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

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

doi:10.14218/JCTH.2022.00110

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

J Clin Transl Hepatol. 2023 Oct 28;11(5):1035-1049. doi: 10.14218/JCTH.2022.00110. Epub 2023 Apr 19.

Authors

Jian-Bin Zhang^{1

2}, Meng-Ting Li^{1

3}, Shuang-Zhe Lin¹, Yu-Qing Cheng¹, Jian-Gao Fan¹, Yuan-Wen Chen^{2

4}

Affiliations

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.

Abstract

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 dysfunction-associated 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-aspartyl-lysyl-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 β4-meprin α/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 β-oxidation-related genes, and attenuated hepatic inflammation by decreasing MMP8/9 and PGP. Moreover, KYP2047 restored HFD-induced impaired autophagy and this was verified in HepG2 cells.

Conclusions: These findings suggest that increased PREP activity/expression during MAFLD development might be a key factor in the transition from simple steatosis to steatohepatitis, and KYP-2047 might possess therapeutic potential for MAFLD treatment.

Keywords: KYP-2047; Metabolic dysfunction-associated fatty liver disease; N-acetyl-seryl-aspartyl-lysyl-proline; Proline-glycine-proline; Prolyl endopeptidase.