Department of Medical Science, College of Medicine, Chungnam National University, Daejeon, South Korea.
Department of Internal Medicine, College of Medicine, Chungnam National University School of Medicine, Daejeon, South Korea.
PLoS One. 2019 Feb 8;14(2):e0210828. doi: 10.1371/journal.pone.0210828. eCollection 2019.
Non-alcoholic fatty liver disease (NAFLD) is one of the main causes of chronic liver disease. NAFLD begins with excessive lipid accumulation in the liver and progresses to nonalcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is closely linked to dysregulated hepatic lipid metabolism. Although recent studies have reported that epidermal growth factor receptor (EGFR) signaling regulates lipid metabolism, the roles of EGFR and EGFR inhibitors as modulators of lipid metabolism are largely unknown. Here, we investigated whether inhibiting EGFR using the EGFR tyrosine kinase inhibitor (TKI) PD153035 improves NAFLD. Our results demonstrate that EGFR was activated in liver tissues from high fat diet (HFD)-induced NAFLD mice. Inhibiting EGFR using PD153035 significantly reduced phosphatidylinositol-3-kinase/protein kinase B signaling and sterol responsive elementary binding protein 1 and 2 expression, which prevented HFD-induced hepatic steatosis and hypercholesterolemia by reducing de novo lipogenesis and cholesterol synthesis and enhancing fatty acid oxidation. Additionally, inhibiting EGFR improved HFD-induced glucose intolerance. In conclusion, these results indicate that EGFR plays an important role in NAFLD and is a potential therapeutic target.
非酒精性脂肪性肝病（NAFLD）是慢性肝病的主要病因之一。NAFLD 始于肝脏内脂质过度积累，并进展为非酒精性脂肪性肝炎（NASH）和肝硬化。NAFLD 与肝内脂质代谢失调密切相关。尽管最近的研究报告称表皮生长因子受体（EGFR）信号调节脂质代谢，但 EGFR 及其 EGFR 抑制剂作为脂质代谢调节剂的作用在很大程度上仍是未知的。在这里，我们研究了使用 EGFR 酪氨酸激酶抑制剂（TKI）PD153035 抑制 EGFR 是否可以改善 NAFLD。我们的结果表明，高脂饮食（HFD）诱导的 NAFLD 小鼠的肝组织中 EGFR 被激活。使用 PD153035 抑制 EGFR 可显著降低磷酸肌醇-3-激酶/蛋白激酶 B 信号和固醇调节元件结合蛋白 1 和 2 的表达，从而通过减少从头脂肪生成和胆固醇合成并增强脂肪酸氧化来防止 HFD 诱导的肝脂肪变性和高胆固醇血症。此外，抑制 EGFR 可改善 HFD 诱导的葡萄糖不耐受。总之，这些结果表明 EGFR 在 NAFLD 中起重要作用，是一个有潜力的治疗靶点。
