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Function of Platelet Glycosphingolipid Microdomains/Lipid Rafts
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Convergence: Lactosylceramide-Centric Signaling Pathways Induce Inflammation, Oxidative Stress, and Other Phenotypic Outcomes

Department of Pediatrics, Cardiology Division, Johns Hopkins University School of Medicine, Baltimore, MD 21287-3654, USA
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Author to whom correspondence should be addressed.
Academic Editor: Kazunori Hamamura
Int. J. Mol. Sci. 2021, 22(4), 1816; https://doi.org/10.3390/ijms22041816
Received: 29 December 2020 / Revised: 2 February 2021 / Accepted: 6 February 2021 / Published: 12 February 2021
(This article belongs to the Special Issue Roles of Glycosphingolipids in Metabolism)
Lactosylceramide (LacCer), also known as CD17/CDw17, is a member of a large family of small molecular weight compounds known as glycosphingolipids. It plays a pivotal role in the biosynthesis of glycosphingolipids, primarily by way of serving as a precursor to the majority of its higher homolog sub-families such as gangliosides, sulfatides, fucosylated-glycosphingolipids and complex neutral glycosphingolipids—some of which confer “second-messenger” and receptor functions. LacCer is an integral component of the “lipid rafts,” serving as a conduit to transduce external stimuli into multiple phenotypes, which may contribute to mortality and morbidity in man and in mouse models of human disease. LacCer is synthesized by the action of LacCer synthase (β-1,4 galactosyltransferase), which transfers galactose from uridine diphosphate galactose (UDP-galactose) to glucosylceramide (GlcCer). The convergence of multiple physiologically relevant external stimuli/agonists—platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), stress, cigarette smoke/nicotine, tumor necrosis factor-α (TNF-α), and in particular, oxidized low-density lipoprotein (ox-LDL)—on β-1,4 galactosyltransferase results in its phosphorylation or activation, via a “turn-key” reaction, generating LacCer. This newly synthesized LacCer activates NADPH (nicotinamide adenine dihydrogen phosphate) oxidase to generate reactive oxygen species (ROS) and a highly “oxidative stress” environment, which trigger a cascade of signaling molecules and pathways and initiate diverse phenotypes like inflammation and atherosclerosis. For instance, LacCer activates an enzyme, cytosolic phospholipase A2 (cPLA2), which cleaves arachidonic acid from phosphatidylcholine. In turn, arachidonic acid serves as a precursor to eicosanoids and prostaglandin, which transduce a cascade of reactions leading to inflammation—a major phenotype underscoring the initiation and progression of several debilitating diseases such as atherosclerosis and cancer. Our aim here is to present an updated account of studies made in the field of LacCer metabolism and signaling using multiple animal models of human disease, human tissue, and cell-based studies. These advancements have led us to propose that previously unrelated phenotypes converge in a LacCer-centric manner. This LacCer synthase/LacCer-induced “oxidative stress” environment contributes to inflammation, atherosclerosis, skin conditions, hair greying, cardiovascular disease, and diabetes due to mitochondrial dysfunction. Thus, targeting LacCer synthase may well be the answer to remedy these pathologies. View Full-Text
Keywords: lactosylceramide; glycosphingolipids; cell proliferation; angiogenesis; inflammation; atherosclerosis lactosylceramide; glycosphingolipids; cell proliferation; angiogenesis; inflammation; atherosclerosis
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MDPI and ACS Style

Chatterjee, S.; Balram, A.; Li, W. Convergence: Lactosylceramide-Centric Signaling Pathways Induce Inflammation, Oxidative Stress, and Other Phenotypic Outcomes. Int. J. Mol. Sci. 2021, 22, 1816. https://doi.org/10.3390/ijms22041816

AMA Style

Chatterjee S, Balram A, Li W. Convergence: Lactosylceramide-Centric Signaling Pathways Induce Inflammation, Oxidative Stress, and Other Phenotypic Outcomes. International Journal of Molecular Sciences. 2021; 22(4):1816. https://doi.org/10.3390/ijms22041816

Chicago/Turabian Style

Chatterjee, Subroto; Balram, Amrita; Li, Wendy. 2021. "Convergence: Lactosylceramide-Centric Signaling Pathways Induce Inflammation, Oxidative Stress, and Other Phenotypic Outcomes" Int. J. Mol. Sci. 22, no. 4: 1816. https://doi.org/10.3390/ijms22041816

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