Adiponectin's mechanisms in high-density lipoprotein biogenesis and cholesterol efflux Anouar Hafiane a, ⁎, Stella S. Daskalopoulou a,b, ⁎⁎ a Department of Medicine, Faculty of Medicine, Research Institute of the McGill University Health Centre, McGill University, 1001 Decarie Blvd, Bloc E01.3370H, Montréal, Qc H4A 3J1, Canada b Department of Medicine, Division of Internal Medicine, McGill University, Research Institute of the McGill University Health Centre, 1001 Decarie Blvd, EM1.2230, Montreal, Quebec H4A 3J1, Canada abstract article info Article history: Received 27 July 2020 Accepted 7 October 2020 Keywords: Adiponectin Apolipoprotein A-I ATP-binding cassette transporter AI ATP-binding cassette transporter G1 High-density lipoprotein Cholesterol efflux Aim: Among adiponectin's beneficial properties is its ability to promote cellular cholesterol efflux, thereby gen- erating high-density lipoprotein (HDL) particles. However, adiponectin's role in the regulation of macrophage lipid metabolism, a crucial process in atherogenesis, remains poorly investigated. The aim of this study was to characterize the adiponectin's role in HDL biogenesis. Methods and results: We perform kinetics studies in baby hamster kidney (BHK) and Tamm-Horsfall protein 1 (THP-1) cell lines to elucidate adiponectin's role in HDL biogenesis. In cholesterol-enriched cells, specific molar doses of adiponectin stimulated cholesterol efflux with high efficiency to apoA-I. In the presence of adiponectin, BHK cells expressing ATP binding cassette transporter A1 (ABCA1) or ABCG1 generated lipidated particles having α electrophoretic mobility (α-HDL) and a molecular size of 7.5–20 nm. Interestingly, in THP-1 macrophages, cho- lesterol efflux was associated with more lipidated preβ1-HDL particles. Direct molecular interaction of adiponectin with apoA-I enhanced the affinity of apoA-I to free cholesterol and resulted in an increase in preβ1-HDL particles from plasma ex vivo. Adiponectin increased ABCA1 and ABCG1 protein expression and acti- vated the formation of ABCA1-linked cholesterol oxidase sensitive plasma membrane domains. Conclusion: Adiponectin upregulated ABCA1 and ABCG1 protein expression, reduced lipid accumulation, and ef- ficiently promoted nascent HDL formation. These results highlight that these cellular processes are intercon- nected through adiponectin and ABCA1- and ABCG1-dependent. In this pathway, adiponectin increased the affinity of apoA-I to cholesterol and effectively accelerated cholesterol removal from the plasma membrane to HDL particles. Thus, by accelerating HDL biogenesis, adiponectin may have therapeutic potential for atheroscle- rotic cardiovascular disease prevention and management. © 2020 Elsevier Inc. All rights reserved. Translational perspective High-density lipoprotein (HDL) biogenesis and maturation occurs through the removal of excess cellular cholesterol, a key atheroprotective step that alleviates the lipid loaded macrophages. This study provides evidence that adiponectin may play a key role in ac- celerating and upregulating efficiently HDL biogenesis. Given the disap- pointing results on outcomes of previous trials that aimed to increase HDL levels in the circulation (quantity), it has been increasingly realized that we need to gear our research efforts towards efficiently increasing HDL quality and functionality in order to protect against atherosclerosis. Therefore, accelerating HDL biogenesis through adiponectin may have therapeutic potential in the prevention and management of atheroscle- rotic cardiovascular disease. 1. Introduction The efflux of cellular free cholesterol (FC) and phospholipid to apo- lipoprotein A-I (apoA-I) promoted by the ATP binding cassette trans- porter A1 (ABCA1) is essential for HDL biogenesis and metabolism [1]. During lipid accumulation in various tissues, the efflux function of ABCA1 is essential in preventing build-up of excess cholesterol in cellu- lar membranes and in cholesteryl ester (CE)-enriched foam cells [1,2]. The therapeutic potential of modulating the reverse cholesterol trans- port pathway (RCT) to reduce atherosclerotic cardiovascular disease (CVD) has become increasingly investigated, especially after the ab- sence of a causal link between therapeutic increase in HDL cholesterol levels and CVD risk reduction [3]. To date, research activities have in- volved modulation of HDL biogenesis by upregulating apoA-I or Metabolism Clinical and Experimental 113 (2020) 154393 ⁎ Correspondence to: A. Hafiane, Department of Medicine, Research Institute of the McGill University Health Centre, McGill University, Montreal, QC H4A 3J1, Canada. ⁎⁎ Correspondence to: S.S. Daskalopoulou, Department of Medicine, Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, EM1.2230, Montreal, Quebec H4A 3J1, Canada. E-mail addresses: anouar.hafiane@mail.mcgill.ca (A. Hafiane), stella.daskalopoulou@mcgill.ca (S.S. Daskalopoulou). https://doi.org/10.1016/j.metabol.2020.154393 0026-0495/© 2020 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Metabolism Clinical and Experimental journal homepage: www.metabolismjournal.com