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Journal of Biomolecular Screening
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Article

Identification of Novel Human High-Density Lipoprotein Receptor Up-regulators Using a Cell-Based High-Throughput Screening Assay

Yuan Yang1, Zhongbing Zhang2, Wei Jiang2, Lei Gao2, Guiyu Zhao2, Zhihui Zheng2, Min Wang3, Shuyi Si2*, Bin Hong2

1 School of Life Science and Technology, China Pharmaceutical University, Nanjing, China; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
2 Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
3 School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.

* To whom correspondence should be addressed. E-mail: sisyimb{at}hotmail.com.


  Abstract

Scavenger receptor class B type I (SR-BI) is the high-affinity high-density lipoprotein (HDL) receptor, and CLA-1 is the human homologue of the murine SR-BI. CLA-1/SR-BI receptor has been suggested as a new preventative and/or therapeutic target for atherosclerosis due to its pivotal role in overall HDL cholesterol (HDL-C) metabolism and its antiatherogenic activity in vivo. To search for active compounds that can increase CLA-1 transcription, a novel cell-based assay was developed for application in high-throughput screening (HTS). Human hepatoma HepG2 cells were transfected with a CLA-1-promoter-luciferase reporter gene construct, and the stable transfected cell line was selected and named CLAp-LUC HepG2. With rosiglitazone as a positive control, this stable cell line was used to establish a specific CLA-1 gene expression assay in a 96-well microplate format. The evaluating parameter Z' value of 0.64 showed that this cell-based HTS assay was robust and reliable. Screening of 6000 microbial secondary metabolite crude extracts identified 8 positive strains. Between 2 identified CLA-1 up-regulators produced by actinomycete strain 04-4776, 4776B may stimulate not only the expression of CLA-1 on the transcriptional and translational levels but also the activity of CLA-1 to uptake the HDL-C in HepG2 cells. The active compounds originated from this HTS assay may be developed to drug candidates or lead compounds for new antiatherosclerosis agents.

Key Words: CLA-1/SR-BI, up-regulator, high-throughput screening, microbial secondary metabolites, atherosclerosis

First published on January 26, 2007, doi:10.1177/1087057106297568

Journal of Biomolecular Screening 2007;12:211.

A more recent version of this article appeared on March 1, 2007

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J. Gao, Y. Xu, Y. Yang, Y. Yang, Z. Zheng, W. Jiang, B. Hong, X. Yan, and S. Si
Identification of Upregulators of Human ATP-Binding Cassette Transporter A1 via High-Throughput Screening of a Synthetic and Natural Compound Library
J Biomol Screen, August 1, 2008; 13(7): 648 - 656.
[Abstract] [PDF]