Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
J Gastroenterol Hepatol. 2021 Dec;36(12):3438-3447. doi: 10.1111/jgh.15627. Epub 2021 Jul 30.
Insulin-like growth factor binding protein 1 (IGFBP1) is recently proved to be associated with glucose regulation and insulin resistance. However, little is known about its direct impact on nonalcoholic fatty liver disease (NAFLD). This study aims to investigate the effect and potential mechanism of IGFBP1 in NAFLD.
We first measured the expression level of IGFBP1 in NAFLD patients, mice, and cells. Then in in vivo study, C57BL/6 mice were fed with a methionine/choline-deficient (MCD) diet for 4 weeks to establish the model of NAFLD. And for the last 2 weeks, the mice were injected intraperitoneally with vehicle or recombinant mouse IGFBP1 0.015 mg/kg/d. The L02 cells were treated with free fatty acids (FFA) or palmitate acids (PA) and recombinant IGFBP1 for 48 h. Integrin-linked kinase (ILK) inhibitor and small interfering RNA were used to explore the potential interactions between IGFBP1 and integrin β1 (ITGB1).
The expression of IGFBP1 was increased in NAFLD patients, mice, and cells. IGFBP1 treatment significantly ameliorated lipid accumulation and hepatic injury in MCD-fed mice. IGFBP1 downregulated hepatic lipogenesis and upregulated lipid β-oxidation. In addition, IGFBP1 attenuated the nuclear factor-kappa B (NF-κB) and extracellular regulated protein kinases (ERK) signaling pathways. In vitro, we proved that IGFBP1 relieved FFA-induced lipid accumulation via interacting with ITGB1 and alleviated inflammation by inhibiting NF-κB and ERK signaling pathways.
IGFBP1 treatment significantly ameliorated hepatic steatosis by interacting with ITGB1 and suppressed inflammation by inhibiting NF-κB and ERK signaling pathways. Therefore, IGFBP1 might be a potential therapeutic target for NAFLD.
胰岛素样生长因子结合蛋白 1（IGFBP1）最近被证明与葡萄糖调节和胰岛素抵抗有关。然而，其对非酒精性脂肪性肝病（NAFLD）的直接影响知之甚少。本研究旨在探讨 IGFBP1 在 NAFLD 中的作用及潜在机制。
我们首先测量了 NAFLD 患者、小鼠和细胞中 IGFBP1 的表达水平。然后在体内研究中，用蛋氨酸/胆碱缺乏（MCD）饮食喂养 C57BL/6 小鼠 4 周建立 NAFLD 模型。在最后 2 周，小鼠腹腔内注射溶剂或重组鼠 IGFBP1 0.015mg/kg/d。用游离脂肪酸（FFA）或棕榈酸（PA）和重组 IGFBP1 处理 L02 细胞 48h。用整合素连接激酶（ILK）抑制剂和小干扰 RNA 探索 IGFBP1 与整合素 β1（ITGB1）之间的潜在相互作用。
IGFBP1 的表达在 NAFLD 患者、小鼠和细胞中增加。IGFBP1 治疗显著改善 MCD 喂养小鼠的脂质积聚和肝损伤。IGFBP1 下调肝脂肪生成，上调脂质β-氧化。此外，IGFBP1 减弱核因子-κB（NF-κB）和细胞外调节蛋白激酶（ERK）信号通路。在体外，我们证明 IGFBP1 通过与 ITGB1 相互作用缓解 FFA 诱导的脂质积聚，并通过抑制 NF-κB 和 ERK 信号通路缓解炎症。
IGFBP1 通过与 ITGB1 相互作用显著改善肝脂肪变性，并通过抑制 NF-κB 和 ERK 信号通路抑制炎症，因此 IGFBP1 可能是 NAFLD 的潜在治疗靶点。
