Aucubin administration suppresses STING signaling and mitigated high-fat diet-induced atherosclerosis and steatohepatosis in LDL receptor deficient mice

Abstract

The rising obesity epidemic in developed countries is associated with many chronic inflammatory diseases including atherosclerosis and nonalcoholic steatohepatitis (NASH). Consuming aucubin may benefit health by suppressing inflammation. Herein, we studied the effects of aucubin consumption on atherosclerosis and NASH progression induced by high-fat diet (HFD) in LDL receptor deficient (LDLr^-/-) mice. Adult LDLr^-/- mice were fed with HFD for 12 weeks and received oral administration of aucubin for the last 6 weeks. Aucubin did not alter body weight or dyslipidemia, but lowered hyperglycemia and mitigated HFD-induced atherosclerosis and hepatic impairments in LDLr^-/- mice. Aucubin administration inhibited HFD-induced inflammation and downregulated mRNA and protein expression of stimulator of IFN genes (STING) in both aortas and livers of LDLr^-/- mice. In vitro, aucubin suppressed mitochondrial DNA (mtDNA)-induced activation of STING/NFκB pathway and downregulated gene expression of pro-inflammatory cytokines in cultured bone marrow-derived macrophages (BMDM). Furthermore, aucubin enhanced microRNA-181a-5p (miR-181a-5p) levels in both aortas and livers of LDLr^-/- mice. Importantly, miR-181a-5p mimicked the inhibitory effect of aucubin on STING/NFκB pathway and inflammation in BMDM. In conclusion, aucubin consumption attenuated HFD-induced atherosclerosis and NASH progression in LDLr^-/- mice, possibly through modulating miR-181a-5p/STING and inhibiting inflammation.

Keywords: Dyslipidemia; Inflammation; Mitochondrial DNA; Stimulator of IFN genes; microRNA.