Pantoprazole ameliorates liver fibrosis and suppresses hepatic stellate cell activation in bile duct ligation rats by promoting YAP degradation  

作　　者：Zhen-ning Lu Wei-xiao Niu Na Zhang Mao-xu Ge Yun-yang Bao Yu Ren Xiu-li Guo Hong-wei He 

机构地区：[1]Key Laboratory of Biotechnology of Antibiotics,the National Health and Family Planning Commission(NHFPC),Institute of Medicinal Biotechnology,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China [2]Department of Pharmacy,Qilu Hospital of Shandong University,Jinan 250012,China [3]Department of Pharmacology,Key Laboratory of Chemical Biology(Ministry of Education),Drug Screening Unit Platform,School of Pharmaceutical Sciences,Shandong University,Jinan 250012,China

出　　处：《Acta Pharmacologica Sinica》2021年第11期1808-1820,共13页中国药理学报（英文版）

基　　金：This wofunded by the National Natural Science Foundation of China(No.81673497 and 81903695);the CAMS Innovation Fund for Medical Sciences(No.2016-I2M-1-001 and 2019-I2M-1-001);the Natural Science Foundation of Shandong Province[ZR2020MH419].

摘　　要：Liver fibrosis is one of the most severe pathologic consequences of chronic liver diseases,and effective therapeutic strategies are urgently needed.Proton pump inhibitors(PPIs)are H+/K+-ATPase inhibitors and currently used to treat acid-related diseases such as gastric ulcers,which have shown other therapeutic effects in addition to inhibiting acid secretion.However,few studies have focused on PPIs from the perspective of inhibiting hepatic fibrosis.In the present study,we investigated the effects of pantoprazole(PPZ),a PPI,against liver fibrosis in a bile duct ligation(BDL)rat model,human hepatic stellate cell(HSC)line LX-2 and mouse primary HSCs(pHSCs),and explored the potential mechanisms underlying the effects of PPZ in vitro and in vivo.In BDL rats,administration of PPZ(150 mg·kg^(−1)·d^(−1),i.p.for 14 d)significantly attenuated liver histopathological injury,collagen accumulation,and inflammatory responses,and suppressed fibrogenesis-associated gene expression including Col1a1,Acta2,Tgfβ1,and Mmp-2.In LX-2 cells and mouse pHSCs,PPZ(100–300μM)dose-dependently suppressed the levels of fibrogenic markers.We conducted transcriptome analysis and subsequent validation in PPZ-treated LX-2 cells,and revealed that PPZ inhibited the expression of Yes-associated protein(YAP)and its downstream targets such as CTGF,ID1,survivin,CYR61,and GLI2.Using YAP overexpression and silencing,we demonstrated that PPZ downregulated hepatic fibrogenic gene expression via YAP.Furthermore,we showed that PPZ promoted the proteasome-dependent degradation and ubiquitination of YAP,thus inhibiting HSC activation.Additionally,we showed that PPZ destabilized YAP by disrupting the interaction between a deubiquitinating enzyme OTUB2 and YAP,and subsequently blocked the progression of hepatic fibrosis.

关 键 词：liver fibrosis PANTOPRAZOLE bile duct ligation hepatic stellate cells YAP OTUB2 

分 类 号：R285.5[医药卫生—中药学]