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

Abstract

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.

• Authors: Chuang Guo , 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
• Journal: Food & function (Food Funct) Vol. 11 Issue 8 Pg. 7183-7196 (Aug 01 2020) ISSN: 2042-650X [Electronic] England
• PMID: 32756704 (Publication Type: Journal Article)

Chemical References

• Antioxidants
• Cation Transport Proteins
• Cryoprotective Agents
• Hepcidins
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Recombinant Proteins
• Srebf2 protein, mouse
• Sterol Regulatory Element Binding Protein 2
• Vascular Endothelial Growth Factor A
• metal transporting protein 1
• vascular endothelial growth factor A, mouse
• Iron
• Lactoferrin

Topics

• Animals
• Antioxidants (pharmacology)
• Autophagy (drug effects)
• Cation Transport Proteins (metabolism)
• Cell Death (drug effects)
• Cryoprotective Agents (pharmacology)
• Disease Models, Animal
• Disease Progression
• Down-Regulation (drug effects)
• Endoplasmic Reticulum Stress (drug effects)
• Hemostasis (drug effects)
• Hepatocytes (drug effects)
• Hepcidins (metabolism)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Injections, Intraperitoneal
• Iron (metabolism)
• Lactoferrin (pharmacology)
• Lipid Metabolism (drug effects)
• Mice
• Non-alcoholic Fatty Liver Disease (drug therapy, etiology, metabolism)
• Recombinant Proteins (pharmacology)
• Sterol Regulatory Element Binding Protein 2 (metabolism)
• Up-Regulation (drug effects)
• Vascular Endothelial Growth Factor A (metabolism)