Vidéo JAV Doriane Henry.mov

Sept. 29, 2022
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Topic: Cardiovascular and Metabolic Diseases

 

The transrepressive activity of PPARα induced by pemafibrate in the liver is sufficient to reduce atherosclerosis development in LDLr deficient mice

Doriane Henry1, Eric Baugé1, Nathalie Hennuyer1, Bruno Derudas1, Emmanuelle Vallez1, Audrey Deprince1, Joel T Haas1, Philippe Lefebvre1, Bart Staels1, Fanny Lalloyer1

 

1Univ. Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000, Lille, France

 

Background: Atherosclerotic cardiovascular disease (ASCVD) is currently the leading cause of death in the world. Beyond lifestyle intervention and statin treatment, residual ASCVD risk persists in many patients, and hypertriglyceridemia has emerged as a contributing factor in this residual risk. Therefore, agents that target the nuclear receptor peroxisome proliferator-activated receptor α (PPARα), such as fibrates, represent interesting therapeutic candidates, given their beneficial effects on lipoprotein and lipid metabolism, inflammation and metabolic homeostasis. Insights from preclinical studies have suggested that pemafibrate, a novel highly potent and selective PPARα agonist, has potential in managing cardiovascular risk, but the mechanisms of its atheroprotective effects are not well understood.

Objectives: The aim of the study was 1) to evaluate the impact of pemafibrate on atherogenic dyslipidemia and atherosclerosis development in the well-known LDLr-deficient mouse model of hyperlipidemia and atherosclerosis, and 2) to determine the importance of liver PPARα in its effects.

Methods: LDLr-/- mice, deficient (LDLr-/- PPARα-/-) or not (LDLr-/- PPARα+/+) for PPARα, were submitted to a western diet supplemented or not with pemafibrate during 8 weeks. To dissect the contribution of hepatic PPARα, we used only LDLr-/- PPARα-/- mice injected with AAV8-TBG-PPARαWT (to restore, selectively in the hepatocytes, both the transactivative and transrepressive activities of PPARα), with AAV8-TBG-PPARαDISS (mutant of PPARα only owning the hepatic transrepressive activity of PPARα linked to its anti-inflammatory properties), or with AAV8-TBG-GFP (control). Mice were submitted to the same diets as previously.

Results: Histological analysis showed a strong reduction of atherosclerotic plaque surface by pemafibrate (-50%) in LDLr-/- PPARα+/+, but not in LDLr-/- PPARα-/- mice. This pemafibrate-induced atheroprotection was associated with improved atherogenic dyslipidemia. In LDLr-/- PPARα-/- mice injected with AAV8-TBG-PPARαWT, pemafibrate modulated the expression of both lipid- and inflammation-related genes in the liver, confirming hepatic activation of respectively the transactivative and transrepressive activities of PPARα. Interestingly, these mice exhibited a robust improvement of atherogenic dyslipidemia and a strong reduction of atherosclerosis development (-42%), suggesting a major role of liver PPARα on pemafibrate-induced modulation of dyslipidemia and atherogenesis. Finally, as expected, in LDLr-/- PPARα-/- mice injected with AAV8-TBG-PPARαDISS, pemafibrate was only associated with reduced hepatic expression of inflammatory genes, linked to hepatic PPARα transrepressive activity, without any effects on hepatic lipid metabolism genes. No effect on atherogenic dyslipidemia was observed, but, surprisingly, pemafibrate was still able to induce a strong reduction of atherosclerosis lesion surface (-42%). This result indicates that modulation of hepatic inflammation by pemafibrate, through liver PPARα, is sufficient to reduce atherosclerosis development in LDLr-/- mice.

Conclusion: These data demonstrate that liver PPARα is the key driver of the atheroprotective effects of pemafibrate in the LDLr-deficient mouse model, and that the hepatic PPARα transrepressive activity, associated to hepatic anti-inflammatory effects of PPARα, is sufficient to mediate fibrate-induced atheroprotection.

Key words: Atherosclerosis, PPARα, pemafibrate, liver, inflammation

 

 

Tags: atherosclerosis inflammation liver pemafibrate pparα

 Infos

  • Added by: Doriane Henry (doriane.henry.etu)
  • Speaker(s):
  • Updated on: Sept. 29, 2022, 5:37 p.m.
  • Type: Seminar
  • Main language: English
  • Audience: Doctorate

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