Dataset Information

A Novel Splicing Variant of Peroxisome Proliferator-Activated Receptor-? (Ppar?1sv) Cooperatively Regulates Adipocyte Differentiation with Ppar?2.

ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate expression of a number of genes associated with the cellular differentiation and development. Here, we show the abundant and ubiquitous expression of a newly identified splicing variant of mouse Ppar? (Ppar?1sv) that encodes PPAR?1 protein, and its importance in adipogenesis. The novel splicing variant has a unique 5'-UTR sequence, relative to those of Ppar?1 and Ppar?2 mRNAs, indicating the presence of a novel transcriptional initiation site and promoter for Ppar? expression. Ppar?1sv was highly expressed in the white and brown adipose tissues at levels comparable to Ppar?2. Ppar?1sv was synergistically up-regulated with Ppar?2 during adipocyte differentiation of 3T3-L1 cells and mouse primary cultured preadipocytes. Inhibition of Ppar?1sv by specific siRNAs completely abolished the induced adipogenesis in 3T3-L1 cells. C/EBP? and C/EBP? activated both the Ppar?1sv and Ppar?2 promoters in 3T3-L1 preadipocytes. These findings suggest that Ppar?1sv and Ppar?2 synergistically regulate the early stage of the adipocyte differentiation.

SUBMITTER: Takenaka Y

PROVIDER: S-EPMC3686765 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

A Novel Splicing Variant of Peroxisome Proliferator-Activated Receptor-γ (Pparγ1sv) Cooperatively Regulates Adipocyte Differentiation with Pparγ2.

Takenaka Yasuhiro Y Inoue Ikuo I Nakano Takanari T Shinoda Yuichi Y Ikeda Masaaki M Awata Takuya T Katayama Shigehiro S

PloS one 20130619 6

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate expression of a number of genes associated with the cellular differentiation and development. Here, we show the abundant and ubiquitous expression of a newly identified splicing variant of mouse Pparγ (Pparγ1sv) that encodes PPARγ1 protein, and its importance in adipogenesis. The novel splicing variant has a unique 5'-UTR sequence, relative to those of Pparγ1 and Pparγ2 mRNAs, indicating the presence of a nov ...[more]

PMID: 23840343

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Project description:Although MK886 was originally identified as an inhibitor of 5-lipoxygenase activating protein (FLAP), recent data demonstrate that this activity does not underlie its ability to induce apoptosis [Datta, Biswal and Kehrer (1999) Biochem. J. 340, 371--375]. Since FLAP is a fatty-acid binding protein, it is conceivable that MK886 may affect other such proteins. A family of nuclear receptors that are activated by fatty acids and their metabolites, the peroxisome-proliferator-activated receptors (PPARs), have been implicated in apoptosis and may represent a target for MK886. The ability of MK886 to inhibit PPAR-alpha, -beta and -gamma activity was assessed using reporter assay systems (peroxisome-proliferator response element--luciferase). Using a transient transfection system in monkey kidney fibroblast CV-1 cells, mouse keratinocyte 308 cells and human lung adenocarcinoma A549 cells, 10--20 microM MK886 inhibited Wy14,643 activation of PPAR alpha by approximately 80%. Similar inhibition of PPAR alpha by MK886 was observed with a stable transfection reporter system in CV-1 cells. Only minimal inhibitory effects were seen on PPAR beta and PPAR gamma. MK886 inhibited PPAR alpha by a non-competitive mechanism as shown by its effects on the binding of arachidonic acid to PPAR alpha protein, and a dose-response study using a transient transfection reporter assay in COS-1 cells. An assay assessing PPAR ligand-receptor interactions showed that MK886 prevents the conformational change necessary for active-complex formation. The expression of keratin-1, a protein encoded by a PPAR alpha-responsive gene, was reduced by MK886 in a culture of mouse primary keratinocytes, suggesting that PPAR inhibition has functional consequences in normal cells. Although Jurkat cells express all PPAR isoforms, various PPAR alpha and PPAR gamma agonists were unable to prevent MK886-induced apoptosis. This is consistent with MK886 functioning as a non-competitive inhibitor of PPAR alpha, but may also indicate that PPAR alpha is not directly involved in MK886-induced apoptosis. Although numerous PPAR activators have been identified, the results show that MK886 can inhibit PPAR alpha, making it the first compound identified to have such an effect.

Dataset Information

A Novel Splicing Variant of Peroxisome Proliferator-Activated Receptor-? (Ppar?1sv) Cooperatively Regulates Adipocyte Differentiation with Ppar?2.

Publications

A Novel Splicing Variant of Peroxisome Proliferator-Activated Receptor-γ (Pparγ1sv) Cooperatively Regulates Adipocyte Differentiation with Pparγ2.

Similar Datasets

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