title: Gemfibrozil and fenofibrate, Food and Drug Administration-approved lipid-lowering drugs, up-regulate tripeptidyl-peptidase 1 in brain cells via peroxisome proliferator-activated receptor α: implications for late infantile Batten disease therapy.
abstract: The classical late infantile neuronal ceroid lipofuscinosis (LINCLs) is an autosomal recessive disease, where the defective gene is Cln2, encoding tripeptidyl-peptidase I (TPP1). At the molecular level, LINCL is caused by accumulation of autofluorescent storage materials in neurons and other cell types. Currently, there is no established treatment for this fatal disease. This study reveals a novel use of gemfibrozil and fenofibrate, Food and Drug Administration-approved lipid-lowering drugs, in up-regulating TPP1 in brain cells. Both gemfibrozil and fenofibrate up-regulated mRNA, protein, and enzymatic activity of TPP1 in primary mouse neurons and astrocytes as well as human astrocytes and neuronal cells. Because gemfibrozil and fenofibrate are known to activate peroxisome proliferator-activated receptor-α (PPARα), the role of PPARα in gemfibrozil- and fenofibrate-mediated up-regulation of TPP1 was investigated revealing that both drugs up-regulated TPP1 mRNA, protein, and enzymatic activity both in vitro and in vivo in wild type (WT) and PPARβ(-/-), but not PPARα(-/-), mice. In an attempt to delineate the mechanism of TPP1 up-regulation, it was found that the effects of the fibrate drugs were abrogated in the absence of retinoid X receptor-α (RXRα), a molecule known to form a heterodimer with PPARα. Accordingly, all-trans-retinoic acid, alone or together with gemfibrozil, up-regulated TPP1. Co-immunoprecipitation and ChIP studies revealed the formation of a PPARα/RXRα heterodimer and binding of the heterodimer to an RXR-binding site on the Cln2 promoter. Together, this study demonstrates a unique mechanism for the up-regulation of TPP1 by fibrate drugs via PPARα/RXRα pathway.
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, USA.
authors.forename: Arunava
authors.initials: A
authors.lastname: Ghosh
authors.forename: Grant T
authors.initials: GT
authors.lastname: Corbett
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Kalipada
authors.initials: K
authors.lastname: Pahan
mesh_terms: D000626:Aminopeptidases / Q000096:biosynthesis*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000096:biosynthesis*; D011345:Fenofibrate / Q000494:pharmacology*; D015248:Gemfibrozil / Q000494:pharmacology*; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D009472:Neuronal Ceroid-Lipofuscinoses / Q000188:drug therapy* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism*; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D057057:Serine Proteases / Q000096:biosynthesis*; D000091346:Tripeptidyl-Peptidase 1; D015854:Up-Regulation
chemical_list: D000960:Hypolipidemic Agents; D047493:PPAR alpha; D047490:Retinoid X Receptor alpha; C000717268:Tpp1 protein, mouse; D000091346:Tripeptidyl-Peptidase 1; D057057:Serine Proteases; D000626:Aminopeptidases; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C000717267:TPP1 protein, human; D015248:Gemfibrozil; D011345:Fenofibrate