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Effect of HFE Variants on Sphingolipid Expression by SH-SY5Y Human Neuroblastoma Cells

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Abstract

C282Y and H63D are two common variants of the hemochromatosis protein HFE. SH-SY5Y human neuroblastoma cells stably transfected to express either wild type HFE (WT-HFE), or the C282Y or H63D allele were analyzed for effect of expression of the mutant proteins on transcription of 14 enzymes involved in sphingolipid metabolism. Cells expressing the C282Y variant showed significant increases (>2-fold) in transcription of five genes and decreases in two compared to that seen for cells expressing WT-HFE, while cells expressing the H63D variant showed an elevation in transcription of one gene and a decrease in two. These changes were seen as alterations in ganglioside composition, cell surface binding by the binding subunit of cholera toxin, expression of sphingosine-kinase-1 and synthesis of sphingosine-1-phosphate. These changes may explain why C282Y-HFE is a risk factor for colon and breast cancer and possibly protective against Alzheimer’s disease while H63D-HFE is a risk factor for neurodegenerative diseases.

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Acknowledgments

The authors thank Dr. Jong Yun for helpful discussions, Dr. K.A. Petro for her help with isolating lipid rafts, and Dr. Sang Lee for providing us with the SH-SY5Y cells stably transfected to express either FLAG-tagged WT-, H63D- or C282Y-HFE alleles. We also thank the Jake Gittlen Cancer Research Foundation (JAH), and the George M. Leader Family Corporation (JRC) for their support.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology H171, The Pennsylvania State University College of Medicine, 500 University Dr., Hershey, PA, 17033, USA

    F. Ali-Rahmani & C.-L. Schengrund

  2. Department of Neurosurgery, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA

    F. Ali-Rahmani & J. R. Connor

  3. Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA, 17033, USA

    J. A. Hengst

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  1. F. Ali-Rahmani
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  2. J. A. Hengst
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  4. C.-L. Schengrund
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Correspondence to C.-L. Schengrund.

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Special Issue: In Honor of Dr. Robert Yu.

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Ali-Rahmani, F., Hengst, J.A., Connor, J.R. et al. Effect of HFE Variants on Sphingolipid Expression by SH-SY5Y Human Neuroblastoma Cells. Neurochem Res 36, 1687–1696 (2011). https://doi.org/10.1007/s11064-011-0403-8

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