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Apolipoprotein E-mediated regulation of selenoprotein P transportation via exosomes

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Abstract

Selenoprotein P (SELENOP), secreted from the liver, functions as a selenium (Se) supplier to other tissues. In the brain, Se homeostasis is critical for physiological function. Previous studies have reported that SELENOP co-localizes with the apolipoprotein E receptor 2 (ApoER2) along the blood–brain barrier (BBB). However, the mechanism underlying SELENOP transportation from hepatocytes to neuronal cells remains unclear. Here, we found that SELENOP was secreted from hepatocytes as an exosomal component protected from plasma kallikrein-mediated cleavage. SELENOP was interacted with apolipoprotein E (ApoE) through heparin-binding sites of SELENOP, and the interaction regulated the secretion of exosomal SELENOP. Using in vitro BBB model of transwell cell culture, exosomal SELENOP was found to supply Se to brain endothelial cells and neuronal cells, which synthesized selenoproteins by a process regulated by ApoE and ApoER2. The regulatory role of ApoE in SELENOP transport was also observed in vivo using ApoE−/− mice. Exosomal SELENOP transport protected neuronal cells from amyloid β (Aβ)-induced cell death. Taken together, our results suggest a new delivery mechanism for Se to neuronal cells by exosomal SELENOP.

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Acknowledgements

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (NRF-2016R1A2B4009525). This work was also supported by National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (NRF-2015H1A2A1033613). This work was also partially supported by a Korea University Grant. We also thank the Electron Microscopy core facility at the ConveRgence mEDIcine research cenTer (CREDIT), Asan Medical Center for support and instrumentation for providing the valuable technical services.

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  1. Min Kyo Jung

    Present address: Department of Structure and Function of Neural Network, Korea Brain Research Institute, Daegu, 41068, South Korea

Authors and Affiliations

  1. Laboratory of Cellular and Molecular Biochemistry, Division of Life Sciences, Korea University, Seoul, 02841, Republic of Korea

    Yunjung Jin, Kwan Young Ko, Jun Ki Jang, Minju Ham, Hyunwoo Kang & Ick Young Kim

  2. Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea

    Youn Wook Chung

  3. Asan Institute for Life Sciences, Asan Medical Center & Department of Convergence Medicine, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea

    Min Kyo Jung & Chan Gi Pack

  4. Molecular Neurogenetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Massachusetts General Hospital, and Department of Neurology, Harvard Medical School, Boston, MA, 02114, USA

    Jea Hwang Lee

  5. Department of Biotechnology, College of Life Sciences, Ritsumeikan University, Kusatsu, Shiga, 525-8577, Japan

    Hisaaki Mihara

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Contributions

YJ designed and performed most of the experiments and wrote the manuscript. YWC contributed to animal experiments. MKJ and CGP are responsible for EM analysis. HM and JHL contributed to the design of exosomal study and assisted in the experiments. Additional experiments were helped by KYK, JKJ, MH, and HK. IYK contributed to study design, evaluation of results, and writing of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Ick Young Kim.

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Jin, Y., Chung, Y.W., Jung, M.K. et al. Apolipoprotein E-mediated regulation of selenoprotein P transportation via exosomes. Cell. Mol. Life Sci. 77, 2367–2386 (2020). https://doi.org/10.1007/s00018-019-03287-y

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