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

Research Highlights Life Science

ApoC3 HTRF assay to identify regulator of TG levels

Expert opinion

A long-standing association exists between elevated triglyceride levels and cardiovascular diseases (CVD). However, the extent to which triglycerides promote CVD directly, or represent a biomarker of risk, has been debated for many decades. Liver triglycerides are packaged into lipoproteins called very low-density lipoproteins, or VLDLs, which are dispatched into your blood. VLDLs deliver triglycerides to your heart and muscles to supply energy, and to your fatty tissues for storage. VLDLs are assembled in the liver from triglycerides, cholesterol, and apolipoproteins.Apolipoprotein CIII (Apo-CIII) is a component of very low-density lipoprotein (VLDL). Recent studies in rodents and humans, as well as epidemiological studies on CVD risk management, highlighted the different roles of Apo-CIII in triglyceride homeostasis regulation. Novel therapeutic approaches to manage hypertriglyceridemia and reduce CVD damage are now possible by regulating this protein levels.Sang Jun Lee tested various hepatic cell lines to develop a cell-based assay to identify inhibitors. Using a 1536-well uHTS format, hits were identified, selected, and further characterized. Among the most potent ones, AM580, a highly specific RARα agonist, was identified.Discover how the action of AM580 was assessed, step-by-step, either in cell-based assays or in high-fat diet (HFD) mice. Learn about the pathway that links RXRa and Apo-CIII. The article presents a detailed investigation about the role of the retinoic acid (RA) function and its link with lipid metabolism. This also explain the impact of RA function loss that contributes to impaired hepatic lipid metabolism in NASH.This raises new hope for cardiovascular disease therapies. But for now, a healthy diet, weight control, and regular exercise are key to prevent CVD. Keep this in mind and do your best to control your lipid balance!

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.

Details

NATURE Scientific Reports, 2017 Jul 19;7(1):5824.

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