A Novel Role for RAR? 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 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 RAR? 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 HNF4? and upregulation of SHP1 expression. Collectively, these studies suggest that an RAR? specific agonist may afford a new strategy for lipid-lowering and CVD risk reduction.

SUBMITTER: Lee SJ 

PROVIDER: S-EPMC5517646 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature