Tilianin improves lipid profile and alleviates atherosclerosis in ApoE−/− mice through up-regulation of SREBP2-mediated LDLR expression

Abstract

BackgroundThe huge global burden of atherosclerotic cardiovascular diseases (CVDs) represents an urgent unmet need for the development of novel therapeutics. Dracocephalum moldavica L. has been used as a traditional Uygur medicine to treat various CVDs for centuries. Tilianin is a major flavonoid component of D. moldavica L. and has potential for preventing atherosclerosis. However, the molecular mechanisms that tilianin attenuate atherosclerosis are far from fully understood. PurposesThe purpose of this study is to investigate the efficiency and underlying mechanisms of tilianin in controlling lipid profile and preventing atherogenesis. MethodsThe lipid-lowering effect of tilianin was evaluated in C57BL/6 and ApoE−/− mice by systematically determining serum biochemical parameters. The effects of tilianin on the atherosclerotic lesion were observed in aortic roots and whole aortas of ApoE−/− mice with oil red O staining. Caecal content from ApoE−/− mice were collected for 16S rRNA gene sequence analysis to assess the structure of the gut microbiota. The inhibition of hepatosteatosis was verified by histological examination, and a liver transcriptome analysis was performed to elucidate the tilianin-induced hepatic transcriptional alterations. Effects of tilianin on the expression and function of LDLR were examined in HepG2 cells and ApoE−/− mice. Further mechanisms underlying the efficacy of tilianin were investigated in HepG2 cells. ResultsTilianin treatment improved lipid profiles in C57BL/6 and dyslipidemic ApoE−/− mice, especially reducing the serum LDL-cholesterol (LDL-C) level. Significant reductions of atherosclerotic lesion area and hepatosteatosis were observed in tilianin-treated ApoE−/− mice. The altered gut microbial composition in tilianin groups was associated with lipid metabolism and atherosclerosis. The liver transcriptome revealed that tilianin regulated the transcription of lipid metabolism-related genes. Then both in vitro and in vivo analyses revealed the potent effect of tilianin to enhance hepatic LDLR expression and its mediated LDL-C uptake. Further studies confirmed a critical role of SREBP2 in hepatic LDLR up-regulation by tilianin via increasing precursor and thus mature nuclear SREBP2 level. ConclusionThis study demonstrated the lipid-lowering effect of tilianin through SREBP2-mediated transcriptional activation of LDLR. Our findings reveal a novel anti-atherosclerotic mechanism of tilianin and underlie its potential clinical use in modulating CVDs with good availability and affordability.