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

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 12 leptin-deficient (ob/ob) mice as rodent model of NAFLD, and administered recombinant human Lf (4 mg/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 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, promote the autophagy of damaged hepatocytes and induce the up-regulation of hypoxia inducible factor-1α/vascular endothelial growth factor (HIF-lα/VEGF) to facilitate their regeneration. These findings suggest that recombinant human Lf might be a potential therapeutic agent for mitigating or delaying the pathological process of NAFLD.