A novel small molecule liver X receptor transcriptional regulator, nagilactone B, suppresses atherosclerosis in apoE-deficient mice

Autor: Chengyin Yu, Liang Hu, Hui-hui Li, Cong Xi, Fei Gao, Sheng Yao, Yiping Wang, Yu-zhou Gui, Hong Yan, Ye Yang
Rok vydání: 2016
Předmět:
Male
0301 basic medicine
Apolipoprotein E
Small interfering RNA
Apolipoprotein B
Physiology
030204 cardiovascular system & hematology
Mice
chemistry.chemical_compound
0302 clinical medicine
Promoter Regions
Genetic
Aorta
ATP Binding Cassette Transporter
Subfamily G
Member 1
Hypolipidemic Agents
Liver X Receptors
Mice
Knockout
biology
Plaque
Atherosclerotic
Phenotype
ABCG1
Lipogenesis
RNA Interference
lipids (amino acids
peptides
and proteins)
Diterpenes
Cardiology and Cardiovascular Medicine
ATP Binding Cassette Transporter 1
Signal Transduction
medicine.medical_specialty
Aortic Diseases
Transfection
03 medical and health sciences
Apolipoproteins E
Cell Line
Tumor
Physiology (medical)
Internal medicine
medicine
Animals
Humans
Genetic Predisposition to Disease
Liver X receptor
Binding Sites
Apolipoprotein A-I
Dose-Response Relationship
Drug
Cholesterol
Macrophages
Cholesterol
HDL
Atherosclerosis
Mice
Inbred C57BL
Disease Models
Animal
RAW 264.7 Cells
030104 developmental biology
Endocrinology
chemistry
ABCA1
Mutation
Immunology
biology.protein
Zdroj: Cardiovascular Research. 112:502-514
ISSN: 1755-3245
0008-6363
DOI: 10.1093/cvr/cvw183
Popis: Aims 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. Methods and results 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. Conclusion 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.
Databáze: OpenAIRE
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