Activation of peroxisome proliferator-activated receptor α induces lysosomal biogenesis in brain cells: implications for lysosomal storage disorders.
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.
From the Departments of Neurological Sciences and.
Arunava
A
Ghosh
From the Departments of Neurological Sciences and.
Malabendu
M
Jana
From the Departments of Neurological Sciences and.
Khushbu
K
Modi
the Laboratory of Metabolism, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892.
Frank J
FJ
Gonzalez
the Department of Neurology, Harvard Medical School, Boston, Massachusetts 02114, and.
Katherine B
KB
Sims
Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, Chicago, Illinois 60612.
Elizabeth
E
Berry-Kravis
From the Departments of Neurological Sciences and the Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612 Kalipada_Pahan@rush.edu.
Kalipada
K
Pahan
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D001343:Autophagy / Q000187:drug effects; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015248:Gemfibrozil / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D048068:PPAR-beta / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D047490:Retinoid X Receptor alpha / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D047493:PPAR alpha; D047495:PPAR gamma; D048068:PPAR-beta; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D047490:Retinoid X Receptor alpha; C484068:Tcfeb protein, mouse; D014157:Transcription Factors; D014212:Tretinoin; D015248:Gemfibrozil
Astrocyte; Lysosomal Storage Disease; Neurodegeneration; Peroxisome proliferator-activated Receptor (PPAR); Retinoic Acid