Biotherapeutics Translational Research Center, Korea Research Institute of Bioscience & Biotechnology (KRIBB), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea.
Department of Bioscience, KRIBB School of Bioscience, Korea University of Science and Technology (UST), 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea.
Theranostics. 2023 Jan 22;13(3):1076-1090. doi: 10.7150/thno.79434. eCollection 2023.
Precise regulation of kinases and phosphatases is crucial for human metabolic homeostasis. This study aimed to investigate the roles and molecular mechanisms of protein tyrosine phosphatase type IVA1 (PTP4A1) in regulating hepatosteatosis and glucose homeostasis. mice, adeno-associated virus encoding under liver-specific promoter, adenovirus encoding , and primary hepatocytes were used to evaluate PTP4A1-mediated regulation in the hepatosteatosis and glucose homeostasis. Glucose tolerance test, insulin tolerance test, 2-deoxyglucose uptake assay, and hyperinsulinemic-euglycemic clamp were performed to estimate glucose homeostasis in mice. The staining, including oil red O, hematoxylin & eosin, and BODIPY, and biochemical analysis for hepatic triglycerides were performed to assess hepatic lipids. Luciferase reporter assays, immunoprecipitation, immunoblots, quantitative real-time polymerase chain reaction, and immunohistochemistry staining were conducted to explore the underlying mechanism. Here, we found that deficiency of PTP4A1 aggravated glucose homeostasis and hepatosteatosis in mice fed a high-fat (HF) diet. Increased lipid accumulation in hepatocytes of mice reduced the level of glucose transporter 2 on the plasma membrane of hepatocytes leading to a diminution of glucose uptake. PTP4A1 prevented hepatosteatosis by activating the transcription factor cyclic adenosine monophosphate-responsive element-binding protein H (CREBH)/fibroblast growth factor 21 (FGF21) axis. Liver-specific PTP4A1 or systemic FGF21 overexpression in mice fed an HF diet restored the disorder of hepatosteatosis and glucose homeostasis. Finally, liver-specific PTP4A1 expression ameliorated an HF diet-induced hepatosteatosis and hyperglycemia in wild-type mice. Hepatic PTP4A1 is critical for regulating hepatosteatosis and glucose homeostasis by activating the CREBH/FGF21 axis. Our current study provides a novel function of PTP4A1 in metabolic disorders; hence, modulating PTP4A1 may be a potential therapeutic strategy against hepatosteatosis-related diseases.
精确调节激酶和磷酸酶对于人类代谢稳态至关重要。本研究旨在探讨蛋白酪氨酸磷酸酶 IVA 型 1（PTP4A1）在调节肝脂肪变性和葡萄糖稳态中的作用和分子机制。利用肝特异性启动子表达 PTP4A1 的腺相关病毒（AAV）、表达 的腺病毒以及原代肝细胞，评估 PTP4A1 介导的肝脂肪变性和葡萄糖稳态调节作用。通过葡萄糖耐量试验、胰岛素耐量试验、2-脱氧葡萄糖摄取试验和高胰岛素正葡萄糖钳夹试验评估小鼠的葡萄糖稳态。进行油红 O、苏木精和伊红（H&E）以及 BODIPY 染色以及肝组织甘油三酯的生化分析，以评估肝脂质。通过荧光素酶报告基因分析、免疫沉淀、免疫印迹、实时定量聚合酶链反应（qPCR）和免疫组织化学染色，探索潜在机制。本研究发现，高脂饮食喂养的 PTP4A1 缺陷小鼠葡萄糖稳态和肝脂肪变性加重。肝细胞内脂质堆积减少了肝细胞质膜上葡萄糖转运体 2 的水平，导致葡萄糖摄取减少。PTP4A1 通过激活环磷酸腺苷反应元件结合蛋白 H（CREBH）/成纤维细胞生长因子 21（FGF21）轴来预防肝脂肪变性。高脂饮食喂养的 PTP4A1 过表达或 FGF21 全身性过表达的肝特异性 PTP4A1 恢复了肝脂肪变性和葡萄糖稳态的紊乱。最后，肝特异性 PTP4A1 表达改善了野生型小鼠高脂饮食引起的肝脂肪变性和高血糖。肝脏 PTP4A1 通过激活 CREBH/FGF21 轴对于调节肝脂肪变性和葡萄糖稳态至关重要。本研究为 PTP4A1 在代谢紊乱中的新功能提供了证据；因此，调节 PTP4A1 可能是治疗与肝脂肪变性相关疾病的潜在策略。
