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Researchers identified new cell surface receptors, including MERTK, that interact with high-density lipoprotein (HDL) particles. This discovery advances understanding of HDL

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Area of Science:

  • Lipid Metabolism and Cardiovascular Health
  • Cell Biology and Receptor Signaling
  • Proteomics and Systems Biology

Background:

  • High-density lipoprotein (HDL) plays a crucial role in reverse cholesterol transport (RCT) and cellular protection, but its molecular interactions with cells are not fully understood.
  • HDL function is mediated by interactions with cell surface receptors, yet the full spectrum of these receptors and their dynamics remain largely uncharacterized.
  • Understanding HDL-receptor interplay is vital for elucidating lipid trafficking and cellular signaling pathways relevant to cardiovascular health.

Purpose of the Study:

  • To comprehensively map the cell surface receptors (surfaceome) that interact with HDL particles.
  • To identify novel HDL receptors and co-receptors beyond the known scavenger receptor B1 (SCRB1).
  • To investigate the impact of vascular endothelial growth factor A (VEGF-A) on the HDL-interacting surfaceome and identify co-regulated receptors.

Main Methods:

  • Application of chemoproteomic technologies: automated cell surface capturing (auto-CSC) and HATRIC-based ligand-receptor capturing (HATRIC-LRC).
  • Analysis of four distinct cellular model systems relevant to RCT: EA.hy926, HEPG2, foam cells, and human aortic endothelial cells (HAECs).
  • VEGF-A modulation of HAEC surfaceome analysis using auto-CSC, followed by HATRIC-LRC for specific receptor identification and RNA interference for functional validation.

Main Results:

  • Identification of SCRB1 as a primary HDL receptor, along with 155 additional potential HDL interaction candidates across different cell types.
  • VEGF-A treatment significantly remodeled the HAEC surfaceome, revealing 165 additional receptors co-regulated with SCRB1.
  • HATRIC-LRC identified MERTK as a novel HDL co-receptor, crucial for endothelial HDL binding and uptake, spatially located near SCRB1.

Conclusions:

  • HDL interacts with a complex and dynamic set of cell surface receptors, forming a multifaceted HDL receptome.
  • MERTK, in conjunction with SCRB1, plays a significant role in mediating HDL binding and uptake by endothelial cells.
  • The nanoscale organization of HDL receptors on the cell surface likely influences HDL's functional interactions, offering new therapeutic targets for cardiovascular diseases.