期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 290, 期 16, 页码 10309-10324出版社
ELSEVIER
DOI: 10.1074/jbc.M114.610659
关键词
Astrocyte; Lysosomal Storage Disease; Neurodegeneration; Peroxisome proliferator-activated Receptor (PPAR); Retinoic Acid
资金
- National Institutes of Health [AT6681, NS083054]
- Veteran Affairs [I01BX003033-01]
- Noah's Hope, Hope for Bridgett, Cures Within Reach, and Two Hearts Rock
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) , alone and in conjunction with all-trans-retinoic acid is capable of enhancing TFEB in brain cells. We also observed that PPAR, but not PPAR and PPAR, is involved in gemfibrozil-mediated up-regulation of TFEB. Reporter assay and chromatin immunoprecipitation studies confirmed the recruitment of retinoid X receptor , PPAR, and PGC1 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.
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