Zhang Jian-Bin, Li Meng-Ting, Lin Shuang-Zhe, Cheng Yu-Qing, Fan Jian-Gao, Chen Yuan-Wen
Department of Gastroenterology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Department of Gastroenterology, Huadong Hospital, Fudan University, Shanghai, China.
J Clin Transl Hepatol. 2023 Oct 28;11(5):1035-1049. doi: 10.14218/JCTH.2022.00110. Epub 2023 Apr 19.
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.
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.
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.
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.
脯氨酰内肽酶（PREP）是一种丝氨酸内肽酶，参与多种病理过程，包括炎症、氧化应激和自噬。我们之前的研究发现，在高脂饮食（HFD）或蛋氨酸胆碱缺乏饮食诱导的代谢功能障碍相关脂肪性肝病（MAFLD）中，PREP基因敲除显示出多种益处。然而，累积研究表明，PREP在疾病发展过程中发挥着复杂的功能。因此，进一步了解PREP在MAFLD发展中的作用是PREP干预的基础。
在本研究中，使用不同时间点（4、8、12和16周）的HFD诱导的MAFLD模型来探索PREP脯氨酸-甘氨酸-脯氨酸（PGP）/N-乙酰-丝氨酰-天冬氨酰-赖氨酰-脯氨酸（AcSDKP）系统的动态变化。为了探索其在MAFLD治疗中的潜在价值，从第10周开始向HFD诱导的MAFLD小鼠给予生理盐水或PREP抑制剂KYP-2047，持续至第16周。
从第12周起，与对照小鼠相比，HFD小鼠的PREP活性和表达增加，且PREP的增加主要导致基质金属蛋白酶8/9（MMP8/9）-PREP-PGP轴的激活，而非胸腺素β4-金属内肽酶α/PREP-AcSDKP轴的激活。此外，KYP-2047减轻了HFD诱导的肝损伤和氧化应激，通过抑制脂肪生成基因和诱导β-氧化相关基因改善了脂质代谢，并通过降低MMP8/9和PGP减轻了肝脏炎症。此外，KYP2047恢复了HFD诱导的自噬受损，这在HepG2细胞中得到了验证。
这些发现表明，MAFLD发展过程中PREP活性/表达的增加可能是从单纯性脂肪变性转变为脂肪性肝炎的关键因素，而KYP-2047可能具有治疗MAFLD的潜力。
