Objective To explore the effect and potential mechanism of harpagide on lipid metabolism and bone metabolism in atherosclerosis (AS) mice fed a high-fat diet. Methods AS model was constructed by feeding apolipoprotein E knock-out (ApoE^-/-) mice with high-fat diet for eight weeks, mice were randomly divided into model group, atorvastatin (2.6 mg/kg) group, and harpagide (20 mg/kg) group, with eight mice in each group. Additionally, eight C57BL/6N wild-type mice were included as control group and fed a standard diet. After nine weeks of drug intervention, micro-CT was used to analyze changes in bone microarchitecture. Infrared spectroscopy was employed to examine bone material composition. Hematoxylin-eosin (HE) staining was applied to observe the morphology of femoral trabeculae, and tartrate resistant acid phosphatase (TRAP) staining was used to quantify osteoclast numbers in the femur. Levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), TRAP and C-terminal telopeptide of type I collagen (CTX-1) in serum were measured using biochemical assays. Western blotting was performed to detect protein expression levels of nuclear factor of activated T cells 1 (NFATc1), Fos proto-oncogene (c-Fos), cathepsin K, peroxisome proliferator-activated receptor gamma coactivator-1β (PGC-1β), estrogen-related receptor α (ERRα) and peroxisome proliferator-activated receptor γ (PPARγ) in bone tissue. Results Harpagide significantly improved bone microarchitecture and bone material composition in AS mice (P < 0.05, 0.01), reduced levels of TC, LDL-C, HDL-C in serum and AS index (P < 0.05, 0.01), decreased levels of bone resorption markers CTX-1 and TRAP in serum (P < 0.01), down-regulated the expressions of bone resorption-related proteins c-Fos, NFATc1 and cathepsin K in bone tissue (P < 0.01). Additionally, harpagide suppressed the protein expression levels of PGC-1β, ERRα and PPARγ in bone tissue of AS mice (P < 0.05, 0.01). Conclusion Harpagide ameliorates dyslipidemia and suppresses bone resorption in AS mice, thereby exerting anti-osteoporotic effects. The mechanism may involve the inhibition of PPARγ/ERRα/PGC-1β signaling pathway.

harpagide  /  atherosclerosis  /  osteoporosis  /  bone metabolism  /  lipid metabolism  /  PPARγ/ERRα/PGC-1β signaling pathway