title: Lysosomal cholesterol accumulation inhibits subsequent hydrolysis of lipoprotein cholesteryl ester.
abstract: Human macrophages incubated for prolonged periods with mildly oxidized LDL (oxLDL) or cholesteryl ester-rich lipid dispersions (DISP) accumulate free and esterified cholesterol within large, swollen lysosomes similar to those in foam cells of atherosclerosis. The cholesteryl ester (CE) accumulation is, in part, the result of inhibition of lysosomal hydrolysis due to increased lysosomal pH mediated by excessive lysosomal free cholesterol (FC). To determine if the inhibition of hydrolysis was long lived and further define the extent of the lysosomal defect, we incubated THP-1 macrophages with oxLDL or DISP to produce lysosome sterol engorgement and then chased with acetylated LDL (acLDL). Unlike oxLDL or DISP, CE from acLDL normally is hydrolyzed rapidly. Three days of incubation with oxLDL or DISP produced an excess of CE in lipid-engorged lysosomes, indicative of inhibition. After prolonged oxLDL or DISP pretreatment, subsequent hydrolysis of acLDL CE was inhibited. Coincident with the inhibition, the lipid-engorged lysosomes failed to maintain an acidic pH during both the initial pretreatment and subsequent acLDL incubation. This indicates that the alterations in lysosomes were general, long lived, and affected subsequent lipoprotein metabolism. This same phenomenon, occurring within atherosclerotic foam cells, could significantly affect lesion progression.
authors.affiliation: Department of Pathology, Vanderbilt University School of Medicine, South Nashville, TN 37232-2561, USA. jay.jerome@vanderbilt.edu
authors.forename: W Gray
authors.initials: WG
authors.lastname: Jerome
authors.forename: Brian E
authors.initials: BE
authors.lastname: Cox
authors.forename: Evelyn E
authors.initials: EE
authors.lastname: Griffin
authors.forename: Jody C
authors.initials: JC
authors.lastname: Ullery
mesh_terms: D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism*; D005487:Foam Cells / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D008074:Lipoproteins / Q000737:chemistry / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000648:ultrastructure
chemical_list: D002788:Cholesterol Esters; D008074:Lipoproteins; D002784:Cholesterol