Oxidative tyrosylation of high density lipoprotein by peroxidase enhances cholesterol removal from cultured fibroblasts and macrophage foam cells.
Lipoprotein oxidation is thought to play a pivotal role in atherogenesis, yet the underlying reaction mechanisms remain poorly understood. We have explored the possibility that high density lipoprotein (HDL) might be oxidized by peroxidase-generated tyrosyl radical. Exposure of HDL to L-tyrosine, H2O2, and horseradish peroxidase crosslinked its apolipoproteins and strikingly increased protein-associated fluorescence. The reaction required L-tyrosine but was independent of free metal ions; it was blocked by either catalase or the heme poison aminotriazole. Dityrosine and other tyrosine oxidation products were detected in the apolipoproteins of HDL modified by the peroxidase/L-tyrosine/H2O2 system, implicating tyrosyl radical in the reaction pathway. Further evidence suggests that tyrosylated HDL removes cholesterol from cultured cells more effectively than does HDL. Tyrosylated HDL was more potent than HDL at inhibiting cholesterol esterification by the acyl-CoA:cholesterol acyltransferase reaction, stimulating the incorporation of [14C]acetate into [14C]cholesterol, and depleting cholesteryl ester stores in human skin fibroblasts. Moreover, exposure of mouse macrophage foam cells to tyrosylated HDL markedly diminished cholesteryl ester and free cholesterol mass. We have recently found that myeloperoxidase, a heme protein secreted by activated phagocytes, can also convert L-tyrosine to o,o'-dityrosine. This raises the possibility that myeloperoxidase-generated tyrosyl radical may modify HDL, enabling the lipoprotein to protect the artery wall against pathological cholesterol accumulation.
Francis
G A
GA
Department of Medicine, University of Washington, Seattle 98195.
Mendez
A J
AJ
Bierman
E L
EL
Heinecke
J W
JW
D000818:Animals; D001202:Ascitic Fluid / Q000166:cytology; D001692:Biological Transport; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D003238:Connective Tissue / Q000378:metabolism*; D003239:Connective Tissue Cells; D004951:Esterification; D005347:Fibroblasts / Q000378:metabolism; D005487:Foam Cells / Q000378:metabolism; D005609:Free Radicals; D006735:Horseradish Peroxidase / Q000378:metabolism*; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D010084:Oxidation-Reduction; D012867:Skin / Q000166:cytology; D014443:Tyrosine / Q000378:metabolism*
D005609:Free Radicals; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D014443:Tyrosine; D002784:Cholesterol; D006735:Horseradish Peroxidase