Therapeutic Effect of Prolyl Endopeptidase Inhibitor in High-fat Diet-induced Metabolic Dysfunction-associated Fatty Liver Disease  

作　　者：Jian-Bin Zhang Meng-Ting Li Shuang-Zhe Lin Yu-Qing Cheng Jian-Gao Fan Yuan-Wen Chen 

机构地区：[1]Department of Gastroenterology,Xinhua Hospital,Shanghai Jiaotong University School of Medicine,Shanghai,China [2]Department of Gastroenterology,Huadong Hospital,Fudan University,Shanghai,China [3]Department of Gastroenterology,The Affiliated People's Hospital of Ningbo University,Ningbo,Zhejiang,China [4]Department of Geriatrics,Huadong Hospital,Fudan University,Shanghai,China

出　　处：《Journal of Clinical and Translational Hepatology》2023年第5期1035-1049,共15页临床与转化肝病杂志（英文版）

基　　金：supported by grants from the National Natural Science Foundation of China(81970511,82270620).

摘　　要：Background and Aims:Prolyl endopeptidase(PREP)is a serine endopeptidase that participates in many pathological processes including inflammation,oxidative stress,and autophagy.Our previous studies found that PREP knockout exhibited multiple benefits in high-fat diet(HFD)or methionine choline-deficient diet-induced metabolic dysfunctionassociated fatty liver disease(MAFLD).However,cumulative studies have suggested that PREP performs complex functions during disease development.Therefore,further understanding the role of PREP in MAFLD development is the foundation of PREP intervention.Methods:In this study,an HFD-induced MAFLD model at different time points(4,8,12,and 16 weeks)was used to explore dynamic changes in the PREP proline-glycine-proline(PGP)/N-acetyl-seryl-aspartyllysyl-proline(AcSDKP)system.To explore its potential value in MAFLD treatment,saline,or the PREP inhibitor,KYP-2047,was administered to HFD-induced MAFLD mice from the 10th to 16th weeks.Results:PREP activity and expression were increased in HFD-mice compared with control mice from the 12th week onwards,and increased PREP mainly resulted in the activation of the matrix metalloproteinase 8/9(MMP8/9)-PREP-PGP axis rather than the thymosin B4-meprin a/PREP-AcSDKP axis.In addition,KYP-2047 reduced HFD-induced liver injury and oxidative stress,improved lipid metabolism through the suppression of lipogenic genes and the induction of B-oxidation-related genes,and attenuated hepatic inflam-mation by decreasing MMP8/9 and PGP.Moreover,KYP2047 restored HFD-induced impaired autophagy and this was veri-fied in HepG2 cells.Conclusions:These findings suggest that increased PREP activity/expression during MAFLD de-velopment might be a key factor in the transition from sim-ple steatosis to steatohepatitis,and KYP-2047 might possess therapeutic potential for MAFLD treatment.

关 键 词：Metabolic dysfunction-associated fatty liver disease Prolyl endopeptidase KYP-2047 Proline-glycine-proline N-acetyl-seryl-aspartyl-lysylproline 

分 类 号：R575.5[医药卫生—消化系统]