Oxidized high-density lipoprotein promotes CD36 palmitoylation and increases lipid uptake in macrophages

Abstract

Oxidized high-density lipoprotein (oxHDL) reduces the ability of cells to mediate reverse cholesterol transport and also shows atherogenic properties. Palmitoylation of cluster of differentiation 36 (CD36), an important receptor mediating lipoprotein uptake, is required for fatty acid endocytosis. However, the relationship between oxHDL and CD36 has not been described in mechanistic detail. Here, we demonstrate using acyl-biotin exchange analysis that oxHDL activates CD36 by increasing CD36 palmitoylation, which promotes efficient uptake in macrophages. This modification increased CD36 incorporation into plasma lipid rafts and activated downstream signaling mediators, such as Lyn, Fyn, and c-Jun N-terminal kinase, which elicited enhanced oxHDL uptake and foam cell formation. Furthermore, blocking CD36 palmitoylation with the pharmacological inhibitor 2-bromopalmitate decreased cell surface translocation and lowered oxHDL uptake in oxHDL-treated macrophages. We verified these results by transfecting oxHDL-induced macrophages with vectors expressing wildtype or mutant CD36 (mCD36) in which the cytoplasmic palmitoylated cysteine residues were replaced. We show that cells containing mCD36 exhibited less palmitoylated CD36, disrupted plasma membrane trafficking, and reduced protein stability. Moreover, in ApoE−/−CD36−/− mice, lipid accumulation at the aortic root in mice receiving the mCD36 vector was decreased, suggesting that CD36 palmitoylation is responsible for lipid uptake in vivo. Finally, our data indicated that palmitoylation of CD36 was dependent on DHHC6 (Asp-His-His-Cys) acyltransferase and its cofactor selenoprotein K, which increased the CD36/caveolin-1 interaction and membrane targeting in cells exposed to oxHDL. Altogether, our study uncovers a causal link between oxHDL and CD36 palmitoylation and provides insight into foam cell formation and atherogenesis. Oxidized high-density lipoprotein (oxHDL) reduces the ability of cells to mediate reverse cholesterol transport and also shows atherogenic properties. Palmitoylation of cluster of differentiation 36 (CD36), an important receptor mediating lipoprotein uptake, is required for fatty acid endocytosis. However, the relationship between oxHDL and CD36 has not been described in mechanistic detail. Here, we demonstrate using acyl-biotin exchange analysis that oxHDL activates CD36 by increasing CD36 palmitoylation, which promotes efficient uptake in macrophages. This modification increased CD36 incorporation into plasma lipid rafts and activated downstream signaling mediators, such as Lyn, Fyn, and c-Jun N-terminal kinase, which elicited enhanced oxHDL uptake and foam cell formation. Furthermore, blocking CD36 palmitoylation with the pharmacological inhibitor 2-bromopalmitate decreased cell surface translocation and lowered oxHDL uptake in oxHDL-treated macrophages. We verified these results by transfecting oxHDL-induced macrophages with vectors expressing wildtype or mutant CD36 (mCD36) in which the cytoplasmic palmitoylated cysteine residues were replaced. We show that cells containing mCD36 exhibited less palmitoylated CD36, disrupted plasma membrane trafficking, and reduced protein stability. Moreover, in ApoE−/−CD36−/− mice, lipid accumulation at the aortic root in mice receiving the mCD36 vector was decreased, suggesting that CD36 palmitoylation is responsible for lipid uptake in vivo. Finally, our data indicated that palmitoylation of CD36 was dependent on DHHC6 (Asp-His-His-Cys) acyltransferase and its cofactor selenoprotein K, which increased the CD36/caveolin-1 interaction and membrane targeting in cells exposed to oxHDL. Altogether, our study uncovers a causal link between oxHDL and CD36 palmitoylation and provides insight into foam cell formation and atherogenesis. High-density lipoprotein (HDL) facilitates cholesterol efflux and promotes reverse cholesterol transport (RCT) to the liver for metabolism, which reduces the excess cholesterol from peripheral tissues. In addition to its role in RCT, HDL has other beneficial functions in antiatherosclerosis, such as antioxidation, anti-inflammation, and endothelium-dependent vasodilatation (1Li X.P. Zhao S.P. Zhang X.Y. Liu L. Gao M. Zhou Q.C. Protective effect of high density lipoprotein on endothelium-dependent vasodilatation.Int. J. Cardiol. 2000; 73: 231-236Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar). However, HDL is constantly remodeled and highly susceptible to various modifications, specifically oxidation, which is oxidized even more rapidly than low-density lipoprotein (LDL) (2Nakajima T. Sakagishi Y. Katahira T. Nagata A. Kuwae T. Nakamura H. et al.Characterization of a specific monoclonal antibody 9F5-3a and the development of assay system for oxidized HDL.Biochem. Biophys. Res. Commun. 1995; 217: 407-411Crossref PubMed Scopus (20) Google Scholar, 3Hurtado I. Fiol C. Gracia V. Caldú P. In vitro oxidised HDL exerts a cytotoxic effect on macrophages.Atherosclerosis. 1996; 125: 39-46Abstract Full Text PDF PubMed Scopus (50) Google Scholar). Oxidized HDL (oxHDL) loses its antiatherosclerotic function, turning into a dysfunctional form, which increases macrophage lipid loading (4Thorne R.F. Mhaidat N.M. Ralston K.J. Burns G.F. CD36 is a receptor for oxidized high density lipoprotein: implications for the development of atherosclerosis.FEBS Lett. 2007; 581: 1227-1232Crossref PubMed Scopus (68) Google Scholar), impairs endothelial function (5Wu J. He Z. Gao X. Wu F. Ding R. Ren Y. et al.Oxidized high-density lipoprotein impairs endothelial progenitor cells' function by activation of CD36-MAPK-TSP-1 pathways.Antioxid. Redox Signal. 2015; 22: 308-324Crossref PubMed Scopus (22) Google Scholar), and exhibits proatherogenic properties (6Ito F. Ito T. High-density lipoprotein (HDL) triglyceride and oxidized HDL: new lipid biomarkers of lipoprotein-related atherosclerotic cardiovascular disease.Antioxidants (Basel). 2020; 9: 362Crossref Scopus (13) Google Scholar). OxHDL level is elevated in patients with cardiovascular diseases (7Kresanov P. Ahotupa M. Vasankari T. Kaikkonen J. Kähönen M. Lehtimäki T. et al.The associations of oxidized high-density lipoprotein lipids with risk factors for atherosclerosis: the cardiovascular risk in Young Finns study.Free Radic. Biol. Med. 2013; 65: 1284-1290Crossref PubMed Scopus (20) Google Scholar). The oxHDL is detected to locate in the intima of atheromatous plaques in human abdominal aortae and found relevance to acute myocardial infarction (8Nakajima T. Origuchi N. Matsunaga T. Kawai S. Hokari S. Nakamura H. et al.Localization of oxidized HDL in atheromatous plaques and oxidized HDL binding sites on human aortic endothelial cells.Ann. Clin. Biochem. 2000; 37: 179-186Crossref PubMed Scopus (51) Google Scholar, 9Sawada N. T. S. T. S. T. et oxidized increased in patients with acute myocardial is by Res. 2020; Full Text Full Text PDF PubMed Google Scholar). oxHDL has been to with an increased risk for cardiovascular H. M. S. S. T. et al.Oxidized high-density lipoprotein as a risk for cardiovascular in Full Text Full Text PDF PubMed Scopus Google Scholar). of differentiation 36 (CD36), a receptor is an membrane containing M. of CD36 implications for of fatty acid Biophys. PubMed Scopus Google Scholar). The receptor a and cytoplasmic by and M. of CD36 implications for of fatty acid Biophys. PubMed Scopus Google Scholar). CD36 modification and palmitoylation M. of CD36 implications for of fatty acid Biophys. PubMed Scopus Google Scholar). The sites and the at the has sites M. of CD36 implications for of fatty acid Biophys. PubMed Scopus Google Scholar). In palmitoylation sites on cysteine at the and and and N. CD36 is palmitoylated on and cytoplasmic Biol. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, R. L. J. et of the of CD36 is for or protein CD36 Biochem. PubMed Scopus Google Scholar). CD36 is in various cells and endothelial and and is by H. Y. J. Zhou N. The role of CD36 in cardiovascular Res. PubMed Scopus Google Scholar). from its role in fatty acid uptake, important function of CD36 is to oxidized low-density lipoprotein oxidized the and into which promotes foam cell formation and accumulation of cholesterol in atherosclerotic plaques H. Y. J. Zhou N. The role of CD36 in cardiovascular Res. PubMed Scopus Google Scholar). CD36 functions as an oxHDL which oxHDL uptake in macrophages and in endothelial progenitor cells (4Thorne R.F. Mhaidat N.M. Ralston K.J. Burns G.F. CD36 is a receptor for oxidized high density lipoprotein: implications for the development of atherosclerosis.FEBS Lett. 2007; 581: 1227-1232Crossref PubMed Scopus (68) Google Scholar, J. He Z. Gao X. Wu F. Ding R. Ren Y. et al.Oxidized high-density lipoprotein impairs endothelial progenitor cells' function by activation of CD36-MAPK-TSP-1 pathways.Antioxid. Redox Signal. 2015; 22: 308-324Crossref PubMed Scopus (22) Google Scholar). also that CD36 a role in the M. Gao X. Wu J. Liu H. L. et al.Oxidized high-density lipoprotein in Res. PubMed Scopus Google Scholar), which that CD36 is in the of dysfunctional Palmitoylation the of is a modification by of a to cysteine residues a protein and Biol. 2007; PubMed Scopus Google Scholar). other of protein such as and palmitoylation is a of modification protein and Biol. 2007; PubMed Scopus Google Scholar). Palmitoylation is by various containing (Asp-His-His-Cys) and by such as protein or protein and Biol. 2007; PubMed Scopus Google Scholar). Palmitoylation increases the of the protein and protein membrane trafficking, and protein and Biol. 2007; PubMed Scopus Google Scholar). The palmitoylation of CD36 and CD36 palmitoylation modification is at the and to the for which reduces the of membrane incorporation R.F. Ralston K.J. Mhaidat N.M. Zhang et of the of its in the Biophys. PubMed Scopus Google Scholar). palmitoylation of CD36 uptake and lipid in J. H. Zhao et facilitates fatty acid uptake by Commun. 2020; PubMed Scopus Google Scholar). CD36 palmitoylation and its plasma membrane to with L. Zhang C. X. P. Zhou S. et palmitoylation fatty acid and promotes in Full Text Full Text PDF PubMed Scopus Google Scholar). on the functions of CD36 palmitoylation were on and uptake J. H. Zhao et facilitates fatty acid uptake by Commun. 2020; PubMed Scopus Google Scholar, L. Zhang C. X. P. Zhou S. et palmitoylation fatty acid and promotes in Full Text Full Text PDF PubMed Scopus Google Scholar). the other the signaling by oxHDL and for the atherogenic oxHDL less as with that oxHDL CD36 as a receptor (4Thorne R.F. Mhaidat N.M. Ralston K.J. Burns G.F. CD36 is a receptor for oxidized high density lipoprotein: implications for the development of atherosclerosis.FEBS Lett. 2007; 581: 1227-1232Crossref PubMed Scopus (68) Google Scholar), we to the of oxHDL on CD36 palmitoylation and the role of such modification on CD36 foam cell and lipid accumulation in macrophages and The oxHDL was and we found that the oxHDL increased lipoprotein The oxidized modification a in cell for the was elevated to in macrophages that the oxHDL oxHDL at cell at the of oxHDL on CD36 palmitoylation, the cells were exposed to HDL and various of the oxHDL for We an acyl-biotin exchange assay on from the increased CD36 palmitoylation was in the cells with oxHDL at from to data that oxHDL at palmitoylation modification with the cells Moreover, the palmitoylation level in cells with oxHDL was than cells with HDL We the results by with HDL or oxHDL in macrophages and human oxHDL increased CD36 palmitoylation with or HDL in of cells the in the palmitoylation level detected in cells was the as the level in cells and macrophages and reduced in cells We also that the CD36 level was in and cells increased with oxHDL in the cell the membrane binding of palmitoylated CD36, cells were with HDL or and lipid membrane with high of cholesterol and were by The membrane rafts as were detected in and as by the of its CD36 was in of to in the cells as as the In increased of CD36 in cells were found in and of the lipid suggesting that oxHDL promotes CD36 and membrane and the of oxHDL on CD36 surface we of CD36 and membrane lipid and the was detected by was from in and of the was in cells with suggesting an in membrane of CD36 In between CD36 and an was detected in and that CD36 to at the However, the for CD36 was more from in cells The results that enhanced palmitoylation promotes CD36 from to the plasma that the and a with CD36, and the with the is required for activation of the c-Jun N-terminal in foam cell and formation is with the Fyn, Lyn, and in human S. A. PubMed Scopus Google Scholar, K.J. J. C. et signaling of Biol. Full Text Full Text PDF PubMed Scopus Google Scholar, M. signaling is for macrophage foam cell Full Text Full Text PDF PubMed Scopus Google Scholar, M. specific signaling is required for activation by oxidized low-density Res. PubMed Scopus Google Scholar). we oxHDL promotes and to CD36 and the downstream signaling cells were with HDL and and and were detected the was at oxHDL The of at increased from to in less than the detected in at the of CD36 with and Fyn, the cell were with CD36 and detected by were increased in oxHDL-treated cells with the or which that CD36 a with and in macrophages in to oxHDL We that oxHDL increased CD36, Fyn, and in our in and the in the detected CD36 is by or CD36 we the cells with oxHDL and a lipid CD36 and protein were increased in oxHDL-treated and the of cells with oxHDL and was with the cells and Moreover, is in CD36 and protein between cells with oxHDL and oxHDL and We also found that oxHDL increased in and and these results that oxHDL CD36, Fyn, and and to in the protein We oxHDL macrophages were with oxHDL for from to and the of in the cell was detected by at various we that oxHDL increased the level of in cells at and increased in the data demonstrate that the downstream signaling is activated in to oxHDL we that oxHDL CD36 as by increasing and downstream the of oxHDL on lipid uptake in the cells were exposed to and the the oxHDL uptake level was detected by and was found in cells However, in or and analysis by that oxHDL was increased more than with HDL uptake and that enhanced lipid uptake to increased foam cell we the of oxHDL on lipid accumulation and foam cell formation by oxHDL-treated macrophages a increased lipid which more foam as by than the cells with HDL the role of CD36 in oxHDL a inhibitor of membrane CD36, was to and found that a in the oxHDL uptake and foam cell formation The results were in CD36 in which oxHDL uptake was in macrophages from mice than wildtype mice Moreover, we found that the uptake of oxHDL was reduced in the of in cells suggesting a role of in oxHDL uptake were not in macrophages our data that oxHDL increases lipid CD36 palmitoylation modification is required by oxHDL-induced CD36 and lipid uptake, we palmitoylation by using 2-bromopalmitate a inhibitor of Y. L. of protein palmitoylation, and cell signaling by 2-bromopalmitate and fatty Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). cells were with oxHDL and or oxHDL and the that CD36 palmitoylation was detected in oxHDL-treated cells by We the of reduced CD36 as lipid rafts were by The reduced CD36 into lipid rafts The results from that CD36 was on the cell surface and with in oxHDL cells The of CD36 and was by suggesting reduced of CD36 in the membrane The of CD36 with was more found in suggesting that CD36 is in the by a of palmitoylation We a assay to the of on the The results that CD36 and were less with in the of suggesting that the interaction the was and Finally, we oxHDL uptake was by palmitoylation were with and and a in the uptake of oxHDL by with that is a pharmacological palmitoylation we disrupted CD36 palmitoylation to its role in oxHDL We the CD36 cysteine which palmitoylation and into CD36 (mCD36) and wildtype CD36 were into macrophages. the of the cells were by which has been to CD36 palmitoylation R. 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The results from the assay that was palmitoylated However, the palmitoylation was reduced in the cells with which that was by the and we detected palmitoylation in the of cells in the of oxHDL. results were in which palmitoylation was found in decreased in mCD36 and Moreover, we found that mCD36 membrane lipid was reduced with palmitoylation The results were by In to the of and was less mCD36 detected at the plasma membrane Furthermore, mCD36 with was in more cells than suggesting that CD36 to plasma is or the palmitoylation sites In we the CD36 by oxHDL is by the palmitoylation with and mCD36 were with oxHDL. from the assay that was detected in mCD36 at and the was more at than in of oxHDL uptake in cells that was reduced in to cells Finally, to the of CD36 in mice, we CD36 and mice with or of at aortic were and with The mice containing mCD36 less lipid accumulation than the mice with which for a The plasma and cholesterol not between the The in data at that CD36 palmitoylation is in lipid uptake and foam cell formation in mice, we the of which is also elevated by that oxHDL increases CD36 palmitoylation and lipoprotein we to the the In at as which the J. and Biochem. 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Furthermore, we found that the proatherogenic of oxHDL were by increasing CD36 palmitoylation and downstream and our the that with CD36 modification a for with lipoprotein and CD36 has been to an of the signaling in and to macrophage K.J. J. C. et signaling of Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). et et cholesterol a role in in Biol. PubMed Scopus Google found that high cholesterol and atherogenesis. CD36 results in reduced plasma and and reduced macrophage in S. M. macrophage and and impairs Res. PubMed Scopus Google Scholar). is that HDL properties is oxidized and to I. Fiol C. Gracia V. Caldú P. In vitro oxidised HDL exerts a cytotoxic effect on macrophages.Atherosclerosis. 1996; 125: 39-46Abstract Full Text PDF PubMed Scopus (50) Google Scholar, N. 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