A Novel Role for RARα Agonists as Apolipoprotein CIII Inhibitors Identified from High Throughput Screening
Abstract 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 t...
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2017
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oai:doaj.org-article:3ea9011fb70b4cf78139664545c9293e2021-12-02T15:04:55ZA Novel Role for RARα Agonists as Apolipoprotein CIII Inhibitors Identified from High Throughput Screening10.1038/s41598-017-05163-w2045-2322https://doaj.org/article/3ea9011fb70b4cf78139664545c9293e2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05163-whttps://doaj.org/toc/2045-2322Abstract 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.Sang Jun LeeMadhupriya MahankaliAbdallah BitarHuafei ZouElizabeth ChaoHung NguyenJose GonzalezDawna CaballeroMitch HullDanling WangPeter G. SchultzWeijun ShenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017) |
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Medicine R Science Q 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 A Novel Role for RARα Agonists as Apolipoprotein CIII Inhibitors Identified from High Throughput Screening |
| description |
Abstract 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. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Sang Jun Lee |
| title |
A Novel Role for RARα Agonists as Apolipoprotein CIII Inhibitors Identified from High Throughput Screening |
| title_short |
A Novel Role for RARα Agonists as Apolipoprotein CIII Inhibitors Identified from High Throughput Screening |
| title_full |
A Novel Role for RARα Agonists as Apolipoprotein CIII Inhibitors Identified from High Throughput Screening |
| title_fullStr |
A Novel Role for RARα Agonists as Apolipoprotein CIII Inhibitors Identified from High Throughput Screening |
| title_full_unstemmed |
A Novel Role for RARα Agonists as Apolipoprotein CIII Inhibitors Identified from High Throughput Screening |
| title_sort |
novel role for rarα agonists as apolipoprotein ciii inhibitors identified from high throughput screening |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/3ea9011fb70b4cf78139664545c9293e |
| work_keys_str_mv |
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