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Transcriptomically Revealed Oligo-Fucoidan Enhances the Immune System and Protects Hepatocytes via the ASGPR/STAT3/HNF4A Axis

Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan 35053, Taiwan
Radiation Biology Research Center, Institute for Radiological Research, Chang Gung University/Chang Gung Memorial Hospital at Linkou, Taoyuan 33302, Taiwan
Research and Development Center, Hi-Q Marine Biotech International Ltd. Songshan District, Taipei 10561, Taiwan
Institute of Bioinformatics and Structural Biology, National Tsing-Hua University, Hsinchu 30013, Taiwan
Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 30010, Taiwan
Program in Environmental and Occupational Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
Author to whom correspondence should be addressed.
These authors contributed equally to this paper.
Biomolecules 2020, 10(6), 898;
Received: 6 April 2020 / Revised: 9 June 2020 / Accepted: 10 June 2020 / Published: 12 June 2020
Oligo-fucoidan, a sulfated polysaccharide extracted from brown seaweed, exhibits anti-inflammatory and anti-tumor effects. However, the knowledge concerning the detailed mechanism of oligo-fucoidan on liver cells is obscure. In this study, we investigate the effect of oligo-fucoidan in normal hepatocytes by transcriptomic analysis. Using an oligo-fucoidan oral gavage in wild-type adult zebrafish, we find that oligo-fucoidan pretreatment enhances the immune system and anti-viral genes in hepatocytes. Oligo-fucoidan pretreatment also decreases the expression of lipogenic enzymes and liver fibrosis genes. Using pathway analysis, we identify hepatocyte nuclear factor 4 alpha (HNF4A) to be the potential driver gene. We further investigate whether hepatocyte nuclear factor 4 alpha (HNF4A) could be induced by oligo-fucoidan and the underlying mechanism. Therefore, a normal hepatocyte clone 9 cell as an in vitro model was used. We demonstrate that oligo-fucoidan increases cell viability, Cyp3a4 activity, and Hnf4a expression in clone 9 cells. We further demonstrate that oligo-fucoidan might bind to asialoglycoprotein receptors (ASGPR) in normal hepatocytes through both in vitro and in vivo competition assays. This binding, consequently activating the signal transducer and activator of transcription 3 (STAT3), increases the expression of the P1 isoform of HNF4A. According to our data, we suggest that oligo-fucoidan not only enhances the gene expression associated with anti-viral ability and immunity, but also increases P1-HNF4A levels through ASGPR/STAT3 axis, resulting in protecting hepatocytes. View Full-Text
Keywords: oligo-fucoidan; hepatocyte nuclear factor 4 alpha (HNF4A); hepatocyte oligo-fucoidan; hepatocyte nuclear factor 4 alpha (HNF4A); hepatocyte
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Cheng, C.-C.; Yang, W.-Y.; Hsiao, M.-C.; Lin, K.-H.; Lee, H.-W.; Yuh, C.-H. Transcriptomically Revealed Oligo-Fucoidan Enhances the Immune System and Protects Hepatocytes via the ASGPR/STAT3/HNF4A Axis. Biomolecules 2020, 10, 898.

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