title: LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling.
abstract: The liver X receptors (LXRs) are transcriptional regulators of lipid homeostasis that also have potent anti-inflammatory effects. The molecular basis for their anti-inflammatory effects is incompletely understood, but has been proposed to involve the indirect tethering of LXRs to inflammatory gene promoters. Here we demonstrate that the ability of LXRs to repress inflammatory gene expression in cells and mice derives primarily from their ability to regulate lipid metabolism through transcriptional activation and can occur in the absence of SUMOylation. Moreover, we identify the putative lipid transporter Abca1 as a critical mediator of LXR's anti-inflammatory effects. Activation of LXR inhibits signaling from TLRs 2, 4 and 9 to their downstream NF-κB and MAPK effectors through Abca1-dependent changes in membrane lipid organization that disrupt the recruitment of MyD88 and TRAF6. These data suggest that a common mechanism-direct transcriptional activation-underlies the dual biological functions of LXRs in metabolism and inflammation.
authors.affiliation: Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Ito
authors.affiliation: Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hong
authors.affiliation: Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Xin
authors.initials: X
authors.lastname: Rong
authors.affiliation: Department of Internal Medicine-Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, United States.
authors.forename: Xuewei
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Tarling
authors.affiliation: Laboratory of Fluorescence Dynamics, Biomedical Engineering Department, Center for Complex Biological Systems, University of California, Irvine, Irvine, United States.
authors.forename: Per Niklas
authors.initials: PN
authors.lastname: Hedde
authors.affiliation: Laboratory of Fluorescence Dynamics, Biomedical Engineering Department, Center for Complex Biological Systems, University of California, Irvine, Irvine, United States.
authors.forename: Enrico
authors.initials: E
authors.lastname: Gratton
authors.affiliation: Department of Internal Medicine-Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, United States.
authors.forename: John
authors.initials: J
authors.lastname: Parks
authors.affiliation: Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United States.
authors.forename: Peter
authors.identifier: http://orcid.org/0000-0003-1259-0477
authors.initials: P
authors.lastname: Tontonoz
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000737:chemistry*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D007249:Inflammation; D000071518:Liver X Receptors; D051379:Mice; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D051193:Toll-Like Receptors; C577833:Abca1 protein, mouse
keywords: LXR; Toll-like receptor; cell biology; chromosomes; genes; lipid metabolism; mouse; nuclear receptor