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Selective Intranuclear Redistribution of PPAR Isoforms by RXR

Laboratory of Metabolism (T.E.A., S.S., F.J.G.) and Laboratory of Receptor Biology and Gene Expression (C.T.B., G.L.H.), National Cancer Institute, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Frank J. Gonzalez, Laboratory of Metabolism, National Institutes of Health, Building 37, Room 3E-24, 9000 Rockville Pike, Bethesda, Maryland 20892. E-mail: fjgonz{at}helix.nih.gov.

The intracellular localization of transcriptionally active green fluorescent protein (GFP) chimeras linked to PPARs for human PPAR (GFP-PPARh) and mouse PPAR, ß, and 1 (GFP-PPARm, GFP-PPARmß, and GFP-PPARm, respectively) was examined in the mouse hepatoma cell line, Hepa-1, using fluorescence microscopy. A predominantly nuclear and diffuse distribution of each isoform was found in both the presence and absence of specific ligands for each receptor. GFP-PPARm-G (containing a Glu282Gly substitution of PPARm) and a phosphorylation mutant, GFP-PPARm-A (containing a Ser82Ala substitution of PPARm), exhibited altered transcriptional activities, but displayed similar intracellular localization patterns compared with their respective wild-type receptors. Coexpression of nuclear receptor corepressor suppressed, whereas steroid receptor coactivator-1 enhanced the transcriptional activity of each of the GFP-PPAR isoforms, but did not discernibly alter their intracellular distributions, both in the presence and absence of PPAR ligands. Interestingly, coexpression of the obligate heterodimeric partner of PPARs, RXR, resulted in an intranuclear redistribution of the GFP-PPARm isoform characterized by a reticulated pattern of the green fluorescent label for PPAR within the nucleus, but not in nucleoli, and a heightened concentration of the fluorescent label surrounding nucleolar structures and at the nuclear membrane. Conversely, coexpression of yellow fluorescent protein-RXR and native PPARm resulted in a similar distribution of the yellow fluorescent tag. This localization pattern was not discernibly altered by PPAR or RXR-specific ligands. These results implicate RXR in the nuclear reorganization of PPAR and suggest that PPAR colocalizes with RXR at specific locations within the nucleus independent of added ligand.

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