Inhibiting M1 Macrophage Polarization, Using Small Interfering Forkhead Box Class Family Protein 1 (FOXO1)-Loaded Selenium Nanoparticles, Alleviates Hepatic Steatosis

Abstract

Lipid deposition is a key predisposing factor of nonalcoholic fatty liver disease (NAFLD). FOXO1 is obviously expressed in polarized M1 macrophages and may cause liver cell steatosis. Thus, silencing FOXO1 during M1 macrophage polarization using small interfering RNA (siRNA) technology may alleviate lipid deposition in liver cells. However, a lack of effective and biocompatible carriers is challenging for such siRNA-delivery to macrophages. To improve this, RGDfC peptide-modified selenium nanoparticles (RGDfC-Se NPs) were fabricated as a siFOXO1 delivery carrier system. We showed that RGDfC-Se NPs effectively increased siFOXO1 cellular uptake and silenced FOXO1 expression in human peripheral blood monocyte-like macrophages (THP-1 cells). Additionally, RGDfC-Se@siFOXO1 blocked M1 polarization in these cells. Also, FOXO-1-suppressed cell supernatants extenuated lipid deposition in LO2 liver cells probably by down-regulating the expression of lipid deposition-related fat metabolic enzymes acetyl-CoA carboxylase 1 and fatty acid synthase. Furthermore, our in vivo analyses showed that RGDfC-Se@siFOXO1 attenuated hepatic steatosis by inhibiting M1 macrophage polarization in mouse liver tissue. Our studies represent a new strategy and clinic treatment target for NAFLD.