The novel selective PPARα modulator (SPPARMα) pemafibrate improves dyslipidemia, enhances reverse cholesterol transport and decreases inflammation and atherosclerosis.

Authors:
Nathalie Hennuyer
Nathalie Hennuyer
Ghent University
Belgium
Charlotte Paquet
Charlotte Paquet
Université Lille Nord de France
France
Jonathan Vanhoutte
Jonathan Vanhoutte
University Lille Nord de France
France
Eloise Woitrain
Eloise Woitrain
Institut Pasteur de Lille
Veronique Touche
Veronique Touche
Université Lille Nord de France
France
Sophie Colin
Sophie Colin
Université Lille 2
France
Emmanuelle Vallez
Emmanuelle Vallez
University Lille Nord de France
France

Atherosclerosis 2016 06 4;249:200-8. Epub 2016 Mar 4.

European Genomic Institute for Diabetes (EGID), FR 3508, F-59000 Lille, France; Univ. Lille, F-59000 Lille, France; INSERM UMR 1011, F-59000 Lille, France; Institut Pasteur de Lille, F-59000 Lille, France. Electronic address:

Background: Atherosclerosis is characterized by lipid accumulation and chronic inflammation in the arterial wall. Elevated levels of apolipoprotein (apo) B-containing lipoproteins are a risk factor for cardiovascular disease (CVD). By contrast, plasma levels of functional high-density lipoprotein (HDL) and apoA-I are protective against CVD by enhancing reverse cholesterol transport (RCT). Activation of peroxisome proliferator-activated receptor-α (PPARα), a ligand-activated transcription factor, controls lipid metabolism, cellular cholesterol trafficking in macrophages and influences inflammation.

Objective: To study whether pharmacological activation of PPARα with a novel highly potent and selective PPARα modulator, pemafibrate, improves lipid metabolism, macrophage cholesterol efflux, inflammation and consequently atherosclerosis development in vitro and in vivo using human apolipoprotein E2 Knock-In (apoE2KI) and human apoA-I transgenic (hapoA-I tg) mice.

Approach And Results: Pemafibrate treatment decreases apoB secretion in chylomicrons by polarized Caco-2/TC7 intestinal epithelium cells and reduces triglyceride levels in apoE2KI mice. Pemafibrate treatment of hapoA-I tg mice increases plasma HDL cholesterol, apoA-I and stimulates RCT to feces. In primary human macrophages, pemafibrate promotes macrophage cholesterol efflux to HDL and exerts anti-inflammatory activities. Pemafibrate also reduces markers of inflammation and macrophages in the aortic crosses as well as aortic atherosclerotic lesion burden in western diet-fed apoE2KI mice.

Conclusions: These results demonstrate that the novel selective PPARα modulator pemafibrate exerts beneficial effects on lipid metabolism, RCT and inflammation resulting in anti-atherogenic properties.

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http://dx.doi.org/10.1016/j.atherosclerosis.2016.03.003DOI Listing
June 2016
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