PPARγ isoforms differentially regulate metabolic networks to mediate mouse prostatic epithelial differentiation.
PPARγ isoforms differentially regulate metabolic networks to mediate mouse prostatic epithelial differentiation.
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DOI：
10.1038/cddis.2012.99
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发表时间：
2012-08-09
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
作者：
最近的观察表明前列腺疾病是全身代谢功能障碍的合并症。这些发现揭示了有关前列腺代谢本质的基本问题。我们之前的研究表明，前列腺特异性消融小鼠的PPARγ导致肿瘤发生和活跃的自噬。在这里，我们证明了通过PPARγ敲除前列腺上皮细胞中单个PPARγ亚型的异位表达来控制前列腺上皮代谢的重叠和不同方面。PPARγ 1和PPARγ 2的表达和激活均可减少新生脂肪生成和氧化应激，并通过调节Pdk4、Fabp4、Lpl、Acot1和Cd36等基因介导从葡萄糖到脂肪酸氧化的转换。PPARγ亚型的差异效应包括降低基底细胞分化、Scd1表达和甘油三酯脂肪酸去饱和，并增加PPARγ1的致瘤性。而ppar - γ - 2的表达可显著提高基底细胞分化、Scd1表达和AR表达及应答性。最后，为了证实体外数据，PPARγ激动剂与高脂饮食（HFD）方案在体内证实了PPARγ激动剂增加了前列腺分化标志物，而HFD下调了PPARγ调节基因并降低了前列腺分化。这些数据为研究与全身代谢应激相关的良性和恶性前列腺疾病中葡萄糖和脂肪酸代谢变化的基本代谢理解提供了依据。
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.
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DOI：
10.1152/ajpendo.00219.2010
发表时间：
2011-01-01
影响因子：
5.1
作者：
Hsiao, Gene;Chapman, Justin;Sears, Dorothy D.
通讯作者：
Sears, Dorothy D.
DOI：
10.1073/pnas.2536828100
发表时间：
2003-12-23
影响因子：
11.1
作者：
He, WM;Barak, Y;Evans, RM
通讯作者：
Evans, RM
影响因子：
4.8
作者：
Kelly, LJ;Vicario, PP;Moller, DE
通讯作者：
Moller, DE
影响因子：
12.4
作者：
Jiang, M.;Fernandez, S.;Jerome, W. G.;He, Y.;Yu, X.;Cai, H.;Boone, B.;Yi, Y.;Magnuson, M. A.;Roy-Burman, P.;Matusik, R. J.;Shappell, S. B.;Hayward, S. W.
通讯作者：
Hayward, S. W.
DOI：
10.1016/j.bbalip.2009.09.015
发表时间：
2010-03
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Chavez JA;Summers SA
通讯作者：
Summers SA