Pemafibrate, a selective PPARα modulator, and fenofibrate suppress microglial activation through distinct PPARα and SIRT1-dependent pathways

概要

Pemafibrate, a selective peroxisome proliferator-activated receptor (PPAR) α modulator, is a new drug that specifically modulates PPARα conformation and co-activator recruitment, thereby lowers plasma triglycerides with less off-target effects. Classical PPARα ligands such as fenofibrate suppress inflammatory cells including microglia. However, effects of pemafibrate on microglia have never been addressed. Here we show that pemafibrate, like other PPARα ligands including fenofibrate, potently suppressed NF-κB phosphorylation and reduced LPS-induced mRNA expression of IL-6, IL-1β and TNF-α in microglial cells. PPARα knockdown itself significantly amplified LPS-induced cytokine expression. Moreover, pemafibrate-induced suppression of IL-6 expression was reversed by PPARα knockdown. These data suggest that PPARα is tonically suppressing microglial activation and that anti-inflammatory effect of pemafibrate is mediated through PPARα. However, suppression by fenofibrate was not reversed by PPARα knockdown. The effect of fenofibrate, on the other hand, is attenuated by Sirtuin 1 (SIRT1) knockdown. In conclusion, pemafibrate and fenofibrate similarly suppresses microglial activation but through distinct PPARα and SIRT1-dependet pathways.