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 A1 (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/PGC1α. 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. Abbreviations: Acox1: acyl-Coenzyme A oxidase 1, palmitoyl; Acot: acyl-CoA thioesterase; ACAA: acetyl-Coenzyme A acyltransferase; ABCD3/PMP70: ATP-binding cassette, sub-family D (ALD), member 3; BafA1: bafilomycin A1; Crot: carnitine O-octanoyltransferase; CTSB: cathepsin B; Decr2: 2-4-dienoyl-Coenzyme A reductase 2, peroxisomal; Ech1: enoyl coenzyme A hydratase 1, peroxisomal; Ehhadh: enoyl-Coenzyme A, hydratase/3-hydroxyacyl Coenzyme A dehydrogenase; FDR: false discovery rate; Hsd17b4: hydroxysteroid (17-beta) dehydrogenase 4; NES: normalized enrichment score; NOM: nominal; Pex: peroxin; PPARA: peroxisome proliferator activated receptor alpha; PPARGC1A: peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; TFEB: transcription factor EB.
Keywords: NAFLD; lipid oxidation; lysosomes; peroxisomes; steatohepatitis.