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

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外文摘要：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 hepatocyte-expressed 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 ubiquitina-tion,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 fenofibrate-promoted 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.

外文关键词：

FenofibratePPARαHepatomegalyPartial hepatectomyLiver regenerationYAPTEADUbiquitination

作者：

Shicheng Fan、Yue Gao、Pengfei Zhao、Guomin Xie、Yanying Zhou、Xiao Yang、Xuan Li、Shuaishuai Zhang、Frank J.Gonzalez、Aijuan Qu、Min Huang、Huichang Bi

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作者单位：

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

Guangdong Provincial Key Laboratory of New Drug Design and Evaluation,School of Pharmaceutical Sciences,Sun Yat-sen University,Guangzhou 510006,China

Department of Physiology and Pathophysiology,School of Basic Medical Sciences,Capital Medical University,Beijing 100069,China

The State Key Laboratory of Chemical Oncogenomics,School of Chemical Biology and Biotechnology,Shenzhen Graduate School of Peking University,Shenzhen 518055,China

Laboratory of Metabolism,Center for Cancer Research,National Cancer Institute,National Institutes of Health,Bethesda,MD 20892,USA

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基金：

National Key R&D Program of ChinaNational Key R&D Program of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaShenzhen Science and Technology Program,ChinaScience and Technology Innovation Project of Guangdong Medical Products Administration,ChinaNational Postdoctoral Program for Innovative Talents,ChinaChina Postdoctoral Science FoundationGuangdong Basic and Applied Basic Research Foundation,ChinaGuangdong Medical Research Foundation,ChinaCartoons in graphic abstract were created with BioRender.com

项目编号：

2022YFA11049002022YFA110670082025034U23A2053582304603KQTD201909291740238582023ZDZ06BX202301512023M7315702023A1515012859A2023109NM26IJZBON

出版年：

2024

DOI：

10.1016/j.apsb.2024.03.030

药学学报(英文版)

CSTPCD

ISSN：

年,卷(期)：2024.14(7)