Dataset Information

In vivo activation of PPAR target genes by RXR homodimers.

ABSTRACT: The ability of a retinoid X receptor (RXR) to heterodimerize with many nuclear receptors, including LXR, PPAR, NGF1B and RAR, underscores its pivotal role within the nuclear receptor superfamily. Among these heterodimers, PPAR:RXR is considered an important signalling mediator of both PPAR ligands, such as fatty acids, and 9-cis retinoic acid (9-cis RA), an RXR ligand. In contrast, the existence of an RXR/9-cis RA signalling pathway independent of PPAR or any other dimerization partner remains disputed. Using in vivo chromatin immunoprecipitation, we now show that RXR homodimers can selectively bind to functional PPREs and induce transactivation. At the molecular level, this pathway requires stabilization of the homodimer-DNA complexes through ligand-dependent interaction with the coactivator SRC1 or TIF2. This pathway operates both in the absence and in the presence of PPAR, as assessed in cells carrying inactivating mutations in PPAR genes and in wild-type cells. In addition, this signalling pathway via PPREs is fully functional and can rescue the severe hypothermia phenotype observed in fasted PPARalpha-/- mice. These observations have important pharmacological implications for the development of new rexinoid-based treatments.

SUBMITTER: IJpenberg A

PROVIDER: S-EPMC424365 | biostudies-literature | 2004 May

REPOSITORIES: biostudies-literature

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Publications

In vivo activation of PPAR target genes by RXR homodimers.

IJpenberg Annemieke A Tan Nguan Soon NS Gelman Laurent L Kersten Sander S Seydoux Josiane J Xu Jianming J Metzger Daniel D Canaple Laurence L Chambon Pierre P Wahli Walter W Desvergne Béatrice B

The EMBO journal 20040422 10

The ability of a retinoid X receptor (RXR) to heterodimerize with many nuclear receptors, including LXR, PPAR, NGF1B and RAR, underscores its pivotal role within the nuclear receptor superfamily. Among these heterodimers, PPAR:RXR is considered an important signalling mediator of both PPAR ligands, such as fatty acids, and 9-cis retinoic acid (9-cis RA), an RXR ligand. In contrast, the existence of an RXR/9-cis RA signalling pathway independent of PPAR or any other dimerization partner remains d ...[more]

PMID: 15103326

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Project description:Macrophage foam cells store excess cholesterol as cholesteryl esters, which need to be hydrolyzed for cholesterol efflux. We recently reported that silencing expression of carboxylesterase 1 (CES1) in human THP-1 macrophages [CES1KD (THP-1 cells with CES1 expression knocked down) macrophages] reduced cholesterol uptake and decreased expression of CD36 and scavenger receptor-A in cells loaded with acetylated low-density lipoprotein (acLDL). Here, we report that CES1KD macrophages exhibit reduced transcription of cytochrome P45027A1 (CYP27A1) in nonloaded and acLDL-loaded cells. Moreover, levels of CYP27A1 protein and its enzymatic product, 27-hydroxycholesterol, were markedly reduced in CES1KD macrophages. Transcription of LXR? (liver X receptor ?) and ABCA1 (ATP-binding cassette transporter A1) was also decreased in acLDL-loaded CES1KD macrophages, suggesting reduced signaling through PPAR?-CYP27A1-LXR?. Consistent with this, treatment of CES1KD macrophages with agonists for PPAR?, RAR, and/or RAR/RXR partially restored transcription of CYP27A1 and LXR?, and repaired cholesterol influx. Conversely, treatment of control macrophages with antagonists for PPAR? and/or RXR decreased transcription of CYP27A1 and LXR? Pharmacologic inhibition of CES1 in both wild-type THP-1 cells and primary human macrophages also decreased CYP27A1 transcription. CES1 silencing did not affect transcript levels of PPAR? and RXR in acLDL-loaded macrophages, whereas it did reduce the catabolism of the endocannabinoid 2-arachidonoylglycerol. Finally, the gene expression profile of CES1KD macrophages was similar to that of PPAR? knockdown cells following acLDL exposures, further suggesting a mechanistic link between CES1 and PPAR?. These results are consistent with a model in which abrogation of CES1 function attenuates the CYP27A1-LXR?-ABCA1 signaling axis by depleting endogenous ligands for the nuclear receptors PPAR?, RAR, and/or RXR that regulate cholesterol homeostasis.

Dataset Information

In vivo activation of PPAR target genes by RXR homodimers.

Publications

In vivo activation of PPAR target genes by RXR homodimers.

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