoprotein E, alternative splicing, exon skipping, lipoprotein binding, beta-VLDL, cerebellum, cerebral cortex, astrocytes, lipid uptake, Reelin signaling
MeSH terms
Reelin Protein, Animals, Apolipoproteins E, Astrocytes, Brain, Cells, Cultured, Cerebellum, Cerebral Cortex, Cholesterol, Female, Humans, Mice, Inbred C57BL, Neurons, Receptors, LDL, RNA, Messenger, Alternative Splicing, Mice, Knockout, Gene Expression Regulation, Developmental, Mice, Lipoproteins, IDL

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