1. Academic Validation
  2. A novel small molecule liver X receptor transcriptional regulator, nagilactone B, suppresses atherosclerosis in apoE-deficient mice

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

  • Cardiovasc Res. 2016 Oct;112(1):502-14. doi: 10.1093/cvr/cvw183.
Yuzhou Gui 1 Sheng Yao 1 Hong Yan 1 Liang Hu 1 Chengyin Yu 2 Fei Gao 1 Cong Xi 1 Huihui Li 1 Yang Ye 3 Yiping Wang 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555# Zuchongzhi Road, Shanghai 201203, China.
  • 2 School of Pharmacy and Biomedical Sciences, University of Portsmouth, White Swan Road, Portsmouth PO1 2DT, UK.
  • 3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555# Zuchongzhi Road, Shanghai 201203, China [email protected] [email protected].
Abstract

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.

Keywords

ATP-binding cassette transporter A1; ATP-binding cassette transporter G1; Atherosclerosis; Liver X receptor; Macrophage.

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