Zhao Wen, Zhang Xiaoxiao, Hou Mengmeng, Zhang Yuguo, Tang Yuhui, Li Lu, Dong Shiming, Liu Lingdi, Zhao Dandan, Li Wencong, Nan Yuemin
Department of Traditional and Western Medical Hepatology, Third Hospital of Hebei Medical University, Hebei Provincial Key Laboratory of liver fibrosis in chronic liver diseases, Shijiazhuang, China.
Histol Histopathol. 2021 Sep;36(9):967-979. doi: 10.14670/HH-18-373. Epub 2021 Sep 7.
BACKGROUND/AIMS: The Yiqi Huoxue (YQHX) recipe has been shown to attenuate liver fibrosis, but precise mechanisms have not yet been elucidated. Recently, Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) signaling has been implicated in liver fibrogenesis. This study investigated whether the YAP/TAZ signaling is involved in the therapeutic effect of YQHX on hepatic fibrosis.
Wistar rats were used to generate a model of carbon tetrachloride (CCl₄)-induced liver fibrosis. Chronic hepatitis B (CHB) patients with liver fibrosis were enrolled and assigned to receive either nucleoside/nucleotide analogues (NAs) or NAs plus YQHX. Histology, immunohistochemistry, qRT-PCR, and western blotting were conducted to mechanistically assess the therapeutic effects of YQHX on liver fibrosis.
YQHX markedly alleviated morphological alterations in CCl₄-induced liver fibrosis and decreased markers of hepatic fibrosis in rats. Furthermore, YQHX significantly suppressed CCl₄-meidated activation of the transforming growth factor-beta (TGF-β)/Smad signaling pathway. Notably, CCl₄ induced up-regulation of YAP, TAZ, and connective tissue growth factor (CTGF), which were significantly abrogated by YQHX. Consistent with the above major findings in rats, CHB patients treated with NAs plus YQHX had greater improvement in liver fibrosis than those given NAs alone (71.4% vs. 28.6%; P = 0.057). In addition, hepatic and plasma levels of YAP were significantly decreased after YQHX treatment in CHB patients with liver fibrosis.
YAP/TAZ signaling plays a role, at least in part, in the anti-fibrotic activity of YQHX. The findings may help to better understand the mechanisms of YQHX in the treatment of liver fibrosis.
背景/目的：益气活血（YQHX）方剂已被证明可减轻肝纤维化，但具体机制尚未阐明。最近，Yes相关蛋白（YAP）/具有PDZ结合基序的转录共激活因子（TAZ）信号通路与肝纤维化发生有关。本研究调查YAP/TAZ信号通路是否参与YQHX对肝纤维化的治疗作用。
采用Wistar大鼠建立四氯化碳（CCl₄）诱导的肝纤维化模型。纳入慢性乙型肝炎（CHB）肝纤维化患者，分为接受核苷/核苷酸类似物（NAs）治疗组或NAs联合YQHX治疗组。通过组织学、免疫组化、qRT-PCR和蛋白质印迹法从机制上评估YQHX对肝纤维化的治疗效果。
YQHX显著减轻CCl₄诱导的肝纤维化形态学改变，并降低大鼠肝纤维化标志物水平。此外，YQHX显著抑制CCl₄介导的转化生长因子-β（TGF-β）/Smad信号通路激活。值得注意的是，CCl₄诱导YAP、TAZ和结缔组织生长因子（CTGF）上调，而YQHX可显著消除这种上调。与上述大鼠的主要研究结果一致，接受NAs联合YQHX治疗的CHB患者肝纤维化改善程度高于单纯接受NAs治疗的患者（71.4%对28.6%；P = 0.057）。此外，YQHX治疗后，CHB肝纤维化患者肝脏和血浆中YAP水平显著降低。
YAP/TAZ信号通路至少部分参与了YQHX的抗纤维化活性。这些发现可能有助于更好地理解YQHX治疗肝纤维化的机制。
