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Vol. 17, Issue 4, 1822-1833, April 2006

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Thioredoxin-mediated Negative Autoregulation of Peroxisome Proliferator-activated Receptor Transcriptional Activity

Guang-Hui Liu ^*, Jing Qu ^*, and Xun Shen ^* 

^* Institute of Biophysics and Graduate School, Chinese Academy of Sciences, Beijing 100101, China; Division of Nitric Oxide and Inflammatory Medicine, E-Institutes of Shanghai Universities (Shanghai University of Traditional Chinese Medicine), Shanghai 201203, China

Submitted October 25, 2005; Revised December 14, 2005; Accepted February 1, 2006
Monitoring Editor: William Tansey

PPAR, a member of the nuclear receptor superfamily, and thioredoxin, a critical redox-regulator in cells, were found to form a negative feedback loop, which autoregulates transcriptional activity of PPAR. Thioredoxin was identified as a target gene of PPAR. Activation of PPAR leads to increase of thioredoxin expression as well as its translocation from cytoplasm to nucleus, whereas ectopic overexpression of thioredoxin in the nucleus dramatically inhibited both constitutive and ligand-dependent PPAR activation. As PPAR-target genes, the expression of muscle carnitine palmitoyltransferase I, medium chain acyl CoA dehydrogenase, and apolipoprotein A-I were significantly down-regulated by nucleus-targeted thioredoxin at transcriptional or protein level. The suppression of PPAR transcriptional activity by Trx could be enhanced by overexpression of thioredoxin reductase or knockdown of thioredoxin-interacting protein, but abrogated by mutating the redox-active sites of thioredoxin. Mammalian one-hybrid assays showed that thioredoxin inhibited PPAR activity by modulating its AF-1 transactivation domain. It was also demonstrated by electrophoretic mobility-shift assay that thioredoxin inhibited the binding of PPAR to the PPAR-response element. Together, it is speculated that the reported negative-feedback loop may be essential for maintaining the homeostasis of PPAR activity.

Abbreviations used: EMSA, electrophoretic mobility-shift assay; MCAD, medium chain acyl coenzyme A dehydrogenase; MCPT1, muscle carnitine palmitoyltransferase 1; PPAR, peroxisome proliferator-activated receptor ; PPRE, peroxisome proliferator response element; RXR, retinoid X receptor-; TF, transcription factor; Trx, thioredoxin; TrxR, thioredoxin reductase; Txnip, thioredoxin-interacting protein.

Address correspondence to: Xun Shen (shenxun{at}sun5.ibp.ac.cn).

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