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Identification of microRNAs Implicated in Modulating Senecionine-Induced Liver Toxicity in HepaRG Cells
1,2-unsaturated Pyrrolizidine Alkaloids (PAs) are secondary plant metabolites that occur as food contaminants. Upon consumption, they can cause severe liver damage. PAs have been shown to induce apoptosis, to have cytotoxic and genotoxic effects, and to impair bile acid homeostasis in the human hepa...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8871147/ https://www.ncbi.nlm.nih.gov/pubmed/35206009 http://dx.doi.org/10.3390/foods11040532 |
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author | Enge, Anne-Margarethe Sprenger, Heike Braeuning, Albert Hessel-Pras, Stefanie |
author_facet | Enge, Anne-Margarethe Sprenger, Heike Braeuning, Albert Hessel-Pras, Stefanie |
author_sort | Enge, Anne-Margarethe |
collection | PubMed |
description | 1,2-unsaturated Pyrrolizidine Alkaloids (PAs) are secondary plant metabolites that occur as food contaminants. Upon consumption, they can cause severe liver damage. PAs have been shown to induce apoptosis, to have cytotoxic and genotoxic effects, and to impair bile acid homeostasis in the human hepatoma cell line HepaRG. The major mode of action of PAs is DNA- and protein-adduct formation. Beyond that, nuclear receptor activation has only been observed for one receptor and two PAs, yielding the possibility that other cellular mediators are involved in PA-mediated toxicity. Here, the mode of action of Senecionine (Sc), a prominent and ubiquitous representative of hepatotoxic PAs, was investigated by analyzing 7 hepatic microRNAs (miRNAs) in HepaRG cells. Ultimately, 11 target genes that were predicted with Ingenuity Pathway Analysis software (IPA) were found to be significantly downregulated, while their assigned miRNAs showed significant upregulation of gene expression. According to IPA, these targets are positively correlated with apoptosis and cellular death and are involved in diseases such as hepatocellular carcinoma. Subsequent antagomiR-inhibition analysis revealed a significant correlation between PA-induced miRNA-4434 induction and P21-Activated Kinase-1 (PAK1) downregulation. PAK1 downregulation is usually associated with cell cycle arrest, suggesting a new function of Sc-mediated toxicity in human liver cells. |
format | Online Article Text |
id | pubmed-8871147 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-88711472022-02-25 Identification of microRNAs Implicated in Modulating Senecionine-Induced Liver Toxicity in HepaRG Cells Enge, Anne-Margarethe Sprenger, Heike Braeuning, Albert Hessel-Pras, Stefanie Foods Article 1,2-unsaturated Pyrrolizidine Alkaloids (PAs) are secondary plant metabolites that occur as food contaminants. Upon consumption, they can cause severe liver damage. PAs have been shown to induce apoptosis, to have cytotoxic and genotoxic effects, and to impair bile acid homeostasis in the human hepatoma cell line HepaRG. The major mode of action of PAs is DNA- and protein-adduct formation. Beyond that, nuclear receptor activation has only been observed for one receptor and two PAs, yielding the possibility that other cellular mediators are involved in PA-mediated toxicity. Here, the mode of action of Senecionine (Sc), a prominent and ubiquitous representative of hepatotoxic PAs, was investigated by analyzing 7 hepatic microRNAs (miRNAs) in HepaRG cells. Ultimately, 11 target genes that were predicted with Ingenuity Pathway Analysis software (IPA) were found to be significantly downregulated, while their assigned miRNAs showed significant upregulation of gene expression. According to IPA, these targets are positively correlated with apoptosis and cellular death and are involved in diseases such as hepatocellular carcinoma. Subsequent antagomiR-inhibition analysis revealed a significant correlation between PA-induced miRNA-4434 induction and P21-Activated Kinase-1 (PAK1) downregulation. PAK1 downregulation is usually associated with cell cycle arrest, suggesting a new function of Sc-mediated toxicity in human liver cells. MDPI 2022-02-12 /pmc/articles/PMC8871147/ /pubmed/35206009 http://dx.doi.org/10.3390/foods11040532 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Enge, Anne-Margarethe Sprenger, Heike Braeuning, Albert Hessel-Pras, Stefanie Identification of microRNAs Implicated in Modulating Senecionine-Induced Liver Toxicity in HepaRG Cells |
title | Identification of microRNAs Implicated in Modulating Senecionine-Induced Liver Toxicity in HepaRG Cells |
title_full | Identification of microRNAs Implicated in Modulating Senecionine-Induced Liver Toxicity in HepaRG Cells |
title_fullStr | Identification of microRNAs Implicated in Modulating Senecionine-Induced Liver Toxicity in HepaRG Cells |
title_full_unstemmed | Identification of microRNAs Implicated in Modulating Senecionine-Induced Liver Toxicity in HepaRG Cells |
title_short | Identification of microRNAs Implicated in Modulating Senecionine-Induced Liver Toxicity in HepaRG Cells |
title_sort | identification of micrornas implicated in modulating senecionine-induced liver toxicity in heparg cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8871147/ https://www.ncbi.nlm.nih.gov/pubmed/35206009 http://dx.doi.org/10.3390/foods11040532 |
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