Recombinant human lactoferrin attenuates the progression of hepatosteatosis and hepatocellular death by regulating iron and lipid homeostasis in ob/ob mice
Recombinant human lactoferrin attenuates the progression of hepatosteatosis and hepatocellular death by regulating iron and lipid homeostasis in ob/ob mice
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DOI：
10.1039/d0fo00910e
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发表时间：
2020-08-01
期刊：
影响因子：
6.1
通讯作者：
Zhao, Pu
中科院分区：
文献类型：
--
作者：
Guo, Chuang;Xue, Han;Zhao, Pu
乳铁蛋白（Lf）是一种铁结合糖蛋白，具有抗氧化和抗炎作用，对脂质平衡和非酒精性脂肪肝（NAFLD）有调节作用，但对其调节机制的认识不一致。我们使用瘦素缺陷（ob/ob）小鼠作为NAFLD的啮齿动物模型，并通过腹膜内注射施用重组人Lf（4 mg/kg体重）或对照载体以评价Lf的肝保护作用。用Lf治疗40天后，胰岛素敏感性和肝脏脂肪变性inob/ob小鼠显著改善，甾醇调节元件结合蛋白-2（SREBP 2）下调，表明肝脏脂质代谢和功能改善。我们进一步探讨了其机制，发现Lf可能通过靶向铁调素-铁转运蛋白（FPn）轴增加肝细胞铁输出，进而通过非酶抗氧化系统维持肝脏氧化平衡，最终抑制肝细胞死亡。此外，Lf的细胞保护作用可能与抑制内质网（ER）应激和炎症、促进受损肝细胞的自噬以及诱导缺氧诱导因子-1 α/血管内皮生长因子（HIF-1 α/VEGF）上调以促进肝功能恢复有关。这些结果表明，重组人Lf可能是一种潜在的治疗药物，以减轻或延缓NAFLD的病理过程。
Lactoferrin (Lf), an iron-binding glycoprotein, has been shown to possess antioxidant and anti-inflammatory properties and exert modulatory effects on lipid homeostasis and non-alcoholic fatty liver disease (NAFLD), but our understanding of its regulatory mechanisms is limited and inconsistent. We used leptin-deficient (ob/ob) mice as the rodent model of NAFLD, and administered recombinant human Lf (4 mg per kg body weight) or control vehicle by intraperitoneal injection to evaluate the hepatoprotective effects of Lf. After 40 days of treatment with Lf, insulin sensitivity and hepatic steatosis inob/obmice were significantly improved with the down-regulation of sterol regulatory element binding protein-2 (SREBP2), indicating an improvement in hepatic lipid metabolism and function. We further explored the mechanism, and found that Lf may increase the hepatocellular iron output by targeting the hepcidin-ferroportin (FPn) axis, and then maintains the liver oxidative balance through a nonenzymatic antioxidant system, ultimately suppressing the death of hepatocytes. In addition, the cytoprotective role of Lf may be associated with the inhibition of endoplasmic reticulum (ER) stress and inflammation, promotion of autophagy of damaged hepatocytes and induction of up-regulation of hypoxia inducible factor-1 alpha/vascular endothelial growth factor (HIF-l alpha/VEGF) to facilitate liver function recovery. These findings suggest that recombinant human Lf might be a potential therapeutic agent for mitigating or delaying the pathological process of NAFLD.