A Novel Role for RARα Agonists as Apolipoprotein CIII Inhibitors Identified from High Throughput Screening

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作者
Sang Jun Lee
Madhupriya Mahankali
Abdallah Bitar
Huafei Zou
Elizabeth Chao
Hung Nguyen
Jose Gonzalez
Dawna Caballero
Mitch Hull
Danling Wang
Peter G. Schultz
Weijun Shen
机构
[1] California Institute for Biomedical Research (Calibr),Department of Chemistry
[2] the Scripps Research Institute,undefined
[3] Scripps Translational Science Institute,undefined
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Scientific Reports | / 7卷
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摘要
Elevated triglyceride (TG) levels are well-correlated with the risk for cardiovascular disease (CVD). Apolipoprotein CIII (ApoC-III) is a key regulator of plasma TG levels through regulation of lipolysis and lipid synthesis. To identify novel regulators of TG levels, we carried out a high throughput screen (HTS) using an ApoC-III homogenous time resolved fluorescence (HTRF) assay. We identified several retinoic acid receptor (RAR) agonists that reduced secreted ApoC-III levels in human hepatic cell lines. The RARα specific agonist AM580 inhibited secreted ApoC-III by >80% in Hep3B cells with an EC50 ~2.9 nM. In high-fat diet induced fatty-liver mice, AM580 reduced ApoC-III levels in liver as well as in plasma (~60%). In addition, AM580 treatment effectively reduced body weight, hepatic and plasma TG, and total cholesterol (TC) levels. Mechanistically, AM580 suppresses ApoC-III synthesis by downregulation of HNF4α and upregulation of SHP1 expression. Collectively, these studies suggest that an RARα specific agonist may afford a new strategy for lipid-lowering and CVD risk reduction.
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