Thomas, Maria and Bayha, Christine and Klein, Kathrin and Mueller, Simon and Weiss, Thomas S. and Schwab, Matthias and Zanger, Ulrich M. (2015) The truncated splice variant of peroxisome proliferator-activated receptor alpha, PPAR alpha-tr, autonomously regulates proliferative and pro-inflammatory genes. BMC CANCER, 15: 488. ISSN 1471-2407,
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Background: The peroxisome proliferator-activated receptor alpha (PPAR alpha) controls lipid/energy homeostasis and inflammatory responses. The truncated splice variant PPAR alpha-tr was suggested to exert a dominant negative function despite being unable to bind consensus PPAR alpha DNA response elements. Methods: The distribution and variability factor of each PPAR alpha 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 PPAR alpha-wt and PPAR alpha-tr forms in primary human hepatocytes. Results: Bioinformatic analyses of genome-wide liver expression profiling data suggested a possible role of PPAR alpha-tr in downregulating proliferative and pro-inflammatory genes. Specific gene silencing of both forms in primary human hepatocytes showed that induction of metabolic PPAR alpha-target genes by agonist WY14,643 was prevented by PPAR alpha-wt knock-down but neither prevented nor augmented by PPAR alpha-tr knock-down. WY14,643 treatment did not induce proliferative genes including MYC, CDK1, and PCNA, and knock-down of PPAR alpha-wt had no effect, while PPAR alpha-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 PPAR alpha-tr but not of PPAR alpha-wt. In contrast to human proliferative genes, orthologous mouse genes were readily inducible by WY14,643 in PPAR alpha-tr non-expressing AML12 mouse hepatocytes. Induction was augmented by overexpression of PPAR alpha-wt and attenuated by overexpression of PPAR alpha-tr. Pro-inflammatory genes including IL-1 beta, CCL2 and TNF alpha were induced by WY14,643 in mouse and human cells and both PPAR alpha forms attenuated induction. As potential mechanism of PPAR alpha-tr inhibitory action we suggest crosstalk with WNT/beta-catenin pathway. Finally, treatment with WY14,643 in the presence of PPAR alpha-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 PPAR alpha 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HUMAN LIVER; SPECIES-DIFFERENCES; NUCLEAR RECEPTORS; IN-VITRO; EXPRESSION; CANCER; HEPATOCARCINOGENESIS; AGONISTS; DISEASE; ACID; Alternative splicing; Fibrates; Hepatocarcinogenesis; PPARA; Primary human hepatocytes; Inflammation; Proliferation; WNT/beta-catenin |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Kinder- und Jugendmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 10 Jul 2019 12:57 |
| Last Modified: | 10 Jul 2019 12:57 |
| URI: | https://pred.uni-regensburg.de/id/eprint/5289 |
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