Project description:Specific high-affinity binding sites for non-steroidal anti-oestrogens such as tamoxifen have been identified in many animal and human tissues. The function of these binding sites and the nature of their endogenous ligands are currently unknown. Our laboratory has previously reported that unsaturated fatty acids at micromolar concentrations inhibited [3H]tamoxifen binding to the anti-oestrogen-binding sites in rat liver, raising the possibility that fatty acids might represent endogenous ligands for these sites. These studies have now been extended to examine the mechanism by which fatty acids inhibit [3H]tamoxifen binding to the anti-oestrogen-binding site. Saturation analysis revealed that increasing concentrations of oleic acid progressively decreased the apparent binding affinity of these sites for [3H]tamoxifen without decreasing the total number of binding sites; however, the apparent dissociation constant did not vary linearly with the prevailing oleic acid concentration, suggesting that the inhibition of [3H]tamoxifen binding by fatty acid was not competitive in nature. Kinetic studies of [3H]tamoxifen binding showed that oleic acid did not affect the rate of association, but increased the rate of dissociation of [3H]tamoxifen from the anti-oestrogen-binding site; the latter finding would not be expected if oleic acid acted as a competitive inhibitor. Furthermore, incubation of a rat microsomal fraction with [3H]oleic acid in the absence and presence of excess non-radioactively labelled tamoxifen also failed to demonstrate direct competition between oleic acid and tamoxifen for the same binding site. It is concluded that oleic acid, and presumably other unsaturated fatty acids, do not compete for the anti-oestrogen-binding site and probably reduce its tamoxifen-binding affinity by some other mechanism, such as perturbation of the lipid environment of the binding site. The biological significance of this interaction of unsaturated fatty acids with the anti-oestrogen-binding site remains to be elucidated.

Project description:The epigenetic landscape is vulnerable to variations in diet. Here, we investigated the influence of different PUFA dietary supplements on rodents’ nervous system development and functions and potential consequences for neurodegenerative disorders. We have previously studied the genomic plasticity of these biofunctions in mice fed on high n-3 PUFA enriched diet (ERD). In conjunction, in the present study, we introduced a second equicaloric diet with n-3 PUFA optimally balanced by n-6 PUFA (BLD). The typical lab diet with high n-6 PUFA was the baseline. Randomly grouped C57BL/6j mice were fed on any of these three diets from their neonatal age to late adolescent. Post-euthanasia, the transcriptomic landscape of hemibrains was investigated in parallel for two epigenetic mechanisms, namely the miRNA profile and DNA methylation. Integrating data we focused on those genes which had both hypermethylated CpG islands and silenced transcripts. Of these, 308 and 131 genes were perturbed by ERD and BLD, respectively, in comparison to the baseline. Also, miRNA:mRNA pairs were screened to identify those overexpressed miRNAs that silenced gene transcription. There were 18 and 39 miRNAs that met the cutoff in ERD- and BLD-fed mice, respectively. The majority of miRNAs overexpressed by BLD are associated with Alzheimer’s and schizophrenia. BLD allowed hypermethylation of those genes that enriched the networks associated with calcium-releasing neurotransmitters. Downstream networks leading to LTP, memory, cognition and learning were perturbed in sync. ERD permitted hypermethylation of genes that enrich the cytoskeletal development network and promote the formation of neuronal precursors. We present the conclusions taking into full account the limited knowledge regarding the epigenetic influence on biofunctions. Since this study has single time point, we could not verify if these functional attributes are the cause or the consequences of epigenetic plasticity. Hence, a more comprehensive study in this regard is essential.

Dataset Information

Discovery of a protein-metabolite interaction between unsaturated fatty acids and the nuclear receptor Nur77 using a metabolomics approach.

Publications

Discovery of a protein-metabolite interaction between unsaturated fatty acids and the nuclear receptor Nur77 using a metabolomics approach.

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