Fenofibrate-promoted hepatomegaly and liver regeneration are PPARα-dependent and partially related to the YAP pathway  

作　　者：Shicheng Fan Yue Gao Pengfei Zhao Guomin Xie Yanying Zhou Xiao Yang Xuan Li Shuaishuai Zhang Frank JGonzalez Aijuan Qu Min Huangb Huichang Bi 

机构地区：[1]NMPA Key Laboratory for Research and Evaluation of Drug Metabolism&Guangdong Provincial Key Laboratory of New Drug Screening&Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening,School of Pharmaceutical Sciences,Southern Medical University,Guangzhou 510515,China [2]Guangdong Provincial Key Laboratory of New Drug Design and Evaluation,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China [3]Department of Physiology and Pathophysiology,School of Basic Medical Sciences,Capital Medical University,Beijing 100069,China [4]Laboratory of Metabolism,Center for Cancer Research,National Cancer Institute,National Institutes of Health,Bethesda,MD 20892,USA [5]The State Key Laboratory of Chemical Oncogenomics,School of Chemical Biology and Biotechnology,Shenzhen Graduate School of Peking University,Shenzhen 518055,China

出　　处：《Acta Pharmaceutica Sinica B》2024年第7期2992-3008,共17页药学学报（英文版）

基　　金：supported by the National Key R&D Program of China(2022YFA1104900 to Huichang Bi,2022YFA1106700 to Xiao Yang);the National Natural Science Foundation of China(grants 82025034 and U23A20535 to Huichang Bi,grants 82304603 to Shicheng Fan);the Shenzhen Science and Technology Program(No.KQTD20190929174023858 to Huichang Bi,China);the Science and Technology Innovation Project of Guangdong Medical Products Administration(2023ZDZ06 to Huichang Bi,China);the National Postdoctoral Program for Innovative Talents(BX20230151 to Shicheng Fan,China);the China Postdoctoral Science Foundation(2023M731570 to Shicheng Fan);the Guangdong Basic and Applied Basic Research Foundation(2023A1515012859 to Shicheng Fan,China);the Guangdong Medical Research Foundation(A2023109 to Shicheng Fan,China).

摘　　要：Fenofibrate,a peroxisome proliferator-activated receptor α(PPARα)agonist,is widely prescribed for hyperlipidemia management.Recent studies also showed that it has therapeutic potential in various liver diseases.However,its effects on hepatomegaly and liver regeneration and the involved mechanisms remain unclear.Here,the study showed that fenofibrate significantly promoted liver enlargement and regeneration post-partial hepatectomy in mice,which was dependent on hepatocyteexpressed PPARα.Yes-associated protein(YAP)is pivotal in manipulating liver growth and regeneration.We further identified that fenofibrate activated YAP signaling by suppressing its K48-linked ubiquitination,promoting its K63-linked ubiquitination,and enhancing the interaction and transcriptional activity of the YAP-TEAD complex.Pharmacological inhibition of YAP-TEAD interaction using verteporfin or suppression of YAP using AAV Yap shRNA in mice significantly attenuated fenofibrate-induced hepatomegaly.Other factors,such as MYC,KRT23,RAS,and RHOA,might also participate in fenofibrate-promoted hepatomegaly and liver regeneration.These studies demonstrate that fenofibratepromoted liver enlargement and regeneration are PPARα-dependent and partially through activating the YAP signaling,with clinical implications of fenofibrate as a novel therapeutic agent for promoting liver regeneration.

关 键 词：FENOFIBRATE PPARa HEPATOMEGALY Partial hepatectomy Liver regeneration YAP TEAD UBIQUITINATION 

分 类 号：R575[医药卫生—消化系统] R96[医药卫生—内科学]