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



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.



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.



These results demonstrate that the novel selective PPARα modulator pemafibrate exerts beneficial effects on lipid metabolism, RCT and inflammation resulting in anti-atherogenic properties.
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.
Nathalie
N
Hennuyer
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.
Isabelle
I
Duplan
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.
Charlotte
C
Paquet
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.
Jonathan
J
Vanhoutte
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.
Eloise
E
Woitrain
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.
Véronique
V
Touche
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.
Sophie
S
Colin
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.
Emmanuelle
E
Vallez
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.
Sophie
S
Lestavel
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.
Philippe
P
Lefebvre
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: bart.staels@pasteur-lille.fr.
Bart
B
Staels
D000818:Animals; D016632:Apolipoprotein A-I / Q000737:chemistry; D050197:Atherosclerosis / Q000188:drug therapy*; D001583:Benzoxazoles / Q000494:pharmacology*; D001692:Biological Transport; D002087:Butyrates / Q000494:pharmacology*; D018938:Caco-2 Cells; D002318:Cardiovascular Diseases / Q000097:blood; D002784:Cholesterol / Q000378:metabolism*; D050171:Dyslipidemias / Q000188:drug therapy*; D004848:Epithelium / Q000378:metabolism; D005260:Female; D006720:Homozygote; D006801:Humans; D007249:Inflammation / Q000188:drug therapy*; D007413:Intestinal Mucosa / Q000378:metabolism; D008024:Ligands; D050356:Lipid Metabolism; D008075:Lipoproteins, HDL / Q000097:blood / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D047493:PPAR alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012307:Risk Factors
C540740:(R)-2-(3-((benzoxazol-2-yl-d4 (3-(4-methoxyphenoxy-d7)propyl)amino)methyl)phenoxy) butanoic acid; D016632:Apolipoprotein A-I; D001583:Benzoxazoles; D002087:Butyrates; D008024:Ligands; D008075:Lipoproteins, HDL; D047493:PPAR alpha; D002784:Cholesterol
Atherosclerosis; Inflammation; Lipids; Pemafibrate; Reverse cholesterol transport; SPPARMα