Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland.
Department of Cell Biophysics, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, 30-387 Krakow, Poland.
Int J Mol Sci. 2021 Jan 28;22(3):1272. doi: 10.3390/ijms22031272.
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.
非酒精性脂肪性肝病是指在没有过量饮酒或任何继发原因的情况下，肝脏内积聚过多脂肪。尽管该疾病通常无症状，但慢性肝炎症导致纤维化、肝硬化，甚至发展为肝细胞癌（HCC）。纤维化是由上皮-间充质转化（EMT）引起的，这导致上皮细胞去分化为具有间充质样表型的细胞。在 EMT 过程中，上皮细胞中高表达 E-钙黏蛋白，受生长因子、细胞因子和炎症过程的影响，通过增强表达波形蛋白、纤维连接蛋白和 N-钙黏蛋白等物质发生形态变化。EMT 的诱导剂，也是纤维化发展的诱导剂，是转化生长因子β（TGFβ），这是一种与肝癌发生进展相关的多功能细胞因子。然而，指导脂肪变性发展为脂肪性肝炎和肝纤维化的分子事件仍不完全清楚。我们的研究表明，肝癌细胞体外长时间暴露于脂肪酸和小鼠高脂肪饮食（20 周）均会导致炎症。长时间用脂肪酸处理会增加 TGFβ、MMP9 和 β-连环蛋白的水平，这些都是 EMT 的重要诱导物。此外，高脂肪饮食喂养的小鼠肝脏表现出纤维化特征，TGFβ 和 IL-1 水平升高。IL-1 的表达增加与单核细胞趋化蛋白诱导蛋白 1（MCPIP1）的减少相关，MCPIP1 是炎症反应的负调节剂，调节编码 IL-1 的促炎转录本的稳定性。我们的研究表明，高脂肪饮食通过增加 EMT 激活转录因子（包括 Zeb1、Zeb2 和 Snail）的水平诱导 EMT，并改变蛋白谱，使其呈现出间充质表型的特征。
