From Glycans to Lipids and Vice Versa
Chu-Huang (Mendel) Chen, MD, PhD
Director, Vascular and Medicinal Research, Texas Heart Institute, USA
Chairman, Research Advisory Committee, New York Heart Research Foundation, USA
Chair Professor of Medicine, Kaohsiung Medical University, Taiwan
The human genome has a narrow margin of inter-individual variation; yet, human phenotypes are vastly different between races and among individuals within the same race. Epigenetic modulation of the human genome is believed to play an important role in creating these phenotypic variations. Of the possible mechanisms, post-translational glycosylation of proteins may contribute significantly to the establishment of individualized “epigenetic memory” of the genome. The majority of all proteins are glycosylated, and glycans have numerous important structural, functional, and regulatory roles in various physiological and pathological processes. Glycan addition also occurs to lipids, producing a large variety of glycolipids.Most glycolipids are lipids that form part of the plasma membrane with a short carbohydrate chain covalently attached, and this chain is exposed on the outer surface of the cell. The glycoplipids have a mainly communicative role, often acting as markers for cellular recognition. Additionally, they provide stability for the cell and help cells join to other cells to form tissues. Pathologically, however, excessive glycolipids, such as gangliosides, may enhance sphingomyelinase (SMase) activity of the cell membrane to overproduce ceramide, which in turn induces the senescence of cells, including vascular endothelial cells (ECs) and myoblasts. Low-density lipoprotein (LDL) has a role in aging process, including vascular senescence. However, not all LDL particles are pathogenic, and the culprit LDL entity remains to be identified. In our search for the culprit LDL, we have isolated a highly electronegative entity, L5, from human plasma LDL subfractions (L1-L5) resolved by using anion-exchange chromatography. From evidence based on in vitro, in vivo, and human studies, we have demonstrated L5’s pro-senescent, inflammatory, atherosclerotic, and thrombotic properties, which are not seen in L1-L4. Chemical analysis has revealed that L5 carries excessive apolipoproteins (apoE, A1, CII, CIII, (a), J) in addition to apoB100, which is the only protein in the least electronegative LDL, L1. Further analysis has shown consistent glycosylation on certain residues of both apoE and apoB100 in L5 particles. The associated conformational changes result in hindrance of L5 docking to the normal LDL receptor, forcing an increased residence time of the L5 particles in circulation. The apoB100 molecule in L5 also possesses a prominent SMase-like activity. Consequently, L5 is not only a ceramide-rich lipoprotein but can also induce excessive ceramide production in ECs through SMase-like activity. Additionally, our preliminary studies suggest that L5 is able to glycosylate transmembrane receptors, such as STRA6 (stimulated by retinoic acid 6). Because of STRA6’s role in transducing retinoic acid (vitamin A) signaling, its glycosylation by L5 impedes normal cellular function, adding to complications in disease patterns, as in type 2 diabetes. Thus, L5 is both a glycan receiver and glycan donor/catalyzer. Glycan-lipid interactions are likely to have important biological and clinical implications. Extensive investigations are warranted to delineate the underlying mechanisms to advance our understanding of lipid-associated diseases and to disclose new targets for treatment.