title: A novel small molecule liver X receptor transcriptional regulator, nagilactone B, suppresses atherosclerosis in apoE-deficient mice.
abstract: Atherosclerosis is the most common cause of cardiovascular diseases, such as myocardial infarction and stroke. We hypothesized that nagilactone B (NLB), a small molecule extracted from the root bark of Podocarpus nagi (Podocarpaceae), suppresses atherosclerosis in an atherosclerotic mouse model.
  
  
  
  Male apoE-deficient mice on C57BL/6J background received NLB (10 and 30 mg/kg) for 12 weeks. Compared with the model group, NLB treatment (10 and 30 mg/kg) significantly reduced en face lesions of total aorta areas. In RAW264.7 cells, NLB significantly ameliorated cholesterol accumulation in macrophages via enhancing apolipoprotein A-I and HDL-mediated cholesterol efflux. Mechanistically, NLB induced messenger RNA and protein expression of the ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) in RAW264.7 and THP-1 cells. Liver X receptor (LXR) site mutations in the mouse ABCA1 promoter abrogated NLB-mediated luciferase reporter activity. LXRα and LXRβ small interfering RNA suppressed NLB-mediated induction of ABCA1 expression. Consistent with in vitro results, NLB induced ABCA1 expression and suppressed macrophage areas in the aortic sinus. Moreover, NLB treatment did not induce the protein expression of LXR in liver. Hepatic and intestinal cholesterol accumulation was significantly alleviated on NLB treatment. Besides, NLB significantly improved plasma lipid profiles in apoE-deficient mice.
  
  
  
  Selective LXR activation in macrophages with NLB induces ABCA1- and ABCG1-mediated cholesterol efflux while exerting minimal effects on lipogenesis and lipid accumulation in liver, resulting in regression of atherosclerosis, and therefore might be a promising strategy for therapeutics.
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555# Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Yuzhou
authors.initials: Y
authors.lastname: Gui
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555# Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Yao
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555# Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yan
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555# Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Hu
authors.affiliation: School of Pharmacy and Biomedical Sciences, University of Portsmouth, White Swan Road, Portsmouth PO1 2DT, UK.
authors.forename: Chengyin
authors.initials: C
authors.lastname: Yu
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555# Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555# Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Xi
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555# Zuchongzhi Road, Shanghai 201203, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Li
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555# Zuchongzhi Road, Shanghai 201203, China yye@mail.shcnc.ac.cn ypwang@mail.shcnc.ac.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Ye
authors.affiliation: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555# Zuchongzhi Road, Shanghai 201203, China yye@mail.shcnc.ac.cn ypwang@mail.shcnc.ac.cn.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Wang
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D016632:Apolipoprotein A-I / Q000378:metabolism; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001665:Binding Sites; D045744:Cell Line, Tumor; D008076:Cholesterol, HDL / Q000378:metabolism; D004195:Disease Models, Animal; D004224:Diterpenes / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D020022:Genetic Predisposition to Disease; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D000071518:Liver X Receptors / Q000819:agonists* / Q000187:drug effects* / Q000235:genetics; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D011401:Promoter Regions, Genetic; D000067996:RAW 264.7 Cells; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D004224:Diterpenes; D000960:Hypolipidemic Agents; D000071518:Liver X Receptors; C577836:ABCA1 protein, human; C577833:Abca1 protein, mouse; C419353:ABCG1 protein, human; C487540:ABCG1 protein, mouse; C004552:nagilactone C
keywords: ATP-binding cassette transporter A1; ATP-binding cassette transporter G1; Atherosclerosis; Liver X receptor; Macrophage