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Fatty Acids and a High-Fat Diet Induce Epithelial–Mesenchymal Transition by Activating TGFβ and β-Catenin in Liver Cells
Nonalcoholic fatty liver disease is defined as the accumulation of excessive fat in the liver in the absence of excessive alcohol consumption or any secondary cause. Although the disease generally remains asymptomatic, chronic liver inflammation leads to fibrosis, liver cirrhosis, and even to the de...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865431/ https://www.ncbi.nlm.nih.gov/pubmed/33525359 http://dx.doi.org/10.3390/ijms22031272 |
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author | Kwapisz, Oliwia Górka, Judyta Korlatowicz, Agata Kotlinowski, Jerzy Waligórska, Agnieszka Marona, Paulina Pydyn, Natalia Dobrucki, Jurek W. Jura, Jolanta Miekus, Katarzyna |
author_facet | Kwapisz, Oliwia Górka, Judyta Korlatowicz, Agata Kotlinowski, Jerzy Waligórska, Agnieszka Marona, Paulina Pydyn, Natalia Dobrucki, Jurek W. Jura, Jolanta Miekus, Katarzyna |
author_sort | Kwapisz, Oliwia |
collection | PubMed |
description | Nonalcoholic fatty liver disease is defined as the accumulation of excessive fat in the liver in the absence of excessive alcohol consumption or any secondary cause. Although the disease generally remains asymptomatic, chronic liver inflammation leads to fibrosis, liver cirrhosis, and even to the development of hepatocellular carcinoma (HCC). Fibrosis results from epithelial–mesenchymal transition (EMT), which leads to dedifferentiation of epithelial cells into cells with a mesenchymal-like phenotype. During EMT, epithelial cells with high expression of E-cadherin, influenced by growth factors, cytokines, and inflammatory processes, undergo morphological changes via enhanced expression of, e.g., vimentin, fibronectin, and N-cadherin. An inducer of EMT and, consequently, of fibrosis development is transforming growth factor beta (TGFβ), a pleiotropic cytokine associated with the progression of hepatocarcinogenesis. However, the understanding of the molecular events that direct the development of steatosis into steatohepatitis and liver fibrosis remains incomplete. Our study revealed that both prolonged exposure of hepatocarcinoma cells to fatty acids in vitro and high-fat diet in mice (20 weeks) result in inflammation. Prolonged treatment with fatty acids increased the levels of TGFβ, MMP9, and β-catenin, important EMT inducers. Moreover, the livers of mice fed a high-fat diet exhibited features of liver fibrosis with increased TGFβ and IL-1 levels. Increased expression of IL-1 correlated with a decrease in monocyte chemoattractant protein-induced protein 1 (MCPIP1), a negative regulator of the inflammatory response that regulates the stability of proinflammatory transcripts encoding IL-1. Our study showed that a high-fat diet induced EMT by increasing the levels of EMT-activating transcription factors, including Zeb1, Zeb2, and Snail and changed the protein profile to a profile characteristic of the mesenchymal phenotype. |
format | Online Article Text |
id | pubmed-7865431 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-78654312021-02-07 Fatty Acids and a High-Fat Diet Induce Epithelial–Mesenchymal Transition by Activating TGFβ and β-Catenin in Liver Cells Kwapisz, Oliwia Górka, Judyta Korlatowicz, Agata Kotlinowski, Jerzy Waligórska, Agnieszka Marona, Paulina Pydyn, Natalia Dobrucki, Jurek W. Jura, Jolanta Miekus, Katarzyna Int J Mol Sci Article Nonalcoholic fatty liver disease is defined as the accumulation of excessive fat in the liver in the absence of excessive alcohol consumption or any secondary cause. Although the disease generally remains asymptomatic, chronic liver inflammation leads to fibrosis, liver cirrhosis, and even to the development of hepatocellular carcinoma (HCC). Fibrosis results from epithelial–mesenchymal transition (EMT), which leads to dedifferentiation of epithelial cells into cells with a mesenchymal-like phenotype. During EMT, epithelial cells with high expression of E-cadherin, influenced by growth factors, cytokines, and inflammatory processes, undergo morphological changes via enhanced expression of, e.g., vimentin, fibronectin, and N-cadherin. An inducer of EMT and, consequently, of fibrosis development is transforming growth factor beta (TGFβ), a pleiotropic cytokine associated with the progression of hepatocarcinogenesis. However, the understanding of the molecular events that direct the development of steatosis into steatohepatitis and liver fibrosis remains incomplete. Our study revealed that both prolonged exposure of hepatocarcinoma cells to fatty acids in vitro and high-fat diet in mice (20 weeks) result in inflammation. Prolonged treatment with fatty acids increased the levels of TGFβ, MMP9, and β-catenin, important EMT inducers. Moreover, the livers of mice fed a high-fat diet exhibited features of liver fibrosis with increased TGFβ and IL-1 levels. Increased expression of IL-1 correlated with a decrease in monocyte chemoattractant protein-induced protein 1 (MCPIP1), a negative regulator of the inflammatory response that regulates the stability of proinflammatory transcripts encoding IL-1. Our study showed that a high-fat diet induced EMT by increasing the levels of EMT-activating transcription factors, including Zeb1, Zeb2, and Snail and changed the protein profile to a profile characteristic of the mesenchymal phenotype. MDPI 2021-01-28 /pmc/articles/PMC7865431/ /pubmed/33525359 http://dx.doi.org/10.3390/ijms22031272 Text en © 2021 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Kwapisz, Oliwia Górka, Judyta Korlatowicz, Agata Kotlinowski, Jerzy Waligórska, Agnieszka Marona, Paulina Pydyn, Natalia Dobrucki, Jurek W. Jura, Jolanta Miekus, Katarzyna Fatty Acids and a High-Fat Diet Induce Epithelial–Mesenchymal Transition by Activating TGFβ and β-Catenin in Liver Cells |
title | Fatty Acids and a High-Fat Diet Induce Epithelial–Mesenchymal Transition by Activating TGFβ and β-Catenin in Liver Cells |
title_full | Fatty Acids and a High-Fat Diet Induce Epithelial–Mesenchymal Transition by Activating TGFβ and β-Catenin in Liver Cells |
title_fullStr | Fatty Acids and a High-Fat Diet Induce Epithelial–Mesenchymal Transition by Activating TGFβ and β-Catenin in Liver Cells |
title_full_unstemmed | Fatty Acids and a High-Fat Diet Induce Epithelial–Mesenchymal Transition by Activating TGFβ and β-Catenin in Liver Cells |
title_short | Fatty Acids and a High-Fat Diet Induce Epithelial–Mesenchymal Transition by Activating TGFβ and β-Catenin in Liver Cells |
title_sort | fatty acids and a high-fat diet induce epithelial–mesenchymal transition by activating tgfβ and β-catenin in liver cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7865431/ https://www.ncbi.nlm.nih.gov/pubmed/33525359 http://dx.doi.org/10.3390/ijms22031272 |
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