Cyanotoxin cylindrospermopsin disrupts lipid homeostasis and metabolism in a 3D in vitro model of the human liver.

Autor: Chowdhury RR; RECETOX, Faculty of Science, Masaryk University, Kotlářská 2, Brno, Czech Republic., Grosso MF; RECETOX, Faculty of Science, Masaryk University, Kotlářská 2, Brno, Czech Republic., Gadara DC; RECETOX, Faculty of Science, Masaryk University, Kotlářská 2, Brno, Czech Republic., Spáčil Z; RECETOX, Faculty of Science, Masaryk University, Kotlářská 2, Brno, Czech Republic., Vidová V; RECETOX, Faculty of Science, Masaryk University, Kotlářská 2, Brno, Czech Republic., Sovadinová I; RECETOX, Faculty of Science, Masaryk University, Kotlářská 2, Brno, Czech Republic., Babica P; RECETOX, Faculty of Science, Masaryk University, Kotlářská 2, Brno, Czech Republic. Electronic address: pavel.babica@recetox.muni.cz.
Jazyk: angličtina
Zdroj: Chemico-biological interactions [Chem Biol Interact] 2024 Jul 01; Vol. 397, pp. 111046. Date of Electronic Publication: 2024 May 10.
DOI: 10.1016/j.cbi.2024.111046
Abstrakt: Cylindrospermopsin, a potent hepatotoxin produced by harmful cyanobacterial blooms, poses environmental and human health concerns. We used a 3D human liver in vitro model based on spheroids of HepG2 cells, in combination with molecular and biochemical assays, automated imaging, targeted LC-MS-based proteomics, and lipidomics, to explore cylindrospermopsin effects on lipid metabolism and the processes implicated in hepatic steatosis. Cylindrospermopsin (1 μM, 48 h) did not significantly affect cell viability but partially reduced albumin secretion. However, it increased neutral lipid accumulation in HepG2 spheroids while decreasing phospholipid levels. Simultaneously, cylindrospermopsin upregulated genes for lipogenesis regulation (SREBF1) and triacylglycerol synthesis (DGAT1/2) and downregulated genes for fatty acid synthesis (ACLY, ACCA, FASN, SCD1). Fatty acid uptake, oxidation, and lipid efflux genes were not significantly affected. Targeted proteomics revealed increased levels of perilipin 2 (adipophilin), a major hepatocyte lipid droplet-associated protein. Lipid profiling quantified 246 lipid species in the spheroids, with 28 significantly enriched and 15 downregulated by cylindrospermopsin. Upregulated species included neutral lipids, sphingolipids (e.g., ceramides and dihexosylceramides), and some glycerophospholipids (phosphatidylethanolamines, phosphatidylserines), while phosphatidylcholines and phosphatidylinositols were mostly reduced. It suggests that cylindrospermopsin exposures might contribute to developing and progressing towards hepatic steatosis or metabolic dysfunction-associated steatotic liver disease (MASLD).
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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