scholarly journals Interactions between Human Liver Fatty Acid Binding Protein and Peroxisome Proliferator Activated Receptor Selective Drugs

PPAR Research ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-14 ◽  
Author(s):  
Tony Velkov
Keyword(s):  
Fatty Acid ◽  
Chemical Shift ◽  
Conformational Changes ◽  
Gene Activation ◽  
Chemical Shift Perturbation ◽  
Peroxisome Proliferator ◽  
Nmr Chemical Shift ◽  
Fatty Acid Binding ◽  
Regulatory Pathways ◽  
Subtype Selective

Fatty acid binding proteins (FABPs) act as intracellular shuttles for fatty acids as well as lipophilic xenobiotics to the nucleus, where these ligands are released to a group of nuclear receptors called the peroxisome proliferator activated receptors (PPARs). PPAR mediated gene activation is ultimately involved in maintenance of cellular homeostasis through the transcriptional regulation of metabolic enzymes and transporters that target the activating ligand. Here we show that liver- (L-) FABP displays a high binding affinity for PPAR subtype selective drugs. NMR chemical shift perturbation mapping and proteolytic protection experiments show that the binding of the PPAR subtype selective drugs produces conformational changes that stabilize the portal region of L-FABP. NMR chemical shift perturbation studies also revealed that L-FABP can form a complex with the PPAR ligand binding domain (LBD) of PPARα. This protein-protein interaction may represent a mechanism for facilitating the activation of PPAR transcriptional activity via the direct channeling of ligands between the binding pocket of L-FABP and the PPARαLBD. The role of L-FABP in the delivery of ligands directly to PPARαvia this channeling mechanism has important implications for regulatory pathways that mediate xenobiotic responses and host protection in tissues such as the small intestine and the liver where L-FABP is highly expressed.

scholarly journals The anti-inflammatory agent bindarit acts as a modulator of fatty acid-binding protein 4 in human monocytic cells

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Sergio Oddi ◽  
Lucia Scipioni ◽  
Antonio Totaro ◽  
Clotilde Angelucci ◽  
Beatrice Dufrusine ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Binding Protein ◽  
Molecular Mechanisms ◽  
Binding Protein ◽  
Immunomodulatory Activity ◽  
Peroxisome Proliferator ◽  
Monocytic Cells ◽  
Fatty Acid Binding ◽  
Acid Binding Protein ◽  
Anti Inflammatory

Abstract We investigated the cellular and molecular mechanisms by which bindarit, a small indazolic derivative with prominent anti-inflammatory effects, exerts its immunoregulatory activity in lipopolysaccharide (LPS) stimulated human monocytic cells. We found that bindarit differentially regulates the release of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), enhancing the release of IL-8 and reducing that of MCP-1. These effects specifically required a functional interaction between bindarit and fatty acid binding protein 4 (FABP4), a lipid chaperone that couples intracellular lipid mediators to their biological targets and signaling pathways. We further demonstrated that bindarit can directly interact with FABP4 by increasing its expression and nuclear localization, thus impacting on peroxisome proliferator-activated receptor γ (PPARγ) and LPS-dependent kinase signaling. Taken together, these findings suggest a potential key-role of FABP4 in the immunomodulatory activity of bindarit, and extend the spectrum of its possible therapeutic applications to FABP4 modulation.

Improving the analysis of NMR spectra tracking pH-induced conformational changes: Removing artefacts of the electric field on the NMR chemical shift

2009 ◽  
Vol 78 (4) ◽  
pp. 971-984 ◽  
Author(s):  
Predrag Kukić ◽  
Damien Farrell ◽  
Chresten R. Søndergaard ◽  
Una Bjarnadottir ◽  
John Bradley ◽  
...  
Keyword(s):  
Chemical Shift ◽  
Electric Field ◽  
Conformational Changes ◽  
Nmr Spectra ◽  
Nmr Chemical Shift

scholarly journals Divergent evolution of cis-acting peroxisome proliferator-activated receptor elements that differentially control the tandemly duplicated fatty acid-binding protein genes, fabp1b.1 and fabp1b.2, in zebrafish

Genome ◽  
2016 ◽  
Vol 59 (6) ◽  
pp. 403-412 ◽  
Author(s):  
Robert B. Laprairie ◽  
Eileen M. Denovan-Wright ◽  
Jonathan M. Wright
Keyword(s):  
Fatty Acid ◽  
Promoter Activity ◽  
Fatty Acid Binding Protein ◽  
Differential Regulation ◽  
Peroxisome Proliferator ◽  
Duplicated Genes ◽  
Fatty Acid Binding ◽  
Acid Binding Protein ◽  
Selective Agonist ◽  
Ppar Agonists

Gene duplication is thought to facilitate increasing complexity in the evolution of life. The fate of most duplicated genes is nonfunctionalization: functional decay resulting from the accumulation of mutations. According to the duplication–degeneration–complementation (DDC) model, duplicated genes are retained by subfunctionalization, where the functions of the ancestral gene are sub-divided between duplicate genes, or by neofunctionalization, where one of the duplicates acquires a new function. Here, we report the differential regulation of the zebrafish tandemly duplicated fatty acid-binding protein genes, fabp1b.1 and fabp1b.2, by peroxisome proliferator-activated receptors (PPAR). fabp1b.1 mRNA levels were induced in tissue explants of liver, but not intestine, by PPAR agonists. fabp1b.1 promoter activity was induced to a greater extent by rosiglitazone (PPARγ-selective agonist) compared to WY 14,643 (PPARα-selective agonist) in HEK293A cells. Mutation of a peroxisome proliferator response element (PPRE) at –1232 bp in the fabp1b.1 promoter reduced PPAR-dependent activation. fabp1b.2 promoter activity was not affected by PPAR agonists. Differential regulation of the duplicated fabp1b promoters may be the result of PPRE loss in fabp1b.2 during a meiotic crossing-over event. Retention of PPAR inducibility in fabp1b.1 and not fabp1b.2 suggests unique regulation and function of the fabp1b duplicates.

scholarly journals Regulation of cardiac fatty acids metabolism in transgenic mice overexpressing bovine GH

2009 ◽  
Vol 201 (3) ◽  
pp. 419-427 ◽  
Author(s):  
Fausto Bogazzi ◽  
Francesco Raggi ◽  
Federica Ultimieri ◽  
Dania Russo ◽  
Aldo D'Alessio ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Transgenic Mice ◽  
Fatty Acid Transport ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Fatty Acid Binding ◽  
Chain Acyl ◽  
Fatty Acids Metabolism ◽  
Key Enzyme ◽  
Key Steps

Cardiac energy metabolism depends mainly on fatty acid (FA) oxidation; however, regulation of FA metabolism in acromegalic (Acro) heart is unknown. The aim of the study was to evaluate cardiac expression of key proteins of FA metabolism in young and elder transgenic mice overexpressing bovine GH Acro. Expression of proteins regulating FA entry into the cells, their uptake by mitochondria and β-oxidation were evaluated by western blot, while FA content by Fourier transform infrared microspectrometry. Regulatory mechanisms of key steps of FA metabolism were also studied. The expression of plasma-membrane FA carriers (fatty acid-binding protein and fatty acid transport protein-1) and acylCoA synthetase was higher in young and lower in elder Acro than in corresponding controls; likewise, expression of cytoplasm to mitochondria-1 (CPT-1), the key enzyme of mitochondrial FA uptake, and that of medium-chain acyl-CoA dehydrogenase and long-chain acyl-CoA dehydrogenase, two regulatory β-oxidation dehydrogenases, followed a similar pattern. FA content was lower in young and higher in elder Acro than in wild-type, suggesting an increased utilisation in young animals. GH regulated expression of key proteins of FA metabolism through changes in peroxisome proliferator-activated receptor α (PPARα) expression, which varied accordingly. GH effect was confirmed by treatment of Acro mice with a receptor antagonist, which abolished changes in key proteins of FA metabolism in young Acro. GH increased phosphorylation of AMP-activated protein kinase and anti-acetyl-CoA-carboxylase, two regulatory kinases, leading to lower CPT-1 inhibition by malonyl-CoA, and intervened in regulating PPARα expression through the ERK 1/2 pathway. In conclusion, chronic GH excess increased FA metabolism in the young age, whereas its action was overwhelmed in elder ages likely by GH-independent mechanisms, leading to reduced expression of key enzyme of FA metabolism.

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