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The truncated splice variant of peroxisome proliferator-activated receptor alpha, PPARalpha-tr, autonomously regulates proliferative and pro-inflammatory genes

Abstract:

BACKGROUND: The peroxisome proliferator-activated receptor alpha (PPARalpha) controls lipid/energy homeostasis and inflammatory responses. The truncated splice variant PPARalpha-tr was suggested to exert a dominant negative function despite being unable to bind consensus PPARalpha DNA response elements. METHODS: The distribution and variability factor of each PPARalpha variant were assessed in the well-characterized cohort of human liver samples (N = 150) on the mRNA and protein levels. Specific siRNA-mediated downregulation of each transcript as well as specific overexpression with subsequent qRT-PCR analysis of downstream genes was used for investigation of specific functional roles of PPARalpha-wt and PPARalpha-tr forms in primary human hepatocytes. RESULTS: Bioinformatic analyses of genome-wide liver expression profiling data suggested a possible role of PPARalpha-tr in downregulating proliferative and pro-inflammatory genes. Specific gene silencing of both forms in primary human hepatocytes showed that induction of metabolic PPARalpha-target genes by agonist WY14,643 was prevented by PPARalpha-wt knock-down but neither prevented nor augmented by PPARalpha-tr knock-down. WY14,643 treatment did not induce proliferative genes including MYC, CDK1, and PCNA, and knock-down of PPARalpha-wt had no effect, while PPARalpha-tr knock-down caused up to 3-fold induction of these genes. Similarly, induction of pro-inflammatory genes IL1B, PTGS2, and CCL2 by IL-6 was augmented by knock-down of PPARalpha-tr but not of PPARalpha-wt. In contrast to human proliferative genes, orthologous mouse genes were readily inducible by WY14,643 in PPARalpha-tr non-expressing AML12 mouse hepatocytes. Induction was augmented by overexpression of PPARalpha-wt and attenuated by overexpression of PPARalpha-tr. Pro-inflammatory genes including IL-1beta, CCL2 and TNFalpha were induced by WY14,643 in mouse and human cells and both PPARalpha forms attenuated induction. As potential mechanism of PPARalpha-tr inhibitory action we suggest crosstalk with WNT/beta-catenin pathway. Finally, treatment with WY14,643 in the presence of PPARalpha-tr resulted in the significant reduction of cell viability of AML12 and human ovarian cancer cell line, SKOV3. CONCLUSIONS: Our data suggest that the truncated PPARalpha splice variant functions as an endogenous inhibitor of proliferative and pro-inflammatory genes in human cells and that its absence in mouse may explain species-specific differences in fibrate-induced hepatocarcinogenesis.

26122096

Projects: A3.4: Linking signalling to metabolic functions, B5: Cell-cell communication influences detoxifying functions in hepatocytes

BMC Cancer
BMC Cancer. 2015 Jun 30;15:488. doi: 10.1186/s12885-015-1500-x.
30th Jun 2015

M. Thomas, C. Bayha, K. Klein, S. Muller, T. S. Weiss, M. Schwab, U. M. Zanger

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[Maria Thomas] [Kathrin Klein] [Thomas Weiss] [Matthias Schwab] [Ulrich Zanger]

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Views: 1303
  • Created: 17th Sep 2015 at 10:19

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