TY - JOUR
T1 - Proteomics for the discovery of nuclear bile acid receptor FXR targets
AU - Gardmo, Cissi
AU - Tamburro, Antonio
AU - Modica, Salvatore
AU - Moschetta, Antonio
N1 - Funding Information:
We thank S. Murzilli for her precious help during the study; Dr. D. J. Mangelsdorf (Southwestern Medical Center at Dallas, Texas) for providing us with FXR null mice; Dr. L. Adorini (Intercept Italia, Perugia, Italy) for providing us with INT747 compound. A. Moschetta is funded by the Italian Association for Cancer Research (AIRC, IG 10416 ), Italian Ministry of University ( FIRB IDEAS RBID08C9N7 ), Italian Ministry of Health (Young Researchers Grant GR-2008-1143546 ), European Community's Seventh Framework Programme FP7/2007-2013 under grant agreement no. 202272 (LipidomicNet), Telethon ( GPP08259 ), Cariplo (Milan) and Natural Pharma International (NPI Biotech) and University of Bari (Italy).
PY - 2011/8
Y1 - 2011/8
N2 - Nuclear receptors (NRs) are important pharmacological targets for a number of diseases, including cancer and metabolic disorders. To unmask the direct role of NR function it is fundamental to find the NR targets. During the last few years several NRs have been shown to affect microRNA expression, thereby modulating protein levels. The farnesoid X receptor (FXR), the main regulator of bile acid (BA) homeostasis, also regulates cholesterol, lipid and glucose metabolism. Here we used, for the first time, a proteomics approach on mice treated with a FXR ligand to find novel hepatic FXR targets. Nineteen spots with a more than two-fold difference in protein amounts were found by 2D-DIGE and 20 proteins were identified by MALDI-TOF MS as putative novel FXR targets. The most striking feature of the protein list was the great number of mitochondrial proteins, indicating a substantial impact of FXR activation on mitochondrial function in the liver. To examine if the differences found in the proteomics assay reflected differences at the mRNA level, a microarray assay was generated on hepatic samples from wild type and FXR-/- mice treated with a FXR ligand and compared to vehicle treatment. At least six proteins were shown to be regulated only at a post-transcriptional level. In conclusion, our study provides the impetus to include proteomic analysis for the identification of novel targets of transcription factors, such as NRs. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.
AB - Nuclear receptors (NRs) are important pharmacological targets for a number of diseases, including cancer and metabolic disorders. To unmask the direct role of NR function it is fundamental to find the NR targets. During the last few years several NRs have been shown to affect microRNA expression, thereby modulating protein levels. The farnesoid X receptor (FXR), the main regulator of bile acid (BA) homeostasis, also regulates cholesterol, lipid and glucose metabolism. Here we used, for the first time, a proteomics approach on mice treated with a FXR ligand to find novel hepatic FXR targets. Nineteen spots with a more than two-fold difference in protein amounts were found by 2D-DIGE and 20 proteins were identified by MALDI-TOF MS as putative novel FXR targets. The most striking feature of the protein list was the great number of mitochondrial proteins, indicating a substantial impact of FXR activation on mitochondrial function in the liver. To examine if the differences found in the proteomics assay reflected differences at the mRNA level, a microarray assay was generated on hepatic samples from wild type and FXR-/- mice treated with a FXR ligand and compared to vehicle treatment. At least six proteins were shown to be regulated only at a post-transcriptional level. In conclusion, our study provides the impetus to include proteomic analysis for the identification of novel targets of transcription factors, such as NRs. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.
KW - Expression profiling
KW - FXR
KW - Mitochondrial
KW - Nuclear receptor
KW - Post-transcriptional modification
KW - Proteomic analysis
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U2 - 10.1016/j.bbadis.2011.03.009
DO - 10.1016/j.bbadis.2011.03.009
M3 - Article
C2 - 21439373
AN - SCOPUS:79958260884
SN - 0925-4439
VL - 1812
SP - 836
EP - 841
JO - Biochimica et Biophysica Acta - Molecular Basis of Disease
JF - Biochimica et Biophysica Acta - Molecular Basis of Disease
IS - 8
ER -