Adiponectin increases macrophages cholesterol efflux and suppresses foam cell formation in patients with type 2 diabetes mellitus

ObjectivesLow levels of blood adiponectin contribute to an increased risk of cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM). To determine the mechanism through which adiponectin deficiency mediates accelerated cardiovascular disease in patients with diabetes, we investigated the effects of adiponectin on macrophage cholesterol deposition.Methods and results35 diabetic patients and 35 nondiabetic healthy subjects were recruited in this study. Macrophages from patients with diabetes mellitus were cultured in adiponectin-free or adiponectin-supplemented media and exposed to oxidized low-density lipoprotein cholesterol (OxLDL). Adiponectin treatment markedly suppressed foam cell formation in OxLDL-treated macrophages from diabetic subjects only, which was mainly attributed to an increase in cholesterol efflux. Adiponectin treatment significantly increased ATP-binding cassette transporter (ABC) ABCG1 mRNA and protein levels but not ABCA1, without affecting protein expression of scavenger receptors, including scavenger receptor-A (SR-A) and CD36 in diabetics. Pharmacological or genetic inhibition of liver X receptor α (LXRα) blocks the adiponectin-mediated ABCG1 expression, suggesting that LXRα activation is necessary for the attenuation of lipid accumulation of macrophages by adiponectin. In addition, deletion of the adiponectin receptor (adipoR1) in macrophages from diabetic patients accelerated foam cell formation induced by OxLDL. Finally, a strong positive correlation was noted between decreased serum adiponectin levels and impaired cholesterol efflux capacity both before and after adjustment for HDL-C and ApoAI in diabetic patients (both P < 0.001).ConclusionsThe present study identifies reduced adiopoR signaling as a critical mechanism underlying increased foam cell formation and accelerated cardiovascular disease in diabetic subjects.

► Adiponectin treatment induces cholesterol efflux from diabetic macrophages. ► Adiponectin upregulates ABCG1 expression in diabetic macrophages. ► LXRα activation is necessary for the protective effects of adiponectin. ► Deletion of adipoR1 in diabetic macrophages accelerates foam cell formation. ► Serum adiponectin levels are related to cholesterol efflux capacity in T2DM.