Liu Peihao, Song Xin, Chen Qingxia, Cen Li, Tang Chenxi, Yu Chaohui, Xu Chengfu
Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Department of Gastroenterology, Affiliated Hangzhou First People's Hospital, Westlake University School of Medicine, Hangzhou, China; Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou, China; Hangzhou Hospital & Institute of Digestive Diseases, Hangzhou, China.
Department of Gastroenterology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
J Biol Chem. 2024 Nov;300(11):107876. doi: 10.1016/j.jbc.2024.107876. Epub 2024 Oct 11.
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. Ubiquitin-specific peptidase 25 (USP25) in adipocytes has been proven to be involved in insulin resistance, a noteworthy characteristic of NAFLD. However, the roles of USP25 in NAFLD remain unclear. In this study, we aimed to elucidate the role of USP25 in NAFLD. Hepatic USP25 protein levels were measured in NAFLD patients and models. USP25 expression was manipulated in both mice and cells to evaluate its role in NAFLD. A downstream target of USP25 in NAFLD progression was identified through proteomic profiling analyses and confirmed. Additionally, a USP25 inhibitor was used to determine whether USP25 could be a viable treatment target for NAFLD. We found that USP25 protein levels were significantly decreased in the livers of NAFLD patients and NAFLD model mice. USP25 protein levels were also decreased in both mouse primary hepatocytes and Huh7 cells treated with free fatty acids (FFAs). We also found that Usp25 knockout mice presented much more severe hepatic steatosis when they were fed a high-fat diet. Similarly, knocking down USP25 in Huh7 cell lines aggravated FFA-induced steatosis, whereas USP25 overexpression ameliorated FFA-induced steatosis in Huh7 cell lines. Further proteomic profiling revealed that the peroxisome proliferator-activated receptor alpha (PPARα) signaling pathway was a downstream target of USP25, which was confirmed in both mice and cell lines. Moreover, USP25 could stabilize PPARα by promoting its deubiquitination. Finally, a USP25 inhibitor exacerbated diet-induced steatosis in mice. In conclusion, USP25 may play a role in NAFLD through the PPARα signaling pathway and could be a potential therapeutic target for NAFLD.
非酒精性脂肪性肝病（NAFLD）是全球最常见的慢性肝病。脂肪细胞中的泛素特异性肽酶25（USP25）已被证明与胰岛素抵抗有关，而胰岛素抵抗是NAFLD的一个显著特征。然而，USP25在NAFLD中的作用仍不清楚。在本研究中，我们旨在阐明USP25在NAFLD中的作用。我们检测了NAFLD患者和模型中肝脏USP25蛋白水平。在小鼠和细胞中操纵USP25表达以评估其在NAFLD中的作用。通过蛋白质组分析鉴定并证实了USP25在NAFLD进展中的一个下游靶点。此外，使用USP25抑制剂来确定USP25是否可能是NAFLD的一个可行治疗靶点。我们发现，NAFLD患者和NAFLD模型小鼠肝脏中的USP25蛋白水平显著降低。在用游离脂肪酸（FFA）处理的小鼠原代肝细胞和Huh7细胞中，USP25蛋白水平也降低。我们还发现，Usp25基因敲除小鼠在高脂饮食喂养时出现更严重的肝脏脂肪变性。同样，在Huh7细胞系中敲低USP25会加重FFA诱导的脂肪变性，而在Huh7细胞系中过表达USP25则可改善FFA诱导的脂肪变性。进一步的蛋白质组分析表明，过氧化物酶体增殖物激活受体α（PPARα）信号通路是USP25的下游靶点，这在小鼠和细胞系中均得到证实。此外，USP25可通过促进PPARα的去泛素化来稳定PPARα。最后，USP25抑制剂加剧了小鼠饮食诱导的脂肪变性。总之，USP25可能通过PPARα信号通路在NAFLD中发挥作用，并且可能是NAFLD的一个潜在治疗靶点。
