Roca Suarez Armando Andres, Jühling Frank, Moehlin Julien, Mailly Laurent, Virzì Alessia, Brignon Nicolas, Durand Sarah C, Oudot Marine A, Schaeffer Eugenie, Martin Romain, Meiss-Heydmann Laura, Bach Charlotte, Boulahtouf Zakaria, Girard Lea, Osswald Emma, Jamey Carole, Brumaru Daniel, Dali-Youcef Nassim, Mukherji Atish, Saez-Palma Maria, Testoni Barbara, Zoulim Fabien, Koneru Bhuvaneswari, Fujiwara Naoto, Hoshida Yujin, Felli Emanuele, Pessaux Patrick, Tremblay Michel L, Parent Romain, Schuster Catherine, Baumert Thomas F, Lupberger Joachim
Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France.
Inserm U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France.
eGastroenterology. 2025 Jan 27;3(1):e100159. doi: 10.1136/egastro-2024-100159. eCollection 2025 Jan.
Impaired hepatic expression of protein tyrosine phosphatase delta () is associated with increased STAT3 transcriptional activity and reduced survival from hepatocellular carcinoma in patients with chronic hepatitis C virus infection. However, the -expressing hepatic cell types, signalling pathways responsive to PTPRD and their role in non-viral liver disease are largely unknown.
We studied expression in single-cell and bulk liver transcriptomic data from mice and humans, and established a -deficient mouse model for metabolic dysfunction-associated steatohepatitis (MASH). Identified pathways were validated by perturbation studies in human hepatocytes and PTPRD substrates by pull-down assays. The clinical relevance was further explored in a cohort with metabolic disease by ranking patients according to expression and analysing its association with metabolic disease markers.
The analysis of individuals ranked according to expression and -deficient mice, showed that levels were associated with hepatic glucose/lipid signalling and peroxisome function. Hepatic expression is impaired in aetiologies of chronic liver diseases that are associated with metabolic disease. We further validated PTPRD as a STAT3 phosphatase in the liver, acting as a regulator of peroxisomal fatty acid metabolism. During MASH, low PTPRD led to increased liver steatosis in +/- mice and a pronounced unfolded protein response, which impacts insulin signalling. Accordingly, silencing of blunted insulin-induced AKT phosphorylation. Patients with obesity and low hepatic expression exhibit increased levels of metabolic risk factors.
Our data revealed an important regulatory role of the hepatic PTPRD-STAT3 axis in maintaining glucose/lipid homeostasis, which is recapitulated in clinical manifestations of metabolic liver disease.
蛋白酪氨酸磷酸酶δ（PTPRD）的肝脏表达受损与慢性丙型肝炎病毒感染患者中STAT3转录活性增加及肝细胞癌生存率降低相关。然而，表达PTPRD的肝细胞类型、对PTPRD有反应的信号通路及其在非病毒性肝病中的作用在很大程度上尚不清楚。
我们研究了小鼠和人类单细胞及整体肝脏转录组数据中PTPRD的表达，并建立了代谢功能障碍相关脂肪性肝炎（MASH）的PTPRD缺陷小鼠模型。通过在人肝细胞中的干扰研究和下拉试验鉴定PTPRD底物来验证所确定的信号通路。通过根据PTPRD表达对患者进行排名并分析其与代谢疾病标志物的关联，在代谢疾病队列中进一步探讨临床相关性。
根据PTPRD表达对个体和PTPRD缺陷小鼠进行排名分析，结果显示PTPRD水平与肝脏葡萄糖/脂质信号传导及过氧化物酶体功能相关。在与代谢疾病相关的慢性肝病病因中，肝脏PTPRD表达受损。我们进一步验证了PTPRD作为肝脏中的STAT3磷酸酶，作为过氧化物酶体脂肪酸代谢的调节因子。在MASH期间，低水平的PTPRD导致PTPRD+/-小鼠肝脏脂肪变性增加及明显的未折叠蛋白反应，这影响胰岛素信号传导。相应地，PTPRD沉默减弱了胰岛素诱导的AKT磷酸化。肥胖且肝脏PTPRD表达低的患者表现出代谢危险因素水平升高。
我们的数据揭示了肝脏PTPRD-STAT3轴在维持葡萄糖/脂质稳态中的重要调节作用，这在代谢性肝病的临床表现中得以体现。
