Metabolomics and lipidomics combined with serum pharmacochemistry uncover the potential mechanism of Huang-Lian-Jie-Du decoction alleviates atherosclerosis in ApoE−/− mice

Atherosclerosis (AS) is one of the main cardiovascular diseases (CVDs) leading to an increase in global mortality, and its key pathological features are lipid accumulation and oxidative stress . Huang-Lian-Jie-Du decoction (HLJDD), a representative formula for clearing heat and detoxifying, has been shown to reduce aortic lipid plaque and improve AS. However, multiple components and multiple targets of HLJDD pose a challenge in comprehending its comprehensive mechanism in the treatment of AS. This study was designed to illustrate the anti-AS mechanisms of HLJDD in an apolipoprotein E-deficient (ApoE −/− ) mouse model from a metabolic perspective. ApoE −/− mice were kept on a high-fat diet (HFD) to induce AS. Serum total cholesterol (TC), total triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) levels were determined to evaluate the influence of HLJDD on dyslipidemia . Oil red O was used to stain mouse aortic lipid plaques, and hematoxylin and eosin (HE) staining was used to assess the pathological changes in the aortic roots. Metabolomics and lipidomics combined with serum pharmacochemistry were performed to research the HLJDD mechanism of alleviating AS. In this study, HLJDD treatment improved serum biochemical levels and histopathological conditions in AS mice. A total of 6 metabolic pathways (arginine biosynthesis , glycerophospholipid , sphingolipid , arachidonic acid , linoleic acid , and glycerolipid metabolism) related to 25 metabolic biomarkers and 41 lipid biomarkers were clarified, and 22 prototype components migrating to blood were identified after oral administration of HLJDD. HLJDD improved AS induced by HFD in ApoE −/− mice. The effects of HLJDD were mainly attributed to regulating lipid metabolism by regulating the metabolic pathways of glycerophospholipids, sphingolipids, arachidonic acid , linoleic acid , and glycerolipids and reducing the levels of oxidative stress by upregulating arginine biosynthesis. • Metabolomics, lipidomics, and serum pharmacochemistry were combined to study HLJDD for the first time. • HLJDD improved AS through regulating serum oxidative stress and lipid metabolism. • The effects of ApoE gene knockout and an HFD in AS mice were evaluated via lipidomics. • This study proposed a candidate method for exploring the mechanisms of other TCMs.