Pemafibrate, a selective PPARα modulator, and fenofibrate suppress microglial activation through distinct PPARα and SIRT1-dependent pathways
Pemafibrate, a selective PPARα modulator, and fenofibrate suppress microglial activation through distinct PPARα and SIRT1-dependent pathways
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DOI：
10.1016/j.bbrc.2020.01.118
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发表时间：
2020-04-02
影响因子：
3.1
通讯作者：
Tanaka, Tomohiro
中科院分区：
文献类型：
--
作者：
Ogawa, Kento;Yagi, Takashi;Tanaka, Tomohiro
Pemafibrate是一种选择性过氧化物酶体增殖体激活受体（PPAR）调节剂，是一种特异性调节PPAR α构象和共激活剂募集的新药，从而降低血浆甘油三酯，减少脱靶效应。经典的PPAR α配体如非诺贝特抑制炎症细胞，包括小胶质细胞。然而，哌马哌特对小胶质细胞的影响尚未得到解决。本研究表明，与其他PPAR α配体一样，pemafibate能有效抑制小胶质细胞中nf - κ B磷酸化和细胞因子的表达。PPAR α敲低可显著扩增lps诱导的细胞因子表达。帕马替特诱导的IL-6表达抑制被PPAR α敲除逆转。然而，非诺贝特的抑制作用不会被PPAR α敲低逆转，而是被Sirtuin 1 （SIRT1）敲低逆转。综上所述，培马菲特和非诺贝特类似地抑制小胶质细胞的激活，但通过不同的PPAR α和sirt1依赖途径。(C) 2020爱思唯尔公司版权所有。
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.