Dataset Information

Ligand-binding regulation of LXR/RXR and LXR/PPAR heterodimerizations: SPR technology-based kinetic analysis correlated with molecular dynamics simulation.

ABSTRACT: Liver X receptor (LXR) and peroxisome proliferator-activated receptor (PPAR) are two members of nuclear receptors involved in the nutrient metabolisms of dietary fatty acid and cholesterol. They are found to be of cross-talk function in that LXR regulates fatty acid synthesis and PPAR controls fatty acid degradation. LXRs (LXRalpha and LXRbeta) function by forming obligate heterodimers with the retinoid X receptor (RXR), and subsequently binding to specific DNA response elements within the regulatory regions of their target genes. In this work, the kinetic features concerning LXR/RXR and LXR/PPAR interactions have been fully investigated using surface plasmon resonance (SPR) technology. It is found that LXRs could bind to all the three PPAR subtypes, PPARalpha, PPARgamma and PPARdelta with different binding affinities, and such receptor/receptor interactions could be regulated by ligand binding. Moreover, molecular dynamics (MD) simulations were performed on six typical complex models. The results revealed that ligands may increase the interaction energies between the receptor interfaces of the simulated receptor/receptor complexes. The MD results are in agreement with the SPR data. Further analyses on the MD results indicated that the ligand binding might increase the hydrogen bonds between the interfaces of the receptor/receptor complex.

SUBMITTER: Yue L

PROVIDER: S-EPMC2279270 | biostudies-literature | 2005 Mar

REPOSITORIES: biostudies-literature

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Ligand-binding regulation of LXR/RXR and LXR/PPAR heterodimerizations: SPR technology-based kinetic analysis correlated with molecular dynamics simulation.

Yue Liduo L Ye Fei F Gui Chunshan C Luo Haibin H Cai Jianhua J Shen Jianhua J Chen Kaixian K Shen Xu X Jiang Hualiang H

Protein science : a publication of the Protein Society 20050301 3

Liver X receptor (LXR) and peroxisome proliferator-activated receptor (PPAR) are two members of nuclear receptors involved in the nutrient metabolisms of dietary fatty acid and cholesterol. They are found to be of cross-talk function in that LXR regulates fatty acid synthesis and PPAR controls fatty acid degradation. LXRs (LXRalpha and LXRbeta) function by forming obligate heterodimers with the retinoid X receptor (RXR), and subsequently binding to specific DNA response elements within the regul ...[more]

PMID: 15722453

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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

Ligand-binding regulation of LXR/RXR and LXR/PPAR heterodimerizations: SPR technology-based kinetic analysis correlated with molecular dynamics simulation.

Publications

Ligand-binding regulation of LXR/RXR and LXR/PPAR heterodimerizations: SPR technology-based kinetic analysis correlated with molecular dynamics simulation.

Similar Datasets

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