Exposure to Perfluoro-Octanoic Acid Associated With Upstream Uncoupling of the Insulin Signaling in Human Hepatocyte Cell Line

Perfluoro-alkyl substances (PFAS) are chemical pollutants with prevalent stability and environmental persistence. Exposure to PFAS, particularly perfluoro-octanoic acid (PFOA), has been associated with increased diabetes-related cardiovascular mortality in subjects residing areas of high environment...

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Published in:	Frontiers in endocrinology (Lausanne) Vol. 12; p. 632927
Main Authors:	De Toni, Luca, Di Nisio, Andrea, Rocca, Maria Santa, Guidolin, Diego, Della Marina, Alice, Bertazza, Loris, Sut, Stefania, Purpura, Edoardo, Pannella, Micaela, Garolla, Andrea, Foresta, Carlo
Format:	Journal Article
Language:	English
Published:	Switzerland Frontiers Media S.A 03-09-2021
Subjects:	Antigens, CD - genetics Antigens, CD - metabolism Caprylates - adverse effects Carcinoma, Hepatocellular - metabolism Carcinoma, Hepatocellular - pathology Endocrinology Fluorocarbons - adverse effects glut-4 glycogen GM3 Hep G2 Cells Humans Inflammation - chemically induced Inflammation - metabolism Inflammation - pathology Insulin - metabolism Insulin Resistance Liver Neoplasms - metabolism Liver Neoplasms - pathology membrane PDMP Phosphorylation Receptor, Insulin - genetics Receptor, Insulin - metabolism Signal Transduction glut-4 PDMP membrane glycogen GM3
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Summary:	Perfluoro-alkyl substances (PFAS) are chemical pollutants with prevalent stability and environmental persistence. Exposure to PFAS, particularly perfluoro-octanoic acid (PFOA), has been associated with increased diabetes-related cardiovascular mortality in subjects residing areas of high environmental contamination, however the exact pathogenic mechanism remains elusive. Here we used HepG2 cells, an model of human hepatocyte, to investigate the possible role of PFOA exposure in the alteration of hepatic glucose metabolism. HepG2 cells were exposed for 24 hours to PFOA at increasing concentration from 0 to 1000 ng/mL and then stimulated with 100 nm Insulin (Ins). The consequent effect on glycogen synthesis, glucose uptake and Glut-4 glucose transporter translocation was then evaluated by, respectively, Periodic Acid Schiff (PAS) staining, 2-deoxyglucose (2-DG) uptake assay and immunofluorescence. Exposure to PFOA was associated with reduced glycogen synthesis and glucose uptake, at concentration equal or greater than, respectively, 0,1 ng/mL and 10 ng/mL, with parallel impaired membrane translocation of Glut-4 upon Ins stimulation. Western blot analysis showed early uncoupling of Insulin Receptor (InsR) activation from the downstream Akt and GSK3 phosphorylation. Computational docking analysis disclosed the possible stabilizing effect of PFOA on the complex between InsR and GM3 ganglioside, previously shown to be associated with the low grade chronic inflammation-related insulin resistance. Consistently, long term treatment with glucosyl-ceramide synthase inhibitor PDMP was able to largely restore glycogen synthesis, glucose uptake and Glut-4 translocation upon Ins stimulation in HepG2 exposed to PFOA. Our data support a novel pathogenic mechanism linking exposure to PFOA to derangement of hepatocyte cell metabolism.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by: Eric Hajduch, Institut National de la Santé et de la Recherche Médicale (INSERM), France These authors have contributed equally to this work Reviewed by: Frederic Bost, INSERM U1065 Centre Méditerranéen de Médecine Moléculaire, France; Agnieszka Urszula Blachnio-Zabielska, Medical University of Bialystok, Poland This article was submitted to Translational Endocrinology, a section of the journal Frontiers in Endocrinology
ISSN:	1664-2392 1664-2392
DOI:	10.3389/fendo.2021.632927