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Cited by 23Atherosclerosis and Cardiovascular DiseasesCholesterol and Lipid MetabolismLipoproteins and Cardiovascular Health

Progranulin in the hematopoietic compartment protects mice from atherosclerosis

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Nguyen, Andrew D., Nguyen, Thi A., Singh, Rajesh K., Eberlé, Delphine, Zhang, Jiasheng, Abate, Jess Porter, Robles, Anatalia, Koliwad, Suneil +4 more·2018·Atherosclerosis
DOI 10.1016/j.atherosclerosis.2018.08.042PMC PMC6432779
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Abstract

Background and aims Progranulin is a circulating protein that modulates inflammation and is found in atherosclerotic lesions. Here we determined whether inflammatory cell-derived progranulin impacts atherosclerosis development. Methods Ldlr-/- mice were transplanted with bone marrow from wild-type (WT) or Grn-/- (progranulin KO) mice (referred to as Tx-WT and Tx-KO, respectively). Results After 10 weeks of high-fat diet feeding, both groups displayed similarly elevated plasma levels of cholesterol and triglycerides. Despite abundant circulating levels of progranulin, the size of atherosclerotic lesions in Tx-KO mice was increased by 47% in aortic roots and by 62% in whole aortas. Aortic root lesions in Tx-KO mice had increased macrophage content and larger necrotic cores, consistent with more advanced lesions. Progranulin staining was markedly reduced in the lesions of Tx-KO mice, indicating little or no uptake of circulating progranulin. Mechanistically, cultured progranulin-deficient macrophages exhibited increased lysosome-mediated exophagy of aggregated low-density lipoproteins resulting in increased cholesterol uptake and foam cell formation. Conclusions We conclude that hematopoietic progranulin deficiency promotes diet-induced atherosclerosis in Ldlr-/- mice, possibly due to increased exophagy-mediated cholesterol uptake. Circulating progranulin was unable to prevent the increased lesion development, consistent with the importance of progranulin acting via cell-autonomous or local effects.

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  • Loss of GRN leads to intracellular and intra-lysosomal accumulation of long polyunsaturated triacylglycerides in the brains of humans and mice.

    “In addition, a recent study reported that loss of GRN leads to intracellular and intra-lysosomal accumulation of long polyunsaturated triacylglyerides50 in the brains of humans and mice.”

    From Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain (2020) · cites this paper as [50]

    The Introduction and the Results section on lysosomal abnormalities describe increased lysosomal markers in Grn-deficient mouse brains and macrophages. Neither those passages nor searches for polyunsaturated triacylglycerides and triglycerides report accumulation of those lipids in human or mouse brains. The finding that neutral lipids did not accumulate in lysosomes concerns cultured macrophages under a specific treatment, not brains. (LLM, conf=0.72)

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Authors
Nguyen, A. D., Nguyen, T. A., Singh, R. K., Eberlé, D., Zhang, J., Abate, J. P., Robles, A., Koliwad, S., Huang, E. J., Maxfield, F. R., Walther, T. C., & Farese, R. V.
Affiliations
  • Harvard University (US)
  • Gladstone Institutes (US)
  • Weill Cornell Medicine (US)
  • San Francisco VA Medical Center (US)
  • University of California, San Francisco (US)
  • Broad Institute (US)
Corresponding author
  • Walther, Tobias C.
  • Farese, Robert V.
ORCID
Venue
Atherosclerosis
Publisher
Elsevier BV
Published
2018-10
Volume
277
Pages
145-154
ISSN
0021-9150 (ISSN-L)
DOI
10.1016/j.atherosclerosis.2018.08.042
PMC
PMC6432779
OpenAlex
W2889269713
Cited by
23
References
3
Citations by year
2026: 2 · 2025: 3 · 2024: 2 · 2023: 3 · 2022: 5 · 2020: 5 · 2019: 3
FWCI
0.86
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Atherosclerosis (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
Funders
  • NIH (P50 AG023501, R01 HL093324, F32 HL116197)
  • Bluefield Project to Cure FTD
  • VA Merit (BX002978)
  • American Diabetes Association
  • American Heart Association
  • Howard Hughes Medical Institute
  • Gladstone Institutes
  • National Center for Research Resources (RR18928)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Keywords
progranulin, hematopoietic cells, macrophages, exophagy, low-density lipoprotein, cholesterol absorption, foam cell formation, necrotic core, aortic root lesions, high-fat diet, inflammation
MeSH terms
Progranulins, Granulins, Animals, Aorta, Aortic Diseases, Cells, Cultured, Disease Models, Animal, Female, Foam Cells, Lipids, Lysosomes, Macrophages, Mice, Inbred C57BL, Necrosis, Phenotype, Receptors, LDL, Signal Transduction, Bone Marrow Transplantation, Mice, Knockout, Genetic Predisposition to Disease, Atherosclerosis, Plaque, Atherosclerotic, Diet, High-Fat

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