Endocytosis, Transcytosis, and Retroendocytosis of HDL: Mechanisms, Pathophysiology, and Options for Clinical Exploitation.

For over 50 years, many cell types have been shown to internalize HDLs (high-density lipoproteins) as whole particles, either degrading or resecreting them. HDL endocytosis occurs through at least 4 pathways including (1) macropinocytosis, (2) a yet unknown HDL holoparticle receptor activated through signal transduction (eg, purinergic receptors), (3) cooperation between an HDL-binding protein and an endocytic receptor like the cubilin/megalin coreceptors, or (4) endocytic receptors for minor HDL components such as the apoE receptors. These manifold interactions of diverse proteins of HDL and cells, which we term HDL-synapses, are tissue-specific and may explain why the canonical HDL receptor SR-BI (scavenger receptor BI) mediates HDL endocytosis into endothelial and some cancer cells but not hepatocytes. Internalized HDLs have been localized in endosomes, lysosomes, and multivesicular bodies but the molecular mechanisms that traffic HDLs toward lysosomal degradation, immediate resecretion, or intermediate sequestration in multivesicular bodies are little understood. Despite the limited molecular understanding of endocytosis, transcytosis, and retroendocytosis of HDLs, several observations in humans and animal models highlight the relevance of cellular HDL trafficking for health and disease, as well as opportunities for diagnostic and therapeutic exploitation. In this review, we summarize the current understanding and knowledge gaps of endocytosis and cellular trafficking of HDLs on the molecular, pathophysiological, and clinical levels with a focus on liver, kidney, endothelium, macrophages, and intestine.