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LDL receptor-related protein 5 selectively transports unesterified polyunsaturated fatty acids to intracellular compartments

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  • Wenwen Tang

    (Yale University School of Medicine
    Yale University School of Medicine)

  • Yi Luan

    (Yale University School of Medicine
    Yale University School of Medicine)

  • Qianying Yuan

    (Yale University School of Medicine
    Yale University School of Medicine)

  • Ao Li

    (Yale University School of Medicine
    Yale University School of Medicine)

  • Song Chen

    (Yale University School of Medicine)

  • Stanley Menacherry

    (Gateway Community College)

  • Lawrence Young

    (Yale University School of Medicine
    Yale University School of Medicine
    Yale University School of Medicine)

  • Dianqing Wu

    (Yale University School of Medicine
    Yale University School of Medicine)

Abstract

Polyunsaturated fatty acids (PUFAs), which cannot be synthesized by animals and must be supplied from the diet, have been strongly associated with human health. However, the mechanisms for their accretion remain poorly understood. Here, we show that LDL receptor-related protein 5 (LRP5), but not its homolog LRP6, selectively transports unesterified PUFAs into a number of cell types. The LDLa ligand-binding repeats of LRP5 directly bind to PUFAs and are required and sufficient for PUFA transport. In contrast to the known PUFA transporters Mfsd2a, CD36 and FATP2, LRP5 transports unesterified PUFAs via internalization to intracellular compartments including lysosomes, and n-3 PUFAs depend on this transport mechanism to inhibit mTORC1. This LRP5-mediated PUFA transport mechanism suppresses extracellular trap formation in neutrophils and protects mice from myocardial injury during ischemia-reperfusion. Thus, this study reveals a biologically important mechanism for unesterified PUFA transport to intracellular compartments.

Suggested Citation

  • Wenwen Tang & Yi Luan & Qianying Yuan & Ao Li & Song Chen & Stanley Menacherry & Lawrence Young & Dianqing Wu, 2024. "LDL receptor-related protein 5 selectively transports unesterified polyunsaturated fatty acids to intracellular compartments," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47262-z
    DOI: 10.1038/s41467-024-47262-z
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    References listed on IDEAS

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    1. Filippo Veglia & Vladimir A. Tyurin & Maria Blasi & Alessandra Leo & Andrew V. Kossenkov & Laxminarasimha Donthireddy & Tsun Ki Jerrick To & Zach Schug & Subhasree Basu & Fang Wang & Emanuela Ricciott, 2019. "Fatty acid transport protein 2 reprograms neutrophils in cancer," Nature, Nature, vol. 569(7754), pages 73-78, May.
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