A novel small molecule liver X receptor transcriptional regulator, nagilactone B, suppresses atherosclerosis in apoE-deficient mice.
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.
['Gui|Yuzhou|Y|', 'Yao|Sheng|S|', 'Yan|Hong|H|', 'Hu|Liang|L|', 'Yu|Chengyin|C|', 'Gao|Fei|F|', 'Xi|Cong|C|', 'Li|Huihui|H|', 'Ye|Yang|Y|', 'Wang|Yiping|Y|']
D064286:ATP Binding Cassette Transporter 1 D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 D000818:Animals D001011:Aorta D001018:Aortic Diseases D016632:Apolipoprotein A-I D001057:Apolipoproteins E D050197:Atherosclerosis D001665:Binding Sites D045744:Cell Line, Tumor D008076:Cholesterol, HDL D004195:Disease Models, Animal D004224:Diterpenes D004305:Dose-Response Relationship, Drug D020022:Genetic Predisposition to Disease D006801:Humans D000960:Hypolipidemic Agents D000071518:Liver X Receptors D008264:Macrophages 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 D014162:Transfection
Liver X receptor Atherosclerosis Macrophage ATP-binding cassette transporter A1 ATP-binding cassette transporter G1