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PPAR? isoforms differentially regulate metabolic networks to mediate mouse prostatic epithelial differentiation.

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 PPAR? 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 PPAR? isoforms in PPAR? knockout prostate epithelial cells. Expression and activation of either PPAR? 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 PPAR? isoforms included decreased basal cell differentiation, Scd1 expression and triglyceride fatty acid desaturation and increased tumorigenicity by PPAR?1. In contrast, PPAR?2 expression significantly increased basal cell differentiation, Scd1 expression and AR expression and responsiveness. Finally, in confirmation of in vitro data, a PPAR? agonist versus high-fat diet (HFD) regimen in vivo confirmed that PPAR? agonization increased prostatic differentiation markers, whereas HFD downregulated PPAR?-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.

SUBMITTER: Strand DW

PROVIDER: S-EPMC3434663 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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

Strand D W DW Jiang M M Jiang M M Murphy T A TA Yi Y Y Konvinse K C KC Franco O E OE Wang Y Y Young J D JD Hayward S W SW

Cell death & disease 20120809

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 PPARγ isoforms in PPARγ knockout prostate epithelial ...[more]

PMID: 22874998

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Dataset Information

PPAR? isoforms differentially regulate metabolic networks to mediate mouse prostatic epithelial differentiation.

Publications

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

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