Recombinant human lactoferrin attenuates the progression of hepatosteatosis and hepatocellular death by regulating iron and lipid homeostasis in ob/ob mice.,Food & Function

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Recombinant human lactoferrin attenuates the progression of hepatosteatosis and hepatocellular death by regulating iron and lipid homeostasis in ob/ob mice.
Food & Function ( IF 5.1 ) Pub Date : 2020-07-14 , DOI: 10.1039/d0fo00910e
Chuang Guo ₁ , Han Xue , Tian Guo , Wei Zhang , Wen-Qiang Xuan , Yan-Tao Ren , Di Wang , Yan-Hong Chen , Yu-Han Meng , Hui-Ling Gao , Pu Zhao

Affiliation

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 in ob/ob mice 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-1α/vascular endothelial growth factor (HIF-lα/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.

中文翻译：

重组人乳铁蛋白可通过调节ob / ob小鼠体内的铁和脂质体内稳态来减轻肝脂肪变性和肝细胞死亡的进程。

乳铁蛋白（Lf）是一种铁结合糖蛋白，已被证明具有抗氧化和抗炎特性，并且对脂质稳态和非酒精性脂肪肝疾病（NAFLD）发挥调节作用，但我们对其调节机制的了解有限且不一致。我们使用瘦素缺陷型（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（每千克体重4 mg）或对照载体以评估Lf的肝保护作用。用Lf治疗40天后，ob / ob的胰岛素敏感性和肝脂肪变性固醇调节元件结合蛋白2（SREBP2）的下调显着改善了小鼠，表明肝脂质代谢和功能得到改善。我们进一步探索了该机制，发现Lf可以通过靶向铁调素-铁转运蛋白（FPn）轴来增加肝细胞铁的输出，然后通过非酶抗氧化剂系统维持肝脏的氧化平衡，最终抑制了肝细胞的死亡。此外，Lf的细胞保护作用可能与抑制内质网（ER）应激和炎症，促进受损肝细胞自噬以及诱导缺氧诱导因子-1α/血管内皮生长因子（HIF- 1α/ VEGF）促进肝功能恢复。

更新日期：2020-08-19

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