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.
Highlights
Epidemiological and population-based research has suggested another potential role for ApoC-III in cardiovascular disease (CVD) risk management[18]
We carried out a high throughput screen (HTS) of a library of more than 950,000 small molecules to identify small molecule ApoC-III inhibitors
Among all the hits from the screen, we found that all trans-retinoic acid potently blocked ApoC-III secretion up to 55% in culture media (EC50 = 402 nM) (Fig. 1d), and chose to characterize this molecule further
Summary
Epidemiological and population-based research has suggested another potential role for ApoC-III in CVD risk management[18]. This is further substantiated by the American Heart Association (AHA) scientific statement wherein they stated that TGs alone are not pro-atherogenic unless they are associated with ApoC-III19 Taken together, these studies suggest that a novel therapeutic approach to managing hypertriglyceridemia and CVD risk is the regulation of ApoC-III levels. Large-scale screening of small molecule libraries directly targeting ApoC-III production, processing and secretion could potentially provide a novel therapeutic option to be added to the armamentarium of lipid-lowering agents for CVD risk-reduction. To this end, we have developed a novel cell-based homogenous time resolved fluorescence (HTRF) assay for secreted ApoC-III, conducted a high throughput screen of a library of a million small molecules, and identified several novel molecules and known drugs that affect ApoC-III levels. Oral dosing of AM580 in diet-induced fatty liver mice reduced liver and plasma ApoC-III levels, as well as body weight, total cholesterol (TC) and TG levels through inhibition of HNF4α and subsequent up-regulation of SHP1
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