Peroxisome proliferator‐activated receptor alpha accelerates neuronal differentiation and this might involve the mitogen‐activated protein kinase pathway

Abstract

Activation of peroxisome proliferator-activated receptor alpha (PPARα) has been reported to modulate cell proliferation, migration, and differentiation in astrocytes. In this study, we used a retinoic acid (RA)-induced differentiation model of NTERA-2/clone D1 (NT2) cells to explore the functional significance of PPARα in neuronal differentiation. We found that activating PPARα by Wy14643 accelerated neuronal differentiation via regulating the expression of neuronal markers. RT-PCR assays showed a significant increase in NeuroD expression and a decrease in nestin expression in cells treated concomitantly with RA and Wy14643 for 2 days compared to the levels in cells treated with RA alone. Expression of MAP2 protein, a mature neuronal marker, was markedly upregulated at day 10 of Wy14643 treatment, which was maintained after 21 days of neuronal formation. Corresponding to the changes in MAP2 expression, the expression of Cdk5 was upregulated with Wy14643 exposure from day 10 to day 21. Moreover, cells treated with Wy14643 displayed higher expression levels of phospho-ERK and phospho-p38 in the differentiation process than cell treated with RA alone. These results indicated that activation of PPARα accelerated neuronal differentiation through upregulating the expression of NeuroD, MAP2, and Cdk5 and downregulating the expression of nestin. MAPK signals, ERK and p38, might contribute to the accelerated differentiation process. These findings suggest that PPARα plays a role in regulating neuronal differentiation and may be beneficial for functional recovery from neurological disorders.

Peroxisome proliferator-activated receptor-α activation by aspirin facilitates contextual fear extinction and modulates intrinsic excitability of dentate gyrus neurons

“…Optogenetic inhibition of DG activity or silencing the extinction-recruited DG granule neuron ensembles signi cantly impairs contextual fear extinction, while enhancement of DG activity promotes contextual fear extinction, revealing the bidirectional control of contextual fear extinction by the DG 14,18 . Furthermore, several lines of evidence also showed that modulating DG activity through genetic manipulation of proteins related to PPARα, such as adiponectin receptor 2 46 , CKD5 47 greatly affects extinction of contextual fear 35,48 , emphasizing the requirement of ne regulation of DG activity at the molecular level for normal fear extinction learning. Interestingly, we also found that PPARα de cient mice exhibited higher freezing responses when tested for contextual fear retrieval, while mice with DG deletion of PPARα showed no difference comparing with the control group, indicating the enhanced fear retrieval with PPARα de ciency.…”

Fenofibrate inhibits hypoxia‐inducible factor‐1 alpha and carbonic anhydrase expression through activation of AMP‐activated protein kinase/HO‐1/Sirt1 pathway in glioblastoma cells

“…35 We have previously reported that PPARα activation is beneficial for functional recovery from neurological disorders through acceleration of neuronal differentiation. 36 PPAR agonists physiologically modulate the activity of AMPactivated protein kinase (AMPK), an important cellular energy sensor. 37,38 Furthermore, a previous study showed that fenofibrate inhibited the invasion and migration of oral cancer cells through AMPK signaling.…”

“…Importantly, PPARα‐specific agonists exert anti‐tumor growth effects in a large number of human cancer types 35 . We have previously reported that PPARα activation is beneficial for functional recovery from neurological disorders through acceleration of neuronal differentiation 36 …”