Journal
AUTOPHAGY
Volume 15, Issue 8, Pages 1455-1459Publisher
TAYLOR & FRANCIS INC
DOI: 10.1080/15548627.2019.1609847
Keywords
lipid oxidation; lysosomes; NAFLD; peroxisomes; steatohepatitis
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Funding
- National Medical Research Council, Singapore [NMRC/CSA/0054/2013]
- Wellcome Trust/DBT India Alliance Fellowship [IA/I/16/2/502691]
- [NMRC/BNIG/2025/2014]
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Lysosomes influence dynamic cellular processes such as nutrient sensing and transcriptional regulation. To explore novel transcriptional pathways regulated by lysosomes, we performed microarray analysis followed by qPCR validation in a mouse hepatocyte cell line, AML12, treated with bafilomycin A(1) (lysosomal v-type H+-translocating ATPase inhibitor). Pathway enrichment analysis revealed significant downregulation of gene sets related to peroxisomal biogenesis and peroxisomal lipid oxidation upon lysosomal inhibition. Mechanistically, pharmacological inhibition of lysosomes as well as genetic knockdown of Tfeb led to downregulation of the peroxisomal master regulator PPARA and its coactivator PPARGC1A/PGC1 alpha. Consistently, ectopic induction of PPARA transcriptional activity rescues the effects of lysosomal inhibition on peroxisomal gene expression. Collectively, our results uncover a novel metabolic regulation of peroxisomes by lysosomes via PPARA-PPARGC1A transcriptional signalling.
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