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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...

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Autores principales: Kwapisz, Oliwia, Górka, Judyta, Korlatowicz, Agata, Kotlinowski, Jerzy, Waligórska, Agnieszka, Marona, Paulina, Pydyn, Natalia, Dobrucki, Jurek W., Jura, Jolanta, Miekus, Katarzyna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
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.
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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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