Fatty Acids and a High-Fat Diet Induce Epithelial-Mesenchymal Transition by Activating TGFβ and β-Catenin in Liver Cells.

Oliwia Kwapisz,Jolanta Jura,Judyta Górka,Agnieszka Waligórska,Agata Korlatowicz,Natalia Pydyn,Jurek W Dobrucki,Katarzyna Miekus,Jerzy Kotlinowski,Paulina Marona

doi:10.3390/ijms22031272

Abstract

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.

Highlights

We investigated the influence of a high-fat diet (HFD) and free fatty acids (FFAs) on the expression of TGFβ and β-catenin and the regulation of epithelial–mesenchymal transition (EMT) in the liver
We evaluated the ability of Huh7 hepatocellular carcinoma (HCC)
We examined whether a monounsaturated FFA, sodium oleate (SO), changes the transcript level of

Summary

Introduction

Epithelial–mesenchymal transition (EMT) is a process that drives the dedifferentiation of epithelial cells into cells with a mesenchymal-like phenotype. During EMT, intercellular connections are lost; the motility and invasive potential of cells increase due to activation of EMT inducers such as the Slug, Snail, Zeb 1/2, or Twist transcription factors; and Ecadherin expression is lost and replaced by expression of the mesenchymal cell marker. EMT can generate mesenchymal/fibroblastic cells, which could be relevant in the progression of liver fibrotic diseases [4]. Nonalcoholic fatty liver disease (NAFLD) is currently considered the most common chronic liver disease in developed countries. The understanding of the molecular events controlling the development and progression of NAFLD that direct the development of steatosis into steatohepatitis and liver fibrosis is still incomplete. Hepatic accumulation of lipids leading to lipotoxicity, activation of inflammatory cascades, and fibrogenesis, as well as multiple other insults acting together may lead to the development and progression of NAFLD [5,6,7,8]

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