Lipid transfer from lipoprotein particles to cells is essential for lipid homeostasis. High-density lipoprotein (HDL) particles are mainly captured by cell membrane-associated scavenger receptor class B type 1 (SR-B1) from the bloodstream, while low-density and very-low-density lipoprotein (LDL and VLDL, respectively) particles are mostly taken up by receptor-mediated endocytosis. However, the role of the target lipid membrane itself in the transfer process has been largely neglected so far. Here, we study how lipoprotein particles (HDL, LDL, and VLDL) interact with synthetic lipid bilayers and cell-derived membranes and transfer their cargo subsequently. Employing cryo-electron microscopy, spectral imaging, and fluorescence (cross) correlation spectroscopy allowed us to observe integration of all major types of lipoprotein particles into the membrane and delivery of their cargo in a receptor-independent manner. Importantly, the biophysical properties of the target cell membranes change upon delivery of cargo. The concept of receptor-independent interaction of lipoprotein particles with membranes helps us to better understand lipoprotein particle biology and can be exploited for novel treatments of dyslipidemia diseases.

CEITEC Masaryk University University Campus Bohunice Brno 62500 Czech Republic

Johannes Kepler University Linz Institute of Biophysics Linz 4020 Austria

Medical University of Vienna Center for Pathobiochemistry and Genetics Institute of Medical Chemistry Vienna 1090 Austria

MRC Human Immunology Unit MRC Weatherall Institute of Molecular Medicine University of Oxford Oxford OX3 9DS U K

Science for Life Laboratory Department of Women's and Children's Health Karolinska Institutet 17165 Solna Sweden

TU Wien Institute of Applied Physics Vienna 1040 Austria

Upper Austria University of Applied Sciences Campus Linz Linz 4020 Austria

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