--- - |2+ Abstract Aim CCN family member 1 (CCN1) is an extracellular matrix cytokine and appears in atherosclerotic lesions. However, we have no evidence to support the role of CCN1 in regulating cholesterol metabolism and atherosclerosis. Methods Apolipoprotein E‐deficient (apoE−/−) mice were used as in vivo model. Oxidized low‐density lipoprotein (oxLDL)‐induced macrophage‐foam cells were used as in vitro model. RT‐PCR and western blot analysis were used for evaluating gene and protein expression, respectively. Conventional assay kits were used for assessing the levels of cholesterol, triglycerides, and cytokines. Results We show predominant expression of CCN1 in foamy macrophages in atherosclerotic aortas of apoE−/−mice. In apoE−/− mice, CCN1 treatment worsened hyperlipidaemia, systemic inflammation, and the progression of atherosclerosis. In addition, CCN1 decreased the capacity of reverse cholesterol transport and downregulated the protein expression of ATP‐binding cassette transporter A1 (ABCA1) and ABCG1 in atherosclerotic aortas. Notably, CCN1 decreased the protein expression of cholesterol clearance‐related proteins, including ABCG5, ABCG8, liver X receptor α (LXRα), cholesterol 7α‐hydrolase and LDL receptor in liver, and exacerbated hepatic lipid accumulation. In macrophages, treatment with oxLDL increased CCN1 expression. Inhibition of CCN1 activity by neutralizing antibody or small interfering RNA attenuated the oxLDL‐induced lipid accumulation. In contrast, cotreatment with CCN1 or overexpression of CCN1 augmented oxLDL‐induced lipid accumulation by impairing apolipoprotein AI‐ and high‐density lipoprotein‐dependent cholesterol efflux, which was attributed to downregulation of LXRα‐dependent expression of ABCA1 and ABCG1. Conclusion Our findings suggest that CCN1 plays a pivotal role in regulating cholesterol metabolism and the development of atherosclerosis. - 'Acta Physiologica, EarlyView. '