LDL Receptor-Related Protein 5 is a Selective Transporter for Unesterified Polyunsaturated Fatty Acids

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 and actions 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 for PUFA transport. LRP5 transports PUFAs via internalization to intracellular compartments including lysosomes, and n-3 PUFAs depends on this transport mechanism to inhibit mTORC1. This LRP5-mediated PUFA transport mechanism suppresses neutrophil extracellular trap formation in neutrophils and protects mice from myocardial injury during ischemia-reperfusion. Thus, this study reveals a previously unknown and biologically important mechanism for PUFA transport and mTORC1 regulation.