FGF4 protects the liver from nonalcoholic fatty liver disease by activating the AMP-activated protein kinase-Caspase 6 signal axis
FGF4 protects the liver from nonalcoholic fatty liver disease by activating the AMP-activated protein kinase-Caspase 6 signal axis
复制标题
FGF4 通过激活 AMP 激活的蛋白激酶 - Caspase 6 信号轴来保护肝脏免受非酒精性脂肪肝疾病的影响
DOI：
10.1002/hep.32404
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发表时间：
2022
期刊：
影响因子：
13.5
通讯作者：
Zhifeng Huang
中科院分区：
文献类型：
--
作者：
Lintao Song;Luyao Wang;Yushu Hou;Jie Zhou;Chuchu Chen;Xianxi Ye;Wenliya Dong;Huan Gao;Yi Liu;Guanting Qiao;Tongtong Pan;Qiong Chen;Yu Cao;Fengjiao Hu;Zhiheng Rao;Yajing Chen;Yu Han;Minghua Zheng;Yongde Luo;Xiaokun Li;Yongping Chen;Zhifeng Huang
背景和目标 NAFLD 是与肥胖和糖尿病相关的日益严重的健康问题，且尚无有效的药物疗法。越来越多的证据表明，多种 FGF 在肝脏病理生理学的各个方面发挥着重要作用。在这里，我们报告了 FGF4 在肝脏中以前未被认识到的作用。 方法和结果在人类患者和小鼠模型中，肝脏 FGF4 的表达与 NAFLD 病理分级呈负相关。肝脏Fgf4的缺失会加剧由肥胖高脂饮食引起的肝脏脂肪变性和肝脏损伤。相比之下，重组 FGF4 的药理给药可减轻饮食挑战下诱发 NAFLD 和 NASH 的小鼠肝脏中的肝脂肪变性、炎症、肝损伤和纤维化标志物。 FGF4 的这种有益作用主要是通过激活肝 FGF 受体 (FGFR) 4 介导的，FGFR 4 激活下游 Ca2+-Ca2+/钙调蛋白依赖性蛋白激酶激酶 β 依赖性 AMP 激活蛋白激酶 (AMPK)-Caspase 6 信号轴，从而增强脂肪酸氧化、减少肝细胞凋亡并减轻肝损伤。结论我们的研究确定 FGF4 是肝脏病理生理学的应激反应性调节因子，通过 FGFR4-AMPK-Caspase 6 信号通路发挥作用，为治疗 NAFLD 和相关肝脏病理的策略提供线索。
Background and AimsNAFLD represents an increasing health problem in association with obesity and diabetes with no effective pharmacotherapies. Growing evidence suggests that several FGFs play important roles in diverse aspects of liver pathophysiology. Here, we report a previously unappreciated role of FGF4 in the liver.Approach and ResultsExpression of hepatic FGF4 is inversely associated with NAFLD pathological grades in both human patients and mouse models. Loss of hepaticFgf4 aggravates hepatic steatosis and liver damage resulted from an obesogenic high‐fat diet. By contrast, pharmacological administration of recombinant FGF4 mitigates hepatic steatosis, inflammation, liver damage, and fibrogenic markers in mouse livers induced to develop NAFLD and NASH under dietary challenges. Such beneficial effects of FGF4 are mediated predominantly by activating hepatic FGF receptor (FGFR) 4, which activates a downstream Ca2+–Ca2+/calmodulin‐dependent protein kinase kinase beta–dependent AMP‐activated protein kinase (AMPK)‐Caspase 6 signal axis, leading to enhanced fatty acid oxidation, reduced hepatocellular apoptosis, and mitigation of liver damage.ConclusionsOur study identifies FGF4 as a stress‐responsive regulator of liver pathophysiology that acts through an FGFR4‐AMPK‐Caspase 6 signal pathway, shedding light on strategies for treating NAFLD and associated liver pathologies.