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Fatty acid binding profile of the liver X receptor ?.

ABSTRACT: Liver X receptor (LXR)? is a nuclear receptor that responds to oxysterols and cholesterol overload by stimulating cholesterol efflux, transport, conversion to bile acids, and excretion. LXR? binds to and is regulated by synthetic (T-0901317, GW3695) and endogenous (oxysterols) ligands. LXR? activity is also modulated by FAs, but the ligand binding specificity of FA and acyl-CoA derivatives for LXR? remains unknown. We investigated whether LXR? binds FA or FA acyl-CoA with affinities that mimic in vivo concentrations, examined the effect of FA chain length and the degree of unsaturation on binding, and investigated whether FAs regulate LXR? activation. Saturated medium-chain FA (MCFA) displayed binding affinities in the low nanomolar concentration range, while long-chain fatty acyl-CoA did not bind or bound weakly to LXR?. Circular dichroic spectra and computational docking experiments confirmed that MCFA bound to the LXR? ligand binding pocket similar to the known synthetic agonist of LXR? (T0901317), but with limited change to the conformation of the receptor. Transactivation assays showed that MCFA activated LXR?, whereas long-chain FA caused no effect. Our results suggest that LXR? functions as a receptor for saturated FA or acyl-CoA of C10 and C12 in length.

SUBMITTER: Bedi S

PROVIDER: S-EPMC5282955 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Fatty acid binding profile of the liver X receptor α.

Bedi Shimpi S Hines Genesis Victoria GV Lozada-Fernandez Valery V VV de Jesus Piva Camila C Kaliappan Alagammai A Rider S Dean SD Hostetler Heather A HA

Journal of lipid research 20161223 2

Liver X receptor (LXR)α is a nuclear receptor that responds to oxysterols and cholesterol overload by stimulating cholesterol efflux, transport, conversion to bile acids, and excretion. LXRα binds to and is regulated by synthetic (T-0901317, GW3695) and endogenous (oxysterols) ligands. LXRα activity is also modulated by FAs, but the ligand binding specificity of FA and acyl-CoA derivatives for LXRα remains unknown. We investigated whether LXRα binds FA or FA acyl-CoA with affinities that mimic i ...[more]

PMID: 28011707

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Project description:BACKGROUND: New advances in high-throughput technologies have allowed for the massive analysis of genomic data, providing new opportunities for the characterization of the transcriptome architectures. Recent studies in pigs have employed RNA-Seq to explore the transcriptome of different tissues in a reduced number of animals. The main goal of this study was the identification of differentially-expressed genes in the liver of Iberian x Landrace crossbred pigs showing extreme phenotypes for intramuscular fatty acid composition using RNA-Seq. RESULTS: The liver transcriptomes of two female groups (H and L) with phenotypically extreme intramuscular fatty acid composition were sequenced using RNA-Seq. A total of 146 and 180 unannotated protein-coding genes were identified in intergenic regions for the L and H groups, respectively. In addition, a range of 5.8 to 7.3% of repetitive elements was found, with SINEs being the most abundant elements. The expression in liver of 186 (L) and 270 (H) lncRNAs was also detected. The higher reproducibility of the RNA-Seq data was validated by RT-qPCR and porcine expression microarrays, therefore showing a strong correlation between RT-qPCR and RNA-Seq data (ranking from 0.79 to 0.96), as well as between microarrays and RNA-Seq (r=0.72). A differential expression analysis between H and L animals identified 55 genes differentially-expressed between groups. Pathways analysis revealed that these genes belong to biological functions, canonical pathways and three gene networks related to lipid and fatty acid metabolism. In concordance with the phenotypic classification, the pathways analysis inferred that linolenic and arachidonic acids metabolism was altered between extreme individuals. In addition, a connection was observed among the top three networks, hence suggesting that these genes are interconnected and play an important role in lipid and fatty acid metabolism. CONCLUSIONS: In the present study RNA-Seq was used as a tool to explore the liver transcriptome of pigs with extreme phenotypes for intramuscular fatty acid composition. The differential gene expression analysis showed potential gene networks which affect lipid and fatty acid metabolism. These results may help in the design of selection strategies to improve the sensorial and nutritional quality of pork meat.

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Fatty acid binding profile of the liver X receptor ?.

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Fatty acid binding profile of the liver X receptor α.

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