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A Novel Role for RARα Agonists as Apolipoprotein CIII Inhibitors Identified from High Throughput Screening
Sang Jun Lee1, Madhupriya Mahankali1, Abdallah Bitar2,3
1California Institute for Biomedical Research (Calibr), 11119 North Torrey Pines Rd, Suite 100, La Jolla, CA, 92307, USA.
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.
Insights
Novel retinoic acid receptor agonists, like AM580, significantly lower triglyceride levels by reducing Apolipoprotein CIII. This offers a potential new strategy for managing cardiovascular disease risk.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiovascular Research
Background:
- Elevated triglyceride (TG) levels are a significant risk factor for cardiovascular disease (CVD).
- Apolipoprotein CIII (ApoC-III) plays a crucial role in regulating plasma TG levels by influencing lipolysis and lipid synthesis.
- Identifying novel therapeutic targets for TG regulation is essential for CVD risk reduction.
Purpose of the Study:
- To discover novel regulators of TG levels through a high-throughput screen (HTS).
- To investigate the potential of retinoic acid receptor (RAR) agonists in modulating ApoC-III levels and lipid profiles.
- To elucidate the mechanism by which RAR agonists affect ApoC-III synthesis and lipid metabolism.
Main Methods:
- A high-throughput screen (HTS) using an ApoC-III homogenous time-resolved fluorescence (HTRF) assay was employed.
- In vitro studies utilized human hepatic cell lines to assess the impact of identified compounds on ApoC-III secretion.
- In vivo studies involved high-fat diet induced fatty-liver mouse models to evaluate the efficacy of AM580 on lipid parameters and ApoC-III levels.
Main Results:
- Several RAR agonists were identified that effectively reduced secreted ApoC-III levels in human hepatic cell lines.
- The RARα specific agonist AM580 demonstrated potent inhibition of ApoC-III secretion (>80%) with a low EC50 (~2.9 nM) in Hep3B cells.
- In vivo, AM580 significantly reduced ApoC-III levels in both liver and plasma (~60%), decreased body weight, and lowered hepatic and plasma TG and total cholesterol (TC) levels.
- Mechanistically, AM580 was found to suppress ApoC-III synthesis via downregulation of HNF4α and upregulation of SHP1 expression.
Conclusions:
- Retinoic acid receptor alpha (RARα) specific agonists, exemplified by AM580, represent a promising therapeutic strategy for lipid-lowering.
- Targeting ApoC-III reduction through RARα agonists may offer a novel approach to mitigate cardiovascular disease risk.
- The findings provide a foundation for developing new pharmacological interventions for dyslipidemia and associated cardiovascular complications.
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