title: Non-mutagenic Suppression of Enterocyte Ferroportin 1 by Chemical Ribosomal Inactivation via p38 Mitogen-activated Protein Kinase (MAPK)-mediated Regulation: EVIDENCE FOR ENVIRONMENTAL HEMOCHROMATOSIS.
abstract: Iron transfer across the basolateral membrane of an enterocyte into the circulation is the rate-limiting step in iron absorption and is regulated by various pathophysiological factors. Ferroportin (FPN), the only known mammalian iron exporter, transports iron from the basolateral surface of enterocytes, macrophages, and hepatocytes into the blood. Patients with genetic mutations in FPN or repeated blood transfusion develop hemochromatosis. In this study, non-mutagenic ribosomal inactivation was assessed as an etiological factor of FPN-associated hemochromatosis in enterocytes. Non-mutagenic chemical ribosomal inactivation disrupted iron homeostasis by regulating expression of the iron exporter FPN-1, leading to intracellular accumulation in enterocytes. Mechanistically, a xenobiotic insult stimulated the intracellular sentinel p38 MAPK signaling pathway, which was positively involved in FPN-1 suppression by ribosomal dysfunction. Moreover, ribosomal inactivation-induced iron accumulation in Caenorhabditis elegans as a simplified in vivo model for gut nutrition uptake was dependent on SEK-1, a p38 kinase activator, leading to suppression of FPN-1.1 expression and iron accumulation. In terms of gene regulation, ribosomal stress-activated p38 signaling down-regulated NRF2 and NF-κB, both of which were positive transcriptional regulators of FPN-1 transcription. This study provides molecular evidence for the modulation of iron bioavailability by ribosomal dysfunction as a potent etiological factor of non-mutagenic environmental hemochromatosis in the gut-to-blood axis.
authors.affiliation: From the Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan 50612, South Korea and.
authors.forename: Chang-Kyu
authors.initials: CK
authors.lastname: Oh
authors.affiliation: From the Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan 50612, South Korea and.
authors.forename: Seong-Hwan
authors.initials: SH
authors.lastname: Park
authors.affiliation: From the Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan 50612, South Korea and.
authors.forename: Juil
authors.initials: J
authors.lastname: Kim
authors.affiliation: From the Laboratory of Mucosal Exposome and Biomodulation, Department of Biomedical Sciences, Pusan National University School of Medicine, Yangsan 50612, South Korea and the Medical Research Institute, Pusan National University, Busan 46241, South Korea moon@pnu.edu.
authors.forename: Yuseok
authors.initials: Y
authors.lastname: Moon
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D006432:Hemochromatosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D007501:Iron / Q000378:metabolism*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism*; D020298:U937 Cells; D015262:Xenobiotics / Q000009:adverse effects / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000098742:Ferroportin
chemical_list: D029742:Caenorhabditis elegans Proteins; D027682:Cation Transport Proteins; D016328:NF-kappa B; D015262:Xenobiotics; D000098742:Ferroportin; D007501:Iron; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; C516679:sek-1 protein, C elegans
keywords: NF-κB transcription factor; intestine; iron metabolism; nuclear factor 2 (erythroid-derived 2-like factor, NFE2L2, Nrf2); p38 MAPK; ribosomal inactivation