Receptor-mediated HDL-lipid uptake is regulated by elastic properties of the plasma membrane

Proper supply of mammalian cells with cholesterol is crucial for membrane function and cellular survival and is regulated by several mechanisms, including cellular uptake, synthesis, storage and export. Transport of excess cholesterol from the periphery back to the liver for excretion into the bile is achieved by high-density lipoproteins (HDL). HDL particles are captured from the blood stream by the scavenger receptor class B type I (SR-BI), the so-called HDL receptor. The subsequent lipid transfer process, however, is highly speculative: it has been proposed to occur after HDL endocytosis or directly at the cell surface across an unstirred water layer or via a hydrophobic channel in the receptor. Here we show via direct imaging techniques that, upon contact with the membrane, HDL is incorporated into the hydrophobic core of the lipid bilayer and amphiphilic cargo is immediately released to the plasma membrane. Particle incorporation and cargo transfer is abolished at increased membrane cholesterol concentrations, as a consequence of the reduced membrane elasticity. Our observations reveal a mechanism for regulation of lipid uptake, which is based on sensing plasma membrane cholesterol levels: HDL-receptors tether particles close to the plasma membrane; once in proximity, elastic membrane properties regulate the particles’ fusion with the bilayer and subsequent cargo transfer. The data indicate that the plasma membrane itself signals a cellu0027s cholesterol demand: high cholesterol levels act repulsive, low cholesterol levels fusogenic.