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

Atherosclerosis. 2016 Jun;249:200-8. doi: 10.1016/j.atherosclerosis.2016.03.003. Epub 2016 Mar 4.

Abstract

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.

Keywords: Atherosclerosis; Inflammation; Lipids; Pemafibrate; Reverse cholesterol transport; SPPARMα.

MeSH terms

  • Animals
  • Apolipoprotein A-I / chemistry
  • Atherosclerosis / drug therapy*
  • Benzoxazoles / pharmacology*
  • Biological Transport
  • Butyrates / pharmacology*
  • Caco-2 Cells
  • Cardiovascular Diseases / blood
  • Cholesterol / metabolism*
  • Dyslipidemias / drug therapy*
  • Epithelium / metabolism
  • Female
  • Homozygote
  • Humans
  • Inflammation / drug therapy*
  • Intestinal Mucosa / metabolism
  • Ligands
  • Lipid Metabolism
  • Lipoproteins, HDL / blood
  • Lipoproteins, HDL / metabolism
  • Macrophages / metabolism
  • Mice
  • PPAR alpha / antagonists & inhibitors*
  • PPAR alpha / metabolism
  • Risk Factors

Substances

  • (R)-2-(3-((benzoxazol-2-yl-d4 (3-(4-methoxyphenoxy-d7)propyl)amino)methyl)phenoxy) butanoic acid
  • Apolipoprotein A-I
  • Benzoxazoles
  • Butyrates
  • Ligands
  • Lipoproteins, HDL
  • PPAR alpha
  • Cholesterol