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.