ANGPTL8 通过 LILRB2/ERK 信号通路加速 HFD 诱导的炎症活性介导的肝纤维化。
ANGPTL8 accelerates liver fibrosis mediated by HFD-induced inflammatory activity via LILRB2/ERK signaling pathways.
机构信息
Institute of Pediatric Disease, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China; Department of Neurosurgery, Hubei Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan 442000, Hubei, China.
Institute of Pediatric Disease, Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medical Sciences, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, China; College of Pharmacy, Hubei University of Medicine, Shiyan, Hubei 442000, China.
出版信息
J Adv Res. 2023 May;47:41-56. doi: 10.1016/j.jare.2022.08.006. Epub 2022 Aug 27.
INTRODUCTION
High calorie intake is known to induce nonalcoholic fatty liver disease (NAFLD) by promoting chronic inflammation. However, the mechanisms are poorly understood.
OBJECTIVES
This study examined the roles of ANGPTL8 in the regulation of NAFLD-associated liver fibrosis progression induced by high fat diet (HFD)-mediated inflammation.
METHODS
The ANGPTL8 concentration was measured in serum samples from liver cancer and liver cirrhosis patients. ANGPTL8 knockout(KO) mice were used to induce disease models (HFD, HFHC and CCL4) followed by pathological staining, western blot and immunohistochemistry. Hydrodynamic injection of an adeno-associated virus 8 (AAV8) was used to establish a model for restoring ANGPTL8 expression specifically in ANGPTL8 KO mice livers. RNA-sequencing, protein array, Co-IP, etc. were used to study ANGPTL8's mechanisms in regulating liver fibrosis progression, and drug screening was used to identify an effective inhibitor of ANGPTL8 expression.
RESULTS
ANGPTL8 level is associated with liver fibrogenesis in both cirrhosis and hepatocellular carcinoma patients. Mouse studies demonstrated that ANGPTL8 deficiency suppresses HFD-stimulated inflammatory activity, hepatic steatosis and liver fibrosis. The AAV-mediated restoration of liver ANGPTL8 expression indicated that liver-derived ANGPTL8 accelerates HFD-induced liver fibrosis. Liver-derived ANGPTL8, as a proinflammatory factor, activates HSCs (hepatic stellate cells) by interacting with the LILRB2 receptor to induce ERK signaling and increase the expression of genes that promote liver fibrosis. The FDA-approved anti-diabetic drug metformin, an ANGPTL8 inhibitor, inhibited HFD-induced liver fibrosis in vivo.
CONCLUSIONS
Our data support that ANGPTL8 is a proinflammatory factor that accelerates NAFLD-associated liver fibrosis induced by HFD. The serum ANGPTL8 level may be a potential and specific diagnostic marker for liver fibrosis, and targeting ANGPTL8 holds great promise for developing innovative therapies to treat NAFLD-associated liver fibrosis.
简介
高热量摄入可通过促进慢性炎症诱导非酒精性脂肪性肝病（NAFLD）。然而，其机制尚不清楚。
目的
本研究探讨了 ANGPTL8 在高脂肪饮食（HFD）介导的炎症诱导的 NAFLD 相关肝纤维化进展中的作用。
方法
检测肝癌和肝硬化患者血清样本中的 ANGPTL8 浓度。ANGPTL8 敲除（KO）小鼠用于诱导疾病模型（HFD、HFHC 和 CCL4），然后进行病理染色、western blot 和免疫组化。腺相关病毒 8（AAV8）的水力注射用于建立专门在 ANGPTL8 KO 小鼠肝脏中恢复 ANGPTL8 表达的模型。RNA 测序、蛋白芯片、Co-IP 等用于研究 ANGPTL8 调节肝纤维化进展的机制，并进行药物筛选以鉴定 ANGPTL8 表达的有效抑制剂。
结果
ANGPTL8 水平与肝硬化和肝细胞癌患者的肝纤维化有关。小鼠研究表明，ANGPTL8 缺乏可抑制 HFD 刺激的炎症活性、肝脂肪变性和肝纤维化。AAV 介导的肝 ANGPTL8 表达恢复表明，肝源性 ANGPTL8 加速 HFD 诱导的肝纤维化。肝源性 ANGPTL8 作为一种促炎因子，通过与 LILRB2 受体相互作用激活 HSCs（肝星状细胞），诱导 ERK 信号通路并增加促进肝纤维化的基因表达。美国食品和药物管理局批准的抗糖尿病药物二甲双胍是一种 ANGPTL8 抑制剂，可抑制体内 HFD 诱导的肝纤维化。
结论
我们的数据支持 ANGPTL8 是一种促炎因子，可加速 HFD 诱导的 NAFLD 相关肝纤维化。血清 ANGPTL8 水平可能是肝纤维化的潜在和特异诊断标志物，靶向 ANGPTL8 为开发治疗 NAFLD 相关肝纤维化的创新疗法提供了巨大潜力。
Zotero 插件