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Pure Appl. Chem., 2011, Vol. 83, No. 9, pp. 1731-1740

Published online 2011-07-10

Chemical composition-oriented receptor selectivity of L5, a naturally occurring atherogenic low-density lipoprotein

Liang-Yin Ke1,2, David A. Engler3, Jonathan Lu2, Risë K. Matsunami3, Hua-Chen Chan4,2, Guei-Jane Wang4,5,2, Chao-Yuh Yang4,2, Jan-Gowth Chang1 and Chu-Huang Chen6,4,2*

1 Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, and Department of Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
2 Vascular and Medicinal Research, Texas Heart Institute, Houston, TX 77030, USA
3 The Methodist Hospital Research Institute, Houston, TX 77030, USA
4 L5 Research Center, China Medical University Hospital, Taichung, Taiwan
5 National Research Institute of Chinese Medicine, Taipei, Taiwan
6 Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA

Abstract: Anion-exchange chromatography resolves human plasma low-density lipoprotein (LDL) into 5 subfractions, with increasing negative surface charge in the direction of L1 to L5. Unlike the harmless L1 to L4, the exclusively atherogenic L5 is rejected by the normal LDL receptor (LDLR) but endocytosed into vascular endothelial cells (ECs) through the lectin-like oxidized LDL receptor-1 (LOX-1). Analysis with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and 2-dimensional electrophoresis showed that the protein framework of L1 was composed mainly of apolipoprotein (apo) B100, with an isoelectric point (pI) of 6.620. There was a progressively increased association of additional proteins, including apoE (pI 5.5), apoAI (pI 5.4), apoCIII (pI 5.1), and apo(a) (pI 5.5), from L1 to L5. Liquid chromatography data-independent parallel-fragmentation mass spectrometry (LC/MSE) was used to quantify protein distribution in all subfractions. On the basis of weight percentages, L1 contained 99 % apoB-100 and trace amounts of other proteins. In contrast, L5 contained 60 % apoB100 and substantially increased amounts of apo(a), apoE, apoAI, and apoCIII. The compositional characteristics contribute to L5’s electronegativity, rendering it unrecognizable by LDLR. LOX-1, which has a high affinity for negatively charged ligands, is known to mediate the signaling of proinflammatory cytokines. Thus, the chemical composition-oriented receptor selectivity hinders normal metabolism of L5, enhancing its atherogenicity through abnormal receptors, such as LOX-1.