Hyperlipidemia is a direct cause of atherosclerosis and can damage the heart, brain, and kidneys, leading to coronary heart disease and cerebrovascular conditions. Dendrobium huoshanense (DH) has been demonstrated to regulate lipid metabolism. This study aimed to elucidate the mechanisms through which DH prevents lipid metabolism disorders by examining physiological measures, hepatic lipidomics, and metabolomics. Eighteen mice were divided into three groups: normal control, high-fat diet (HFD), and DH (600 mg/kg/day), with treatments lasting for 12 weeks. DH improved serum lipid levels and alleviated hepatic steatosis in mice with HFD-induced dyslipidemia. Liver lipidomics analysis indicated that DH mitigated lipid profile abnormalities in the HFD-treated mice. Additionally, liver metabolomics revealed critical differential metabolites between the HFD and DH groups. The DH group exhibited increased epinephrine (p < 0.01) and decreased corticosterone levels (p < 0.05). Spearman’s correlation analysis showed significant negative and positive correlations between epinephrine, corticosterone levels, and serum triglyceride levels, respectively. Furthermore, epinephrine and corticosterone were significantly enriched in the regulation of lipolysis in the adipocyte pathway, which was closely linked to the improvement of blood lipids and the regulation of liver lipid metabolism. DH protected liver lipid metabolism, at least in part, by promoting epinephrine secretion and suppressing corticosterone, thereby regulating lipolysis in adipocytes. Our findings provide novel insights into the mechanisms underlying the antidyslipidemic effects of DH.
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