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Lysosomal inhibition attenuates peroxisomal gene transcription via suppression of PPARA and PPARGC1A levels.

Publication ,  Journal Article
Tan, HWS; Anjum, B; Shen, H-M; Ghosh, S; Yen, PM; Sinha, RA
Published in: Autophagy
August 2019

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.

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Published In

Autophagy

DOI

EISSN

1554-8635

Publication Date

August 2019

Volume

15

Issue

8

Start / End Page

1455 / 1459

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Peroxisomes
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • PPAR alpha
  • Mice
  • Lysosomes
  • Gene Expression Regulation
  • Cell Line
  • Biochemistry & Molecular Biology
  • Animals
 

Citation

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Tan, H. W. S., Anjum, B., Shen, H.-M., Ghosh, S., Yen, P. M., & Sinha, R. A. (2019). Lysosomal inhibition attenuates peroxisomal gene transcription via suppression of PPARA and PPARGC1A levels. Autophagy, 15(8), 1455–1459. https://doi.org/10.1080/15548627.2019.1609847
Tan, Hayden Weng Siong, B. Anjum, Han-Ming Shen, Sujoy Ghosh, Paul M. Yen, and Rohit A. Sinha. “Lysosomal inhibition attenuates peroxisomal gene transcription via suppression of PPARA and PPARGC1A levels.Autophagy 15, no. 8 (August 2019): 1455–59. https://doi.org/10.1080/15548627.2019.1609847.
Tan HWS, Anjum B, Shen H-M, Ghosh S, Yen PM, Sinha RA. Lysosomal inhibition attenuates peroxisomal gene transcription via suppression of PPARA and PPARGC1A levels. Autophagy. 2019 Aug;15(8):1455–9.
Tan, Hayden Weng Siong, et al. “Lysosomal inhibition attenuates peroxisomal gene transcription via suppression of PPARA and PPARGC1A levels.Autophagy, vol. 15, no. 8, Aug. 2019, pp. 1455–59. Pubmed, doi:10.1080/15548627.2019.1609847.
Tan HWS, Anjum B, Shen H-M, Ghosh S, Yen PM, Sinha RA. Lysosomal inhibition attenuates peroxisomal gene transcription via suppression of PPARA and PPARGC1A levels. Autophagy. 2019 Aug;15(8):1455–1459.

Published In

Autophagy

DOI

EISSN

1554-8635

Publication Date

August 2019

Volume

15

Issue

8

Start / End Page

1455 / 1459

Location

United States

Related Subject Headings

  • Transcription, Genetic
  • Peroxisomes
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • PPAR alpha
  • Mice
  • Lysosomes
  • Gene Expression Regulation
  • Cell Line
  • Biochemistry & Molecular Biology
  • Animals