Lysosomes are ubiquitous membrane-enclosed organelles filled with an acidic 
interior and are central to the autophagic, endocytic, or phagocytic pathway. In 
contrast to its classical function as the waste management machinery, lysosomes 
are now considered to be an integral part of various cellular signaling 
processes. The diverse functionality of this single organelle requires a very 
complex and coordinated regulation of its activity with transcription factor EB 
(TFEB), a master regulator of lysosomal biogenesis, at its core. However, 
mechanisms by which TFEB is regulated are poorly understood. This study 
demonstrates that gemfibrozil, an agonist of peroxisome proliferator-activated 
receptor (PPAR) α, alone and in conjunction with all-trans-retinoic acid is 
capable of enhancing TFEB in brain cells. We also observed that PPARα, but not 
PPARβ and PPARγ, is involved in gemfibrozil-mediated up-regulation of TFEB. 
Reporter assay and chromatin immunoprecipitation studies confirmed the 
recruitment of retinoid X receptor α, PPARα, and PGC1α on the PPAR-binding site 
on the Tfeb promoter as well. Subsequently, the drug-mediated induction of TFEB 
caused an increase in lysosomal protein and the lysosomal abundance in cell. 
Collectively, this study reinforces the link between lysosomal biogenesis and 
lipid metabolism with TFEB at the crossroads. Furthermore, gemfibrozil may be of 
therapeutic value in the treatment of lysosomal storage disorders in which 
autophagy-lysosome pathway plays an important role.