Pemafibrate, a selective peroxisome proliferator-activated receptor (PPAR) a modulator, is a new drug that specifically modulates PPAR alpha conformation and co-activator recruitment, thereby lowers plasma triglycerides with less off-target effects. Classical PPAR alpha 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 PPAR alpha ligands, potently suppressed NF-kappa B phosphorylation and cytokine expression in microglial cells. PPAR alpha knockdown significantly amplified LPSinduced cytokine expression. Pemafibrate-induced suppression of IL-6 expression was reversed by PPAR alpha knockdown. However, suppression by fenofibrate was not reversed by PPAR alpha knockdown but by Sirtuin 1 (SIRT1) knockdown. In conclusion, pemafibrate and fenofibrate similarly suppresses microglial activation but through distinct PPAR alpha and SIRT1-dependet pathways. (C) 2020 Elsevier Inc. All rights reserved.