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

Wenwen Tang (), Yi Luan, Qianying Yuan, Ao Li, Song Chen, Stanley Menacherry, Lawrence Young and Dianqing Wu ()
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Wenwen Tang: Yale University School of Medicine
Yi Luan: Yale University School of Medicine
Qianying Yuan: Yale University School of Medicine
Ao Li: Yale University School of Medicine
Song Chen: Yale University School of Medicine
Stanley Menacherry: Gateway Community College
Lawrence Young: Yale University School of Medicine
Dianqing Wu: Yale University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-47262-z

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