蛋白酪氨酸磷酸酶 1B 在非酒精性脂肪性肝炎进展和逆转中的双重作用。

OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. Protein tyrosine phosphatase 1B (PTP1B), a negative modulator of insulin and cytokine signaling, is a therapeutic target for type 2 diabetes and obesity. We investigated the impact of PTP1B deficiency during NAFLD, particularly in non-alcoholic steatohepatitis (NASH). METHODS: NASH features were evaluated in livers from wild-type (PTP1BWT) and PTP1B-deficient (PTP1BKO) mice fed methionine/choline-deficient diet (MCD) for 8 weeks. A recovery model was established by replacing MCD to chow diet (CHD) for 2-7 days. Non-parenchymal liver cells (NPCs) were analyzed by flow cytometry. Oval cells markers were measured in human and mouse livers with NASH, and in oval cells from PTP1BWT and PTP1BKO mice. RESULTS: PTP1BWT mice fed MCD for 8 weeks exhibited NASH, NPCs infiltration, and elevated Fgf21, Il6 and Il1b mRNAs. These parameters decreased after switching to CHD. PTP1B deficiency accelerated MCD-induced NASH. Conversely, after switching to CHD, PTP1BKO mice rapidly reverted NASH compared to PTP1BWT mice in parallel to the normalization of serum triglycerides (TG) levels. Among NPCs, a drop in cytotoxic natural killer T (NKT) subpopulation was detected in PTP1BKO livers during recovery, and in these conditions M2 macrophage markers were up-regulated. Oval cells markers (EpCAM and cytokeratin 19) significantly increased during NASH only in PTP1B-deficient livers. HGF-mediated signaling and proliferative capacity were enhanced in PTP1BKO oval cells. In NASH patients, oval cells markers were also elevated. CONCLUSIONS: PTP1B elicits a dual role in NASH progression and reversion. Additionally, our results support a new role for PTP1B in oval cell proliferation during NAFLD.

目的：非酒精性脂肪性肝病（NAFLD）是西方国家最常见的慢性肝病。蛋白酪氨酸磷酸酶 1B（PTP1B）是胰岛素和细胞因子信号的负调节剂，是 2 型糖尿病和肥胖症的治疗靶点。我们研究了 PTP1B 在 NAFLD 中的缺失，特别是在非酒精性脂肪性肝炎（NASH）中的作用。

方法：在给予蛋氨酸/胆碱缺乏饮食（MCD）8 周的野生型（PTP1BWT）和 PTP1B 缺失型（PTP1BKO）小鼠的肝脏中评估 NASH 特征。建立了一个通过用标准饮食（CHD）代替 MCD 2-7 天的恢复模型。通过流式细胞术分析非实质细胞（NPC）。用 NASH 患者和 PTP1BWT 和 PTP1BKO 小鼠的肝脏以及 NPC 中测量了卵圆细胞标记物。

结果：用 MCD 喂养 8 周的 PTP1BWT 小鼠表现出 NASH、NPCs 浸润和 Fgf21、Il6 和 Il1b mRNA 水平升高。这些参数在用 CHD 代替后降低。PTP1B 缺失加速了 MCD 诱导的 NASH。相反，在用 CHD 代替后，与 PTP1BWT 小鼠相比，PTP1BKO 小鼠迅速恢复 NASH，同时血清甘油三酯（TG）水平正常化。在 NPC 中，在恢复期间检测到 PTP1BKO 肝脏中细胞毒性自然杀伤 T（NKT）亚群下降，并且在这些条件下 M2 巨噬细胞标记物上调。只有在 PTP1B 缺失的肝脏中，卵圆细胞标记物（EpCAM 和细胞角蛋白 19）在 NASH 期间才显著增加。在 PTP1BKO 卵圆细胞中，HGF 介导的信号和增殖能力增强。在 NASH 患者中，卵圆细胞标记物也升高。

结论：PTP1B 在 NASH 进展和恢复中发挥双重作用。此外，我们的结果支持 PTP1B 在 NAFLD 期间卵圆细胞增殖中的新作用。