Role of epidermal growth factor receptor in liver injury and lipid metabolism: Emerging new roles for an old receptor
Role of epidermal growth factor receptor in liver injury and lipid metabolism: Emerging new roles for an old receptor
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DOI：
10.1016/j.cbi.2020.109090
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发表时间：
2020-06-01
影响因子：
5.1
通讯作者：
Michalopoulos, George K.
中科院分区：
文献类型：
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作者：
Bhushan, Bharat;Michalopoulos, George K.
众所周知，表皮生长因子受体（EGFR）在肝细胞增殖、肝再生中发挥着至关重要的作用，并且还与肝细胞癌发生有关。除了这些增殖作用外，EGFR 还与临床相关的对乙酰氨基酚过量小鼠模型中各种肝细胞中的细胞凋亡信号传导、线粒体功能障碍和急性肝坏死有关，因此有必要进一步全面探索 EGFR 在肝毒性中的这种矛盾作用。除了配体依赖性激活外，EGFR还可以非配体依赖性方式激活，这主要与肝损伤有关。最近的证据也表明 EGFR 在静止和再生肝脏的脂质和脂肪酸代谢中发挥重要作用。基于这些发现，EGFR 还被证明通过调节控制脂肪酸合成和脂肪分解的主转录因子，在临床相关的小鼠 NAFLD 模型的脂肪变性中发挥重要作用。此外，多项证据表明，EGFR 还参与慢性肝损伤模型（包括重复 CCl4 暴露、高脂饮食和快餐饮食模型）中的肝细胞损伤、氧化应激、炎症、直接星状细胞活化和纤维化。除了简要总结 EGFR 在肝再生中的作用外，本综述还全面讨论了 EGFR 的所有这些非传统的新兴作用。考虑到 EGFR 在这些病理生理过程中各个层面的多方面作用的证据，EGFR 可能成为各种肝脏疾病的有希望的治疗靶点，包括急性肝衰竭和 NAFLD，需要进一步探索。 EGFR 的这些作用也与酒精性肝病 (ALD) 相关，从而为未来探索 EGFR 在 ALD 中的作用的研究提供了有效的依据。
Epidermal growth factor receptor (EGFR) is conventionally known to play a crucial role in hepatocyte proliferation, liver regeneration and is also associated with hepatocellular carcinogenesis. In addition to these proliferative roles, EGFR has also implicated in apoptotic cell death signaling in various hepatic cells, mitochondrial dysfunction and acute liver necrosis in a clinically relevant murine model of acetaminophen overdose, warranting further comprehensive exploration of this paradoxical role of EGFR in hepatotoxicity. Apart from ligand dependent activation, EGFR can also be activated in ligand-independent manner, which is mainly associated to liver injury. Recent evidence has also emerged demonstrating important role of EGFR in lipid and fatty acid metabolism in quiescent and regenerating liver. Based on these findings, EGFR has also been shown to play an important role in steatosis in clinically relevant murine NAFLD models via regulating master transcription factors governing fatty acid synthesis and lipolysis. Moreover, several lines of evidences indicate that EGFR is also involved in hepatocellular injury, oxidative stress, inflammation, direct stellate cell activation and fibrosis in chronic liver injury models, including repeated CCl4 exposure, high-fat diet and fast-food diet models. In addition to briefly summarizing role of EGFR in liver regeneration, this review comprehensively discusses all these non-conventional emerging roles of EGFR. Considering evidences of multi-facet role of EGFR at various levels in these pathophysiological process, EGFR can be a promising therapeutic target for various liver diseases, including acute liver failure and NAFLD, requiring further exploration. These roles of EGFR are relevant for alcoholic liver diseases (ALD) as well, thus providing a valid rationale for future investigations exploring a role of EGFR in ALD.