Inhibition of miR-103a-3p suppresses lipopolysaccharide-induced sepsis and liver injury by regulating FBXW7 expression

Abstract

Inflammation, apoptosis, and oxidative stress are involved in septic liver dysfunction. Herein, the role of miR-103a-3p/FBXW7 axis in lipopolysaccharides (LPS)-induced septic liver injury was investigated in mice. Hematoxylin-eosin staining was used to evaluate LPS-induced liver injury. Quantitative real-time polymerase chain reaction was performed to determine the expression of microRNA (miR) and messenger RNA, and western blot analysis was conducted to examine the protein levels. Dual-luciferase reporter assay was used to confirm the binding between miR-103a-3p and FBXW7. Both annexin V-fluoresceine isothiocyanate/propidium iodide staining and caspase-3 activity were employed to determine cell apoptosis. First, miR-103a-3p was upregulated in the septic serum of mice and patients with sepsis, and miR-103a-3p was elevated in the septic liver of LPS-induced mice. Then, interfering miR-103a-3p significantly decreased apoptosis by suppressing Bax expression and upregulating Bcl-2 levels in LPS-induced AML12 and LO2 cells, and septic liver of mice. Furthermore, inhibition of miR-103a-3p repressed LPS-induced inflammation by downregulating the expression of tumor necrosis factor, interleukin 1β, and interleukin 6 in vitro and in vivo. Meanwhile, interfering miR-103a-3p obviously attenuated LPS-induced overactivation of oxidation via promoting expression of antioxidative enzymes, including catalase, superoxide dismutase, and glutathione in vitro and in vivo. Moreover, FBXW7 was a target of miR-103a-3p, and overexpression of FBXW7 significantly ameliorated LPS-induced septic liver injury in mice. Finally, knockdown of FBXW7 markedly reversed anti-miR-103a-3p-mediated suppression of septic liver injury in mice. In conclusion, interfering miR-103a-3p or overexpression of FBXW7 improved LPS-induced septic liver injury by suppressing apoptosis, inflammation, and oxidative reaction.

Keywords: FBXW7; LPS; liver failure; miR-103a-3p; sepsis.