PPARα in lysosomal biogenesis: A perspective

Abstract

Lysosomes are membrane-bound vesicles containing hydrolytic enzymes, ubiquitously present in all eukaryotic cells. Classically considered to be central to the cellular waste management machinery, recent studies revealed the role of lysosomes in a wide array of cellular processes like, degradation, cellular development, programmed cell death, secretion, plasma membrane repair, nutritional responses, and lipid metabolism. We recently studied the regulation of TFEB, considered to be the master regulator of lysosomal biogenesis, by activation of peroxisomal proliferator activated receptor α (PPARα), one of the key regulators of lipid metabolism. In this article, we discuss how the recent finding could be put in to perspective with the previous findings that relate lysosomal biogenesis to lipid metabolism, and comment on the possibility of a bi-directional interplay between these two distinct cellular processes upon activation of PPARα.

The Association between the Usage of Non-Steroidal Anti-Inflammatory Drugs and Cognitive Status: Analysis of Longitudinal and Cross-Sectional Studies from the Global Alzheimer’s Association Interactive Network and Transcriptomic Data

“…Stimulation of cytosolic PPARα by aspirin binding results in the dimerization of PPARα and retinoid X receptor gamma (RXRγ) and subsequent translocation to the nucleus [ 27 , 28 ]. Once in the nucleus, the dimer associates with PPARG coactivator 1 alpha (PGC1α) and binds to the promoter region of the transcription factor EB (TFEB) gene [ 28 , 29 ]. Production of unphosphorylated TFEB, a master regulator of lysosomal biogenesis, promotes both a positive feedback loop that leads to production of more TFEB as well as promotes the expression of essential lysosomal components [ 28 , 29 , 30 ].…”

“…Once in the nucleus, the dimer associates with PPARG coactivator 1 alpha (PGC1α) and binds to the promoter region of the transcription factor EB (TFEB) gene [ 28 , 29 ]. Production of unphosphorylated TFEB, a master regulator of lysosomal biogenesis, promotes both a positive feedback loop that leads to production of more TFEB as well as promotes the expression of essential lysosomal components [ 28 , 29 , 30 ]. The increase in lysosome production and activity may increase the clearing of accumulated Tau proteins and decrease the entanglement of neurofibrillary fibers, a hallmark of AD, through the autophagy-lysosome pathway (ALP) [ 29 , 30 ].…”

Treatment with fibrates is associated with higher LAL activity in dyslipidemic patients

“…TFEB is the master regulator of lysosomal 249 biogenesis and, consequently, of LAL expression. Recently, peroxisome proliferator 250 responsive elements were identified in the promoter region of TFEB and it has been shown 251 that PPARα, together with PPAR gamma coactivator 1α and retinoid X receptors, can 252 promote the transcriptional activation of TFEB [23]. In addition, PPARα agonists could directly 253 promote LAL activity through their modulation of intracellular lipid metabolism.…”

Treatment with Fibrates is Associated with Higher Lal Activity in Dyslipidemic Patients

“…TFEB is the master regulator of lysosomal biogenesis and, consequently, of LAL expression. Recently, peroxisome proliferator responsive elements were identified in the promoter region of TFEB and it has been shown that PPARα, together with PPAR gamma coactivator 1α and retinoid X receptors, can promote the transcriptional activation of TFEB [23]. In addition, PPARα agonists could directly promote LAL activity through their modulation of intracellular lipid metabolism.…”