PPARγ isoforms differentially regulate metabolic networks to mediate mouse prostatic epithelial differentiation

D. W. Strand, M. Jiang, T. A. Murphy, Y. Yi, K. C. Konvinse, O. E. Franco, Y. Wang, J. D. Young, S. W. Hayward

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Recent observations indicate prostatic diseases are comorbidities of systemic metabolic dysfunction. These discoveries revealed fundamental questions regarding the nature of prostate metabolism. We previously showed that prostate-specific ablation of PPARγ in mice resulted in tumorigenesis and active autophagy. Here, we demonstrate control of overlapping and distinct aspects of prostate epithelial metabolism by ectopic expression of individual PPARc isoforms in PPARγ knockout prostate epithelial cells. Expression and activation of either PPARγ 1 or 2 reduced de novo lipogenesis and oxidative stress and mediated a switch from glucose to fatty acid oxidation through regulation of genes including Pdk4, Fabp4, Lpl, Acot1 and Cd36. Differential effects of PPARγ isoforms included decreased basal cell differentiation, Scd1 expression and triglyceride fatty acid desaturation and increased tumorigenicity by PPARγ1. In contrast, PPARγ2 expression significantly increased basal cell differentiation, Scd1 expression and AR expression and responsiveness. Finally, in confirmation of in vitro data, a PPARγ agonist versus high-fat diet (HFD) regimen in vivo confirmed that PPARγ agonization increased prostatic differentiation markers, whereas HFD downregulated PPARγ-regulated genes and decreased prostate differentiation. These data provide a rationale for pursuing a fundamental metabolic understanding of changes to glucose and fatty acid metabolism in benign and malignant prostatic diseases associated with systemic metabolic stress.

Original languageEnglish (US)
Article numbere361
JournalCell Death and Disease
Volume3
Issue number8
DOIs
StatePublished - Aug 2012

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Peroxisome Proliferator-Activated Receptors
Metabolic Networks and Pathways
Protein Isoforms
Prostate
Prostatic Diseases
Fatty Acids
High Fat Diet
Cell Differentiation
Glucose
Lipogenesis
Physiological Stress
Differentiation Antigens
Autophagy
Genes
Comorbidity
Carcinogenesis
Triglycerides
Oxidative Stress
Down-Regulation
Epithelial Cells

Keywords

  • Androgen receptor
  • Differentiation
  • Fatty acid metabolism
  • Peroxisome proliferator-activated receptor gamma (g)
  • PPARg
  • Prostate

ASJC Scopus subject areas

  • Cell Biology
  • Immunology
  • Cancer Research
  • Cellular and Molecular Neuroscience

Cite this

PPARγ isoforms differentially regulate metabolic networks to mediate mouse prostatic epithelial differentiation. / Strand, D. W.; Jiang, M.; Murphy, T. A.; Yi, Y.; Konvinse, K. C.; Franco, O. E.; Wang, Y.; Young, J. D.; Hayward, S. W.

In: Cell Death and Disease, Vol. 3, No. 8, e361, 08.2012.

Research output: Contribution to journalArticle

Strand, DW, Jiang, M, Murphy, TA, Yi, Y, Konvinse, KC, Franco, OE, Wang, Y, Young, JD & Hayward, SW 2012, 'PPARγ isoforms differentially regulate metabolic networks to mediate mouse prostatic epithelial differentiation', Cell Death and Disease, vol. 3, no. 8, e361. https://doi.org/10.1038/cddis.2012.99
Strand, D. W. ; Jiang, M. ; Murphy, T. A. ; Yi, Y. ; Konvinse, K. C. ; Franco, O. E. ; Wang, Y. ; Young, J. D. ; Hayward, S. W. / PPARγ isoforms differentially regulate metabolic networks to mediate mouse prostatic epithelial differentiation. In: Cell Death and Disease. 2012 ; Vol. 3, No. 8.
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