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

Strand DW, Jiang M, Murphy TA, Yi Y, Konvinse KC, Franco OE, Wang Y, Young JD, Hayward SW
Cell Death Dis. 2012 3: e361

PMID: 22874998 · PMCID: PMC3434663 · DOI:10.1038/cddis.2012.99

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 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.

MeSH Terms (21)

Animals Cell Differentiation Cell Line Cell Transformation, Neoplastic Diet, High-Fat Down-Regulation Epithelial Cells Fatty Acids Gene Expression Regulation Gene Knockout Techniques Glucose Lipogenesis Male Metabolic Networks and Pathways Mice Oxidative Stress PPAR gamma Prostate Protein Isoforms Stearoyl-CoA Desaturase Thiazolidinediones

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