LXR-induced reverse cholesterol transport in human airway smooth muscle is mediated exclusively by ABCA1

1 Department of Biochemistry and Biomedical Sciences and 2 Department of Medicine, McMaster University; and 3 Firestone Institute for Respiratory Health, St. Joseph's Healthcare, Hamilton, Ontario, Canada Submitted 23 July 2008 ; accepted in final form 22 September 2008 The association of hypercholesterolemia and obesity with airway hyperresponsiveness has drawn increasing attention to the potential role of cholesterol and lipid homeostasis in lung physiology and in chronic pulmonary diseases such as asthma. We have recently shown that activation of the nuclear hormone receptor liver X receptor (LXR) stimulates cholesterol efflux in human airway smooth muscle (hASM) cells and induces expression of the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, members of a family of proteins that mediate reverse cholesterol and phospholipid transport. We show here that ABCA1 is responsible for all LXR-mediated cholesterol and phospholipid efflux to both apolipoprotein AI and high-density lipoprotein acceptors. In contrast, ABCG1 does not appear to be required for this process. Moreover, we show that hASM cells respond to increased levels of cholesterol by inducing expression of ABCA1 and ABCG1 transporters, a process that is dependent on LXR expression. These findings establish a critical role for ABCA1 in reverse cholesterol and phospholipid transport in airway smooth muscle cells and suggest that dysregulation of cholesterol homeostasis in these cells may be important in the pathogenesis of diseases such as asthma. lung; asthma; nuclear hormone receptors; ABC transporters Address for reprint requests and other correspondence: J. P. Capone, Faculty of Science, 1280 Main St. W., BSB Rm. 102, McMaster Univ., Hamilton, Ontario, Canada L8S 4K1 (e-mail: caponej{at}mcmaster.ca )