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. Author manuscript; available in PMC: 2015 Mar 12.
Published in final edited form as: Nat Rev Immunol. 2013 Sep 2;13(10):709–721. doi: 10.1038/nri3520

Figure 2. Mechanisms governing macrophage lipoprotein uptake and efflux.

Figure 2

Macrophages internalize native (low density lipoprotein, LDL; very low density lipoprotein, VLDL) and oxidized lipoproteins in the plaque via macropinocytosis, phagocytosis of aggregated LDL and scavenger receptor-mediated uptake (including by scavenger receptor A (SRA), LOX1, SRB1 and CD36). The internalized lipoproteins and their associated lipids are digested in the lysosome resulting in the release of free cholesterol that can travel to the plasma membrane and be effluxed from the cell or to the endoplasmic reticulum (ER) membrane and be esterified by acyl-coA cholesterol acyltransferase (ACAT) and ultimately stored in this form in cytosolic lipid droplets. These stored lipids can be mobilized for efflux via either lipolysis by neutral cholesterol ester hydrolases (nCEH) or lipophagy, a form of autophagy, which results in delivery of lipid droplets to lysosomes. The accumulation of cellular cholesterol activates the liver-X-receptor (LXR)/retinoid X receptor (RXR) heterodimeric transcription factor that upregulates expression of the ABC transporters ABCA1 and ABCG1, that mediate the transfer of free cholesterol to lipid poor APOA-I to form nascent high-density lipoprotein (HDL) or more lipidated HDL particles in which free cholesterol has been esterified and stored the core of the particle (mature HDL),. Excessive free cholesterol accumulation can induce cholesterol crystal formation in the lysosome to activate the NLRP3 inflammasome, and may also interfere with the function of the ER (ER stress), which if prolonged results in cell death by apoptosis, and Lipid rafts are enriched in sphingomyelin, which forms a complex with free cholesterol. As the cholesterol content of lipid rafts increases, pro-inflammatory Toll-like receptor 4 (TLR4) signalling is promoted, which can also be induced by oxidized low-density lipoprotein (LDL) through a heterotrimeric complex composed of CD36–TLR4–TLR6. This signalling resulted in the activation of nuclear factor-κB (NF-κB) and production of pro-inflammatory cytokines and chemokines.