DHA and EPA alleviate atherosclerosis by synergistically regulating the aorta–liver axis via miRNA networks

The anti-atherosclerotic effects of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are well-documented, yet the underlying molecular mechanisms, particularly via cross-organ crosstalk, remain unclear. Here, a high-fat diet-induced atherosclerosis (AS) model in ApoE –/– mice was constructed. Compared with controls, AS mice exhibited elevated serum total cholesterol, triglyceride and low-density lipoprotein cholesterol levels, along with reduced high-density lipoprotein cholesterol levels, impaired hepatic and cardiac function, enlarged aortic plaque area, and pronounced hepatic steatosis and cardiac lipid deposition. DHA/EPA intervention reversed these biochemical and histopathological abnormalities, and conferred superior hepatoprotection than Atorvastatin. Transcriptomics identified 1453 and 1663 differentially expressed genes in liver and aorta of AS mice, respectively. DHA/EPA up-regulated genes related to hepatic cholesterol metabolism and bile acid synthesis, and aortic genes encoding ABC transporters and PPAR signaling components. Conversely, they suppressed hepatic IL-17 signaling and endothelial adhesion molecules. MicroRNA quantification showed significant modulation of aortic miR-33a, miR-146a-3p, miR-155 and miR-223-3p levels, implicating regulation of lipid metabolism and inflammation. Collectively, these data indicate that DHA and EPA exert synergistic anti-atherosclerotic effects via the aorta-liver axis, regulating lipid metabolism, inflammation and vascular remodeling via a miR-30a/146a-3p/223-3p mediated network. These findings provide experimental and mechanistic supports for nutritional intervention of AS.