title: Modification of low density lipoprotein by lipoprotein lipase or hepatic lipase induces enhanced uptake and cholesterol accumulation in cells.
abstract: Incubation of low density lipoprotein(s) (LDL) with either lipoprotein lipase or hepatic lipase led to modification of the core lipid composition of LDL. Both lipases modified LDL by substantially reducing core triglyceride content without producing marked differences in size, charge, or lipid peroxide content in comparison to native LDL. The triglyceride-depleted forms of LDL that result from treatment with these two enzymes were degraded at approximately twice the rate of native LDL by human monocyte-derived macrophages (HMDM). Lipase-modified LDL degradation was inhibited by chloroquine, suggesting lysosomal involvement in LDL cellular processing. The increased degradation by macrophages of the LDL modified by these lipases was accompanied by enhanced cholesterol esterification rates, as well as by an increase in cellular free and esterified cholesterol content. In a patient with hepatic triglyceride lipase deficiency, degradation of the triglyceride-rich LDL by HMDM was approximately half that of normal LDL. Following in vitro incubation of LDL from this patient with either lipoprotein or hepatic lipase, lipoprotein degradation increased to normal. Several lines of evidence indicate that LDL modified by both lipases were taken up by the LDL receptor and not by the scavenger receptor. 1) The degradation of lipase-modified LDL in nonphagocytic cells (human skin fibroblast and arterial smooth muscle cells) as well as in phagocytic cells (HMDM, J-774, HL-60, and U-937 cell lines) could be dissociated from that of acetylated LDL and was always higher than that of native LDL. A similar pattern was found for cellular cholesterol esterification and cholesterol mass. 2) LDL receptor-negative fibroblasts did not degrade lipase-modified LDL. 3) A monoclonal antibody to the LDL receptor inhibited macrophage degradation of the lipase-modified LDL. 4) Excess amounts of unlabeled LDL competed substantially with 125I-labeled lipase-modified LDL for degradation by both macrophages and fibroblasts. Thus, lipase-modified LDL can cause significant cholesterol accumulation in macrophages even though it is taken up by LDL and not by the scavenger receptor. This effect could possibly be related to the reduced triglyceride content in the core of LDL, which may alter presentation of the LDL receptor-binding domain of apolipoprotein B on the particle surface, thereby leading to increased recognition and cellular uptake via the LDL receptor pathway.
authors.affiliation: Department of Medicine, University of Washington, Seattle 98195.
authors.forename: M
authors.initials: M
authors.lastname: Aviram
authors.forename: E L
authors.initials: EL
authors.lastname: Bierman
authors.forename: A
authors.initials: A
authors.lastname: Chait
mesh_terms: D000911:Antibodies, Monoclonal; D053304:Apolipoprotein C-II; D001056:Apolipoproteins C / Q000378:metabolism; D002784:Cholesterol / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008049:Lipase / Q000378:metabolism*; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D008264:Macrophages / Q000201:enzymology; D011973:Receptors, LDL / Q000378:metabolism; D013997:Time Factors
chemical_list: D000911:Antibodies, Monoclonal; D053304:Apolipoprotein C-II; D001056:Apolipoproteins C; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D002784:Cholesterol; D008049:Lipase; D008071:Lipoprotein Lipase