Clinic Center of Human Gene Research, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Cell Death Dis. 2021 Mar 3;12(3):228. doi: 10.1038/s41419-021-03536-8.
Nonalcoholic fatty liver disease (NAFLD) is prevalent clinically and can lead to more serious chronic liver disease. However, the pathological mechanism is still unclear, and thus, there are no approved drugs on the market. Transcriptional coactivator WW domain-binding protein 2 (WBP2) is a newly discovered oncogene that has an important relationship with the occurrence and development of breast cancer and mediates the interaction between Wnt and various other signaling pathways. The expression level of WBP2 was decreased in NAFLD. Overexpression of WBP2 with AAV in vivo alleviated liver fat deposition and insulin resistance induced by a high-fat diet (HFD). Knockdown of WBP2 with AAV aggravated HFD-induced fatty liver and insulin resistance. In vitro experiments showed that in the human normal hepatocyte cell line LO2 and primary hepatocytes isolated from mice, overexpression of WBP2 reduced fat deposition, and knocking out or knocking down WBP2 aggravated PA-induced fat deposition. Through mass spectrometry, we found that WBP2 can bind to AMPKβ1, and by mutating AMPKβ1, we found that WBP2 can induce phosphorylation of AMPKβ1 at S108 and then activate the AMPK pathway to affect lipid metabolism. The effect of WBP2 on NAFLD provides a possible new direction for future research on NAFLD.
非酒精性脂肪性肝病（NAFLD）在临床上较为常见，可导致更严重的慢性肝病。然而，其病理机制尚不清楚，因此市场上尚无批准的药物。转录共激活因子 WW 结构域结合蛋白 2（WBP2）是一种新发现的癌基因，与乳腺癌的发生发展有重要关系，并介导 Wnt 与各种其他信号通路的相互作用。WBP2 的表达水平在 NAFLD 中降低。体内用 AAV 过表达 WBP2 可减轻高脂肪饮食（HFD）引起的肝脂肪沉积和胰岛素抵抗。用 AAV 敲低 WBP2 可加重 HFD 诱导的脂肪肝和胰岛素抵抗。体外实验表明，在人正常肝细胞系 LO2 和从小鼠分离的原代肝细胞中，过表达 WBP2 可减少脂肪沉积，敲除或敲低 WBP2 可加重 PA 诱导的脂肪沉积。通过质谱分析，我们发现 WBP2 可以与 AMPKβ1 结合，通过突变 AMPKβ1，我们发现 WBP2 可以诱导 AMPKβ1 的 S108 磷酸化，从而激活 AMPK 通路，影响脂质代谢。WBP2 对 NAFLD 的作用为 NAFLD 的未来研究提供了一个可能的新方向。
