Endolysosomal phospholipidosis and cytosolic lipid droplet storage and release in macrophages.
This review summarizes the current knowledge of endolysosomal and cytoplasmic lipid storage in macrophages induced by oxidized LDL (Ox-LDL), enzymatically degraded LDL (E-LDL) and other atherogenic lipoprotein modifications, and their relation to the adapter protein 3 (AP-3) dependent ABCA1 and ABCG1 cellular lipid efflux pathways. We compare endolysosomal lipid storage caused either through drug induced phospholipidosis, inheritable endolysosomal and cytosolic lipid storage disorders and Ox-LDL or E-LDL induced phagosomal uptake and cytosolic lipid droplet storage in macrophages. Ox-LDL is resistant to rapid endolysosomal hydrolysis and is trapped within the endolysosomal compartment generating lamellar bodies which resemble the characteristics of phospholipidosis. Various inherited lysosomal storage diseases including sphingolipidosis, glycosphingolipidosis and cholesterylester storage diseases also present a phospholipidosis phenotype. In contrast E-LDL resembling coreless unesterified cholesterol enriched LDL-particles, with a multilamellar, liposome-like structure, lead to rapid phagosomal degradation and cytosolic lipid droplet accumulation. As a consequence the uptake of E-LDL through type I and type II phagocytosis leads to increased lipid droplet formation and moderate upregulation of ABCA1 and ABCG1 while uptake of Ox-LDL leads to a rapid expansion of the lysosomal compartment and a pronounced upregulation of the ABCA1/ABCG1/AP-3 lipid efflux pathway.
Schmitz
Gerd
G
Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss Allee 11, 93049 Regensburg, Germany. gerd.schmitz@klinik.uni-regensburg.de
Grandl
Margot
M
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D033963:Adaptor Protein Complex 3 / Q000378:metabolism; D000818:Animals; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism*; D019992:Databases as Topic; D005089:Exocytosis; D005487:Foam Cells / Q000378:metabolism; D006801:Humans; D052439:Lipid Metabolism Disorders / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D008066:Lipolysis / Q000187:drug effects / Q000235:genetics; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008247:Lysosomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000378:metabolism; D015388:Organelles / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010587:Phagocytosis; D010743:Phospholipids / Q000378:metabolism*
C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D033963:Adaptor Protein Complex 3; D008077:Lipoproteins, LDL; D010743:Phospholipids; C099252:oxidized low density lipoprotein