In the early 1980s, it was established that adipose tissue not only plays an important role in triglyceride storage but also accounts for approximately 25% of total body cholesterol in humans (1). However, in obese individuals this proportion of cholesterol can increase to well over half and could contribute to adipocyte dysfunction and obesity-mediated metabolic syndrome, including low levels of plasma HDL cholesterol (1–4). Consistent with the view that adipose tissue behaves as a cholesterol sink, and its accumulation is proportional to triglycerides in response to nutritional changes to maintain cellular integrity and to regulate cellular hypertrophy, it is not surprising that adipocytes have developed a unique ability to deal with cholesterol (1). It may be for this reason that adipocytes have evolved with an extremely limited capacity to perform de novo cholesterol synthesis (1) but possess multiple strategies to extract cholesterol from circulating lipoproteins (5,6). Despite cholesterol being delivered as cholesteryl ester in adipocytes, approximately 95% of cholesterol paradoxically exists as free cholesterol (FC) (7) and resides in the plasma membrane or the cytosolic interface of lipid droplets where it is readily available for mobilization (8). Cholesterol mobilization involves adipose tissue ATP-binding cassette transporter A1 (ABCA1), which has recently been shown to contribute to HDL biogenesis in vivo (9,10). These findings illustrate an exquisite balance between adipose tissue cholesterol storage and plasma HDL cholesterol concentration and raise the question about the role that HDL cholesterol plays in obesity and associated metabolic complications. ATP-binding cassette transporters ABCA1 and ABCG1 primarily mediate the efflux of cholesterol from peripheral cells. These transporters promote unidirectional cholesterol efflux to lipid-poor apolipoprotein A-I (apoA-I), apoE, or HDL particles, respectively, and are under the transcriptional control of liver X receptors (LXRs), master intracellular sensors that are activated in response to …