title: Liver X receptor beta (LXRbeta) interacts directly with ATP-binding cassette A1 (ABCA1) to promote high density lipoprotein formation during acute cholesterol accumulation.
abstract: Cells have evolved multiple mechanisms for maintaining cholesterol homeostasis, and, among these, ATP-binding cassette protein A1 (ABCA1)-mediated cholesterol efflux is highly regulated at the transcriptional level through the activity of the nuclear receptor liver X receptor (LXR). Here, we show that in addition to its well defined role in transcription, LXRβ directly binds to the C-terminal region ((2247)LTSFL(2251)) of ABCA1 to mediate its post-translational regulation. In the absence of cholesterol accumulation in the macrophage-like cell line THP-1, the ABCA1-LXRβ complex stably localizes to the plasma membrane, but apolipoprotein A-I (apoA-I) binding or cholesterol efflux does not occur. Exogenously added LXR ligands, which mimic cholesterol accumulation, cause LXRβ to dissociate from ABCA1, thus freeing ABCA1 for apoA-I binding and subsequent cholesterol efflux. Photoaffinity labeling experiments with 8-azido-[α-(32)P]ATP showed that the interaction of LXRβ with ABCA1 inhibits ATP binding by ABCA1. This is the first study to show that a protein-protein interaction with the endogenous protein suppresses the function of ABC proteins by inhibiting ATP binding. LXRβ can cause a post-translational response by binding directly to ABCA1, as well as a transcriptional response, to maintain cholesterol homeostasis.
authors.affiliation: Institute for Integrated Cell-Material Sciences, Kyoto University, Kyoto, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Hozoji-Inada
authors.forename: Youichi
authors.initials: Y
authors.lastname: Munehira
authors.forename: Kohjiro
authors.initials: K
authors.lastname: Nagao
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kioka
authors.forename: Kazumitsu
authors.initials: K
authors.lastname: Ueda
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D008075:Lipoproteins, HDL / Q000235:genetics / Q000378:metabolism*; D000071518:Liver X Receptors; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D014158:Transcription, Genetic / Q000235:genetics
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; D046912:Multiprotein Complexes; D057093:Orphan Nuclear Receptors; D000255:Adenosine Triphosphate; D002784:Cholesterol