Regulation of Cyclic AMP Response Element Binding and Hippocampal Plasticity-Related Genes by Peroxisome Proliferator-Activated Receptor α

Roy, Avik; Jana, Malabendu; Corbett, Grant T.; Ramaswamy, Shilpa; Kordower, Jeffrey H.; Gonzalez, Frank J.; Pahan, Kalipada

doi:10.1016/j.celrep.2013.07.028

Cited by 145 publications

(188 citation statements)

References 44 publications

(35 reference statements)

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“…Recently, more and more of WY14643-induced effects on the central nervous system are being reported, such as protective effects against cerebral ischemia/reperfusion (Collino et al 2006), protective effects against oxidative stress-induced cell apoptosis (Collino et al 2006), and inducing neuronal differentiation (Bento-Abreu et al 2007). Roy A et al also found that WY14643 induces the activation of CREB promoter-driven luciferase activity (Roy et al 2013). Here, we supposed that WY14643 may have anti-depressant-like effects.…”

Section: Introductionmentioning

confidence: 81%

WY14643 produces anti-depressant-like effects in mice via the BDNF signaling pathway

et al. 2014

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Section: Introductionmentioning

confidence: 81%

WY14643 produces anti-depressant-like effects in mice via the BDNF signaling pathway

et al. 2014

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“…Although the hippocampus does not metabolize fat, recently we have demonstrated that PPARα is constitutively expressed in the hippocampus and hippocampal neurons (11). Here, we describe that activation of PPARα induces the expression of ADAM10 and subsequent α-secretase proteolysis of APP.…”

mentioning

confidence: 82%

Activation of peroxisome proliferator-activated receptor α stimulates ADAM10-mediated proteolysis of APP

Corbett

Gonzalez

Pahan

2015

Proc. Natl. Acad. Sci. U.S.A.

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120

119

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Amyloid precursor protein (APP) derivative β-amyloid (Aβ) plays an important role in the pathogenesis of Alzheimer's disease (AD). Sequential proteolysis of APP by β-secretase and γ-secretase generates Aβ. Conversely, the α-secretase "a disintegrin and metalloproteinase" 10 (ADAM10) cleaves APP within the eventual Aβ sequence and precludes Aβ generation. Therefore, up-regulation of ADAM10 represents a plausible therapeutic strategy to combat overproduction of neurotoxic Aβ. Peroxisome proliferator-activated receptor α (PPARα) is a transcription factor that regulates genes involved in fatty acid metabolism. Here, we determined that the Adam10 promoter harbors PPAR response elements; that knockdown of PPARα, but not PPARβ or PPARγ, decreases the expression of Adam10; and that lentiviral overexpression of PPARα restored ADAM10 expression in Ppara −/− neurons. Gemfibrozil, an agonist of PPARα, induced the recruitment of PPARα:retinoid x receptor α, but not PPARγ coactivator 1α (PGC1α), to the Adam10 promoter in wild-type mouse hippocampal neurons and shifted APP processing toward the α-secretase, as determined by augmented soluble APPα and decreased Aβ production. Accordingly, Ppara −/− mice displayed elevated SDS-stable, endogenous Aβ and Aβ 1-42 relative to wild-type littermates, whereas 5XFAD mice null for PPARα (5X/α −/− ) exhibited greater cerebral Aβ load relative to 5XFAD littermates. These results identify PPARα as an important factor regulating neuronal ADAM10 expression and, thus, α-secretase proteolysis of APP.is the most prevalent neurodegenerative disease. Although the precise physiologic changes that trigger development of AD remain unknown, abnormal metabolism of the type 1 transmembrane amyloid precursor protein (APP) into amyloid-β (Aβ) plays a causative role in AD (1). Sequential proteolytic processing of APP by the aspartic proteases β-secretase 1 (BACE1) and γ-secretase (reviewed in ref.2) at ectodomain and intramembrane sites, respectively, generates pathogenic Aβ fragments between residues 36 and 43. Conversely, juxtamembrane cleavage of APP between K16/L17 residues by α-secretase precludes Aβ generation and results in clearance of APP (3).Several proteases have been suggested as AD-relevant α-secretases, many of which belong to the "a disintegrin and metalloproteinase" (ADAM) Zn 2+ sheddase family (reviewed in ref. 4) and include ADAM9, ADAM10, and ADAM17. However, ADAM10 has emerged as the constitutive and inducible APP α-secretase in neurons (5). Of note, ADAM9 and ADAM17 do not recover α-secretase proteolysis of APP in the absence of ADAM10 (5), neuron-specific overexpression of ADAM10 decreases Aβ load in a mouse model of AD (6), and impaired ADAM10 trafficking to the synapse generates a model of sporadic AD (7). Similarly, human studies have observed deficits in ADAM10 expression (8), trafficking (9), and activity (10) in AD. Therefore, dysregulation of ADAM10 may play a significant role in the establishment of Aβ pathology. However, little is known about the genetic regulation of ADAM10....

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“…The consensus sequence of the PPRE is AGGTCAAAGGTCA, which consists of a direct repeat of AGGTCA half-sites with one base-pair spacing (DR1) (Kliewer et al, 1992;Wahli and Michalik, 2012). However, imperfect half-sites of the canonical DR1 have been identified in PPARaregulated genes, such as CYP4A1 (AGGGTAAAGTTCA), very low density lipoprotein receptor (AGGTCAGATGGCA), cyclic AMP response element binding (AGGTCAAAGGACA), the mouse hypoxia-inducible lipid droplet associated (AGGG GAAAGGTCA), and the rat ACOX (AGGACAAAGGTCA) (Juge-Aubry et al, 1997;Roy et al, 2013;Gao et al, 2014;Mattijssen et al, 2014). It is widely accepted that the sequence of the 59-flanking region (6-or 7-bp segment) in addition to the consensus DR1 sequence is important for binding of PPAR to various PPREs (Palmer et al, 1995;Juge-Aubry et al, 1997;Chandra et al, 2013).…”

Section: Cyp2c8 Is a Novel Target Of Ppara In Human Livermentioning

confidence: 99%

CYP2C8 Is a Novel Target of Peroxisome Proliferator-Activated Receptor α in Human Liver

Makia

Goldstein

2015

Mol Pharmacol

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Human cytochrome P450 (CYP) 2C enzymes metabolize ∼30% of clinically prescribed drugs and various environmental chemicals. CYP2C8, an important member of this subfamily, metabolizes the anticancer drug paclitaxel, certain antidiabetic drugs, and endogenous substrates, including arachidonic acid, to physiologically active epoxyeicosatrienoic acids. Previous studies from our laboratory showed that microRNA 107 (miR107) and microRNA 103 downregulate CYP2C8 post-transcriptionally. miR107 is located in intron 5 of the pantothenate kinase 1 (PANK1) gene. p53 has been reported to coregulate the induction of PANK1 and miR107. Here, we examine the possible downregulation of CYP2C8 by drugs capable of inducing miR107. Hypolipidemic drugs, such as bezafibrate, known activators of the peroxisome proliferator-activated receptor a (PPARa), induce both the PANK1 gene and miR107 (∼2.5-fold) in primary human hepatocytes. Surprisingly, CYP2C8 mRNA and protein levels were induced by bezafibrate. CYP2C8 promoter activity was increased by ectopic expression of PPARa in HepG2 cells, with a further increase after bezafibrate (∼18-fold), 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid (∼10-fold) treatment, or the antidiabetic drug rosiglitazone, all known PPAR activators. Promoter sequence analyses, deletion studies, mutagenesis studies, and electrophoretic mobility shift assays identified a PPARa response element located at position 22109 base pair relative to the translation start site of CYP2C8. Chromatin immunopreciptation assay analysis confirmed recruitment of PPARa to this PPARa response element after bezafibrate treatment of human hepatocytes. Thus, we show for the first time that CYP2C8 is transcriptionally regulated by PPARa, suggesting the potential for drug-drug interactions due to upregulation of CYP2C8 by PPAR activators.

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Regulation of Cyclic AMP Response Element Binding and Hippocampal Plasticity-Related Genes by Peroxisome Proliferator-Activated Receptor α

Cited by 145 publications

References 44 publications

WY14643 produces anti-depressant-like effects in mice via the BDNF signaling pathway

WY14643 produces anti-depressant-like effects in mice via the BDNF signaling pathway

Activation of peroxisome proliferator-activated receptor α stimulates ADAM10-mediated proteolysis of APP

CYP2C8 Is a Novel Target of Peroxisome Proliferator-Activated Receptor α in Human Liver

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