Antagonism of betulinic acid on LPS-mediated inhibition of ABCA1 and cholesterol efflux through inhibiting nuclear factor-kappaB signaling pathway and miR-33 expression

Guo-Jun Zhao; Shi-Lin Tang; Yun-Cheng Lv; Xin-Ping Ouyang; Ping-Ping He; Feng Yao; Wu-Jun Chen; Qian Lu; Yan-Yan Tang; Min Zhang; Yuchang Fu; Da-Wei Zhang; Kai Yin; Chao-Ke Tang

doi:10.1371/journal.pone.0074782

Antagonism of betulinic acid on LPS-mediated inhibition of ABCA1 and cholesterol efflux through inhibiting nuclear factor-kappaB signaling pathway and miR-33 expression

PLoS One. 2013 Sep 25;8(9):e74782. doi: 10.1371/journal.pone.0074782. eCollection 2013.

Authors

Guo-Jun Zhao¹, Shi-Lin Tang, Yun-Cheng Lv, Xin-Ping Ouyang, Ping-Ping He, Feng Yao, Wu-Jun Chen, Qian Lu, Yan-Yan Tang, Min Zhang, Yuchang Fu, Da-Wei Zhang, Kai Yin, Chao-Ke Tang

Affiliation

¹ Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, University of South China, Hengyang, Hunan, China ; Department of Histology and Embryology, University of South China, Hengyang, Hunan, China.

Abstract

ATP-binding cassette transporter A1 (ABCA1) is critical in exporting cholesterol from macrophages and plays a protective role in the development of atherosclerosis. The purpose of this study was to investigate the effects of betulinic acid (BA), a pentacyclic triterpenoid, on ABCA1 expression and cholesterol efflux, and to further determine the underlying mechanism. BA promoted ABCA1 expression and cholesterol efflux, decreased cellular cholesterol and cholesterol ester content in LPS-treated macrophages. Furthermore, we found that BA promoted ABCA1 expression via down-regulation of miR-33s. The inhibition of LPS-induced NF-κB activation further decreased miR-33s expression and enhanced ABCA1 expression and cholesterol efflux when compared with BA only treatment. In addition, BA suppressed IκB phosphorylation, p65 phosphorylation and nuclear translocation, and the transcription of NF-κB-dependent related gene. Moreover, BA reduced atherosclerotic lesion size, miR-33s levels and NF-κB activation, and promoted ABCA1 expression in apoE(-/-) mice. Taken together, these results reveal a novel mechanism for the BA-mediated ABCA1 expression, which may provide new insights for developing strategies for modulating vascular inflammation and atherosclerosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter 1 / antagonists & inhibitors*
ATP Binding Cassette Transporter 1 / metabolism
Animals
Apolipoproteins E / deficiency
Apolipoproteins E / metabolism
Atherosclerosis / blood
Atherosclerosis / metabolism
Atherosclerosis / pathology
Betulinic Acid
Biological Transport / drug effects
Body Weight / drug effects
Cell Line
Cell Nucleus / drug effects
Cell Nucleus / metabolism
Cholesterol / metabolism*
Gene Expression Regulation / drug effects
Humans
Lipids / blood
Lipopolysaccharides / pharmacology*
Macrophages / drug effects
Macrophages / metabolism
Male
Mice
MicroRNAs / genetics*
MicroRNAs / metabolism
Models, Biological
NF-kappa B / metabolism*
Pentacyclic Triterpenes
Protein Transport / drug effects
Signal Transduction / drug effects
Signal Transduction / genetics
Triterpenes / antagonists & inhibitors*
Triterpenes / pharmacology*

Substances

ABCA1 protein, human
ATP Binding Cassette Transporter 1
Apolipoproteins E
Lipids
Lipopolysaccharides
MIRN33a microRNA, human
MicroRNAs
NF-kappa B
Pentacyclic Triterpenes
Triterpenes
Cholesterol
Betulinic Acid

Grants and funding

The authors gratefully acknowledge the financial support from the National Natural Sciences Foundation of China (81200218, 81070220 and 81170278), and Aid Program for Science and Technology Innovative Research Team in Higher Educational Institutions (2008-244) of Human Province, China. http://www.nsfc.gov.cn. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.