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Title: Analysis of PGC-1{alpha} variants Gly482Ser and Thr612Met concerning their PPAR{gamma}2-coactivation function

Abstract

Peroxisome proliferator-activated receptor-{gamma} coactivator-1{alpha} (PGC-1{alpha}) is a cofactor involved in adaptive thermogenesis, fatty acid oxidation, and gluconeogenesis. Dysfunctions of this protein are likely to contribute to the development of obesity and the metabolic syndrome. This is in part but not definitely confirmed by results of population studies. The aim of this study was to investigate if common genetic variants rs8192678 (Gly482Ser) and rs3736265 (Thr612Met) in the PGC-1{alpha} gene lead to a functional consequence in cofactor activity using peroxisome proliferator-activated receptor-{gamma} 2 (PPAR{gamma}2) as interacting transcription factor. Reporter gene assays in HepG2 cells with wildtype and mutant proteins of both PGC1{alpha} and PPAR{gamma}2 (Pro12Ala, rs1801282) using the acyl-CoA-binding protein (ACBP) promoter showed no difference in coactivator activity. This is First study implicating that the Gly482Ser and Thr612Met polymorphisms in PGC-1{alpha} and Pro12Ala polymorphism in PPAR{gamma}2 do not affect the functional integrity of these proteins.

Authors:
 [1];  [2];  [2];  [2]
  1. Molecular Nutrition, Christian-Albrechts-University of Kiel, Kiel (Germany). E-mail: initz@molnut.uni-kiel.de
  2. Molecular Nutrition, Christian-Albrechts-University of Kiel, Kiel (Germany)
Publication Date:
OSTI Identifier:
20979791
Resource Type:
Journal Article
Resource Relation:
Journal Name: Biochemical and Biophysical Research Communications; Journal Volume: 353; Journal Issue: 2; Other Information: DOI: 10.1016/j.bbrc.2006.12.042; PII: S0006-291X(06)02704-5; Copyright (c) 2006 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved; Country of input: International Atomic Energy Agency (IAEA)
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; CARBOXYLIC ACIDS; GENES; METABOLIC DISEASES; MUTAGENESIS; MUTANTS; OXIDATION; RECEPTORS; TRANSCRIPTION FACTORS

Citation Formats

Nitz, Inke, Ewert, Agnes, Klapper, Maja, and Doering, Frank. Analysis of PGC-1{alpha} variants Gly482Ser and Thr612Met concerning their PPAR{gamma}2-coactivation function. United States: N. p., 2007. Web. doi:10.1016/j.bbrc.2006.12.042.
Nitz, Inke, Ewert, Agnes, Klapper, Maja, & Doering, Frank. Analysis of PGC-1{alpha} variants Gly482Ser and Thr612Met concerning their PPAR{gamma}2-coactivation function. United States. doi:10.1016/j.bbrc.2006.12.042.
Nitz, Inke, Ewert, Agnes, Klapper, Maja, and Doering, Frank. Fri . "Analysis of PGC-1{alpha} variants Gly482Ser and Thr612Met concerning their PPAR{gamma}2-coactivation function". United States. doi:10.1016/j.bbrc.2006.12.042.
@article{osti_20979791,
title = {Analysis of PGC-1{alpha} variants Gly482Ser and Thr612Met concerning their PPAR{gamma}2-coactivation function},
author = {Nitz, Inke and Ewert, Agnes and Klapper, Maja and Doering, Frank},
abstractNote = {Peroxisome proliferator-activated receptor-{gamma} coactivator-1{alpha} (PGC-1{alpha}) is a cofactor involved in adaptive thermogenesis, fatty acid oxidation, and gluconeogenesis. Dysfunctions of this protein are likely to contribute to the development of obesity and the metabolic syndrome. This is in part but not definitely confirmed by results of population studies. The aim of this study was to investigate if common genetic variants rs8192678 (Gly482Ser) and rs3736265 (Thr612Met) in the PGC-1{alpha} gene lead to a functional consequence in cofactor activity using peroxisome proliferator-activated receptor-{gamma} 2 (PPAR{gamma}2) as interacting transcription factor. Reporter gene assays in HepG2 cells with wildtype and mutant proteins of both PGC1{alpha} and PPAR{gamma}2 (Pro12Ala, rs1801282) using the acyl-CoA-binding protein (ACBP) promoter showed no difference in coactivator activity. This is First study implicating that the Gly482Ser and Thr612Met polymorphisms in PGC-1{alpha} and Pro12Ala polymorphism in PPAR{gamma}2 do not affect the functional integrity of these proteins.},
doi = {10.1016/j.bbrc.2006.12.042},
journal = {Biochemical and Biophysical Research Communications},
number = 2,
volume = 353,
place = {United States},
year = {Fri Feb 09 00:00:00 EST 2007},
month = {Fri Feb 09 00:00:00 EST 2007}
}
  • The structural mechanism of allosteric communication between retinoid X receptor (RXR) and its heterodimer partners remains controversial. As a first step towards addressing this question, we report a nuclear magnetic resonance (NMR) study on the GW1929-bound peroxisome proliferator-activated receptor gamma (PPAR{gamma}) ligand-binding domain (LBD) with and without the 9-cis-retinoic acid (9cRA)-bound RXR{alpha} LBD. Sequence-specific {sup 13}C{sup {alpha}}, {sup 13}C{sup {beta}}, and {sup 13}CO resonance assignments have been established for over 95% of the 275 residues in the PPAR{gamma} LBD monomer. The {sup 1}HN, {sup 15}N, and {sup 13}CO chemical shift perturbations induced by the RXR{alpha} LBD binding are located atmore » not only the heterodimer interface that includes the C-terminal residue Y477 but also residues Y473 and K474 in the activation function-2 (AF-2) helix. This result suggests that 9cRA-bound RXR{alpha} can affect the PPAR{gamma} AF-2 helix in solution and demonstrates that NMR is a powerful new tool for studying the mechanism of allosteric ligand activation in RXR heterodimers.« less
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