School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China.
Department of Colorectal Surgery, Tianjin Union Medical Center, Tianjin, China.
Hepatology. 2022 Aug;76(2):387-403. doi: 10.1002/hep.32270. Epub 2022 Jan 22.
Iron overload (IO) is a frequent finding in the general population. As the major iron storage site, the liver is subject to iron toxicity. Farnesoid X receptor (FXR) regulates bile acid metabolism and is implicated in various liver diseases. We aimed to determine whether FXR plays a role in regulating iron hepatotoxicity.
Human and mouse hepatocytes were treated with ferric ammonium citrate or iron dextran (FeDx). Mice were orally administered ferrous sulfate or injected i.p. with FeDx. Wild-type and Fxr mice were fed an iron-rich diet for 1 or 5 weeks. Mice fed an iron-rich diet were coadministered the FXR agonist, GW4064. Forced expression of FXR was carried out with recombinant adeno-associated virus 1 week before iron-rich diet feeding. Serum levels of bile acids and fibroblast growth factor 19 (FGF19) were quantified in adults with hyperferritinemia and children with β-thalassemia. The data demonstrated that iron suppressed FXR expression and signaling in human and mouse hepatocytes as well as in mouse liver and intestine. FXR deficiency potentiated iron hepatotoxicity, accompanied with hepatic steatosis as well as dysregulated iron and bile acid homeostasis. FXR negatively regulated iron-regulatory proteins 1 and 2 and prevented hepatic iron accumulation. Forced FXR expression and ligand activation significantly suppressed iron hepatotoxicity in iron-fed mice. The FXR agonist, GW4064, almost completely restored dysregulated bile acid signaling and metabolic syndrome in iron-fed mice. Conjugated primary bile acids were increased and FGF19 was decreased in serum of adults with hyperferritinemia and children with β-thalassemia.
FXR plays a pivotal role in regulating iron homeostasis and protects mice against iron hepatotoxicity. Targeting FXR may represent a therapeutic strategy for IO-associated chronic liver diseases.
铁过载（IO）在普通人群中很常见。作为主要的铁储存部位，肝脏易受到铁毒性的影响。法尼醇 X 受体（FXR）调节胆汁酸代谢，并与各种肝病有关。我们旨在确定 FXR 是否在调节铁肝毒性中发挥作用。
用柠檬酸铁铵或铁葡聚糖（FeDx）处理人源和鼠源肝细胞。用硫酸亚铁或腹腔注射 FeDx 处理小鼠。用富含铁的饮食喂养野生型和 Fxr 小鼠 1 或 5 周。用 FXR 激动剂 GW4064 共同处理用富含铁的饮食喂养的小鼠。用重组腺相关病毒 1 周前进行 FXR 强制表达，然后用富含铁的饮食喂养。测定成人高血铁症和儿童β地中海贫血患者血清中胆汁酸和成纤维细胞生长因子 19（FGF19）的水平。数据表明，铁抑制了人源和鼠源肝细胞以及鼠肝和肠中的 FXR 表达和信号。FXR 缺乏会加剧铁肝毒性，伴有肝脂肪变性以及铁和胆汁酸代谢失衡。FXR 负调控铁调节蛋白 1 和 2，防止肝铁蓄积。强制 FXR 表达和配体激活可显著抑制铁喂养小鼠的铁肝毒性。FXR 激动剂 GW4064 几乎完全恢复了铁喂养小鼠失调的胆汁酸信号和代谢综合征。高血铁症成人和β地中海贫血儿童血清中结合初级胆汁酸增加，FGF19 减少。
FXR 在调节铁稳态方面发挥着关键作用，可保护小鼠免受铁肝毒性的影响。靶向 FXR 可能代表一种与 IO 相关的慢性肝病的治疗策略。
