title: The macrophage LBP gene is an LXR target that promotes macrophage survival and atherosclerosis.
abstract: The liver X receptors (LXRs) are members of the nuclear receptor superfamily that regulate sterol metabolism and inflammation. We sought to identify previously unknown genes regulated by LXRs in macrophages and to determine their contribution to atherogenesis. Here we characterize a novel LXR target gene, the lipopolysaccharide binding protein (LBP) gene. Surprisingly, the ability of LXRs to control LBP expression is cell-type specific, occurring in macrophages but not liver. Treatment of macrophages with oxysterols or loading with modified LDL induces LBP in an LXR-dependent manner, suggesting a potential role for LBP in the cellular response to cholesterol overload. To investigate this further, we performed bone marrow transplant studies. After 18 weeks of Western diet feeding, atherosclerotic lesion burden was assessed revealing markedly smaller lesions in the LBP(-/-) recipients. Furthermore, loss of bone marrow LBP expression increased apoptosis in atherosclerotic lesions as determined by terminal deoxynucleotidyl transferase dUTP nick end labeling staining. Supporting in vitro studies with isolated macrophages showed that LBP expression does not affect cholesterol efflux but promotes the survival of macrophages in the setting of cholesterol loading. The LBP gene is a macrophage-specific LXR target that promotes foam cell survival and atherogenesis.
authors.affiliation: Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Tamer
authors.initials: T
authors.lastname: Sallam
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Ito
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Xin
authors.initials: X
authors.lastname: Rong
authors.affiliation: Department of Medicine, Division of Endocrinology, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Jason
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Medicine, Division of Endocrinology, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Caroline
authors.initials: C
authors.lastname: van Stijn
authors.affiliation: Department of Chemistry and Biochemistry, California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Chamberlain
authors.affiliation: Department of Chemistry and Biochemistry, California NanoSystems Institute, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Jung
authors.affiliation: Saban Research Institute, Children's Hospital Los Angeles, University of Southern California, Los Angeles, CA.
authors.forename: Lily C
authors.initials: LC
authors.lastname: Chao
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Marius
authors.initials: M
authors.lastname: Jones
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gilliland
authors.affiliation: Division of Cardiology, Department of Medicine, University of California, Los Angeles, Los Angeles, CA.
authors.forename: XiaoHui
authors.initials: X
authors.lastname: Wu
authors.affiliation: Medical Service, Department of Veterans Affairs Medical Center, Ann Arbor, MI Department of Medicine, University of Michigan Medical School, Ann Arbor, MI.
authors.forename: Grace L
authors.initials: GL
authors.lastname: Su
authors.affiliation: Department of Medicine, Division of Endocrinology, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Tangirala
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hong
mesh_terms: D000209:Acute-Phase Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000235:genetics; D005487:Foam Cells / Q000378:metabolism* / Q000473:pathology; D008077:Lipoproteins, LDL / Q000235:genetics / Q000378:metabolism; D000071518:Liver X Receptors / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000099231:Lipopolysaccharide-Binding Protein
chemical_list: D000209:Acute-Phase Proteins; D002352:Carrier Proteins; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; D008562:Membrane Glycoproteins; D000099231:Lipopolysaccharide-Binding Protein
keywords: atherogenesis; lipopolysaccharide binding protein; liver X receptor; nuclear receptor