☆ 4.6 Article

Statin therapy reduces plasma angiopoietin-like 3 (ANGPTL3) concentrations in hypercholesterolemic patients via reduced liver X receptor (LXR) activation

ATHEROSCLEROSIS (2020)

Journal

ATHEROSCLEROSIS

Volume 315, Issue -, Pages 68-75

Publisher

ELSEVIER IRELAND LTD

DOI: 10.1016/j.atherosclerosis.2020.11.013

Keywords

Angiopoietin-like 3 (ANGPTL3); Liver X receptor (LXR); Statin therapy; LDL; Oxysterols; Hypercholersterolemia

Funding

Netherlands Organisation for Scientific Research [016.156.445]

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Abstract

Background and aims: Statins suppress hepatic mRNA expression of ANGPTL3 encoding angiopoietin-like 3 in healthy subjects, but it is unknown if plasma ANGPTL3 concentrations are affected by statins prescribed to hypercholesterolemic patients in clinical practice. We therefore investigated the effect of statin treatment on plasma ANGPTL3 concentrations in hypercholesterolemic patients. In addition, we explored the underlying mechanism by which statins regulate ANGPTL3 in vitro. Methods: Plasma ANGPTL3 concentrations were measured in 93 genetically confirmed familial hypercholesterolemia (FH) patients who were using statin therapy and 61 statin naive FH patients. Moreover, concentrations were measured in 14 hypercholesterolemic patients who discontinued their statin treatment for 4 weeks. In vitro studies were performed with Huh7 human hepatoma cells. Results: Plasma ANGPTL3 concentrations were 15% lower in statin treated FH patients compared to statin naive FH patients (145 (120-193) vs. 167 (135-220) ng/ml, p = 0.012). Statin discontinuation resulted in a 21% (p<0.001) increase of plasma ANGPTL3 concentrations. Simvastatin reduced ANGPTL3 mRNA expression and ANGPTL3 secretion of Huh7 cells. Liver X receptor (LXR) activation with T0901317 increased ANGPTL3 mRNA expression and ANGPTL3 secretion by 6- and 3-fold, respectively. Adding simvastatin did not mitigate this effect but adding the LXR antagonist GSK2230 to simvastatin-incubated Huh7 cells diminished simvastatin-induced reductions in ANGPTL3 mRNA expression and ANGPTL3 secretion. Simvastatin reduced intracellular oxysterol concentrations. Oxysterols are endogenous LXR ligands, implying that simvastatin suppresses ANGPTL3 secretion via reduced oxysterol-mediated LXR activation. Conclusions: Statins lower plasma ANGPTL3 concentrations in hypercholesterolemic patients, likely due to decreased oxysterol-mediated LXR activation.

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The Citrus Flavonoid Nobiletin Downregulates Angiopoietin-like Protein 3 (ANGPTL3) Expression and Exhibits Lipid-Modulating Effects in Hepatic Cells and Adult Zebrafish Models

Ching-Yen Lin, Pei-Yi Chen, Hao-Jen Hsu, Wan-Yun Gao, Ming-Jiuan Wu, Jui-Hung Yen

Summary: This study investigated the lipid-lowering effects of nobiletin and its underlying molecular mechanisms. The results showed that nobiletin can regulate lipid metabolism by targeting the LXR alpha-ANGPTL3-LPL axis. Animal studies also showed that nobiletin can reduce plasma triglycerides and cholesterol levels. These findings suggest that nobiletin may be a potential inhibitor for dyslipidemia and atherosclerotic cardiovascular diseases.

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