PPAR-RXR

Nuclear receptors

Nuclear receptors (NR) are ligand-activated transcription factors that regulate numerous biological processes in metazoans. The human genome encodes 48 NRs (49 in mouse, 21 in Drosophila and >270 in Caenorabditis).

Nuclear receptors share a common structure and are organized in independent functional domains.

Nuclear Receptor Structure

The DNA binding domain (DBD) is the most conserved domain. The structure of the ligand binding domain (LBD), which defines a ligand binding pocket buried in a 3 layer “alpha-helical sandwich” is also well conserved among the nuclear receptors. The conformational changes induced upon ligand binding modifies the interactions with various proteins, including cofactors involved in chromatin remodeling, nucleosome modification and interactions with the basal transcription machinery.

Nuclear receptors regulate gene expression as monomers, homodimers or heterodimers, which contributes to define the type of DNA response element they can bind to in the promoters of their target genes. Traditionnally 4 classes of nuclear receptors have been defined:

Classes of Nuclear Receptors

  • Steroid hormone receptors (androgen receptor AR, estrogen receptors ER, glucocorticoid receptor GR, mineralocorticoid receptor MR and progesterone receptor PR) comprise the class I nuclear receptors. These receptors function as homodimers, are activated by low doses of steroid hormones, bind IR3-like response elements (inverted repeats separated by 3 nucleotides) and regulate numerous physiological processes, including reproduction, metabolism or immunity.

  • Class II is composed of the nuclear receptors that function as heterodimers with the RXR (Retinoïd X Receptors). They include the PPARs, LXRs, FXR, RAR, PXR, CAR, VDR and TR. They generally bind to DR-like response elements (direct repeats of the consensus motif AGGTCA separated by a variable number of nucleotides) but other types of response elements have also been described.

  • Class III members are the non-steroid hormone nuclear receptors that also function as homodimers such as RXRs, HNF4 or COUP-TF and typically bind DR-like motifs.

  • Nuclear receptors of Class IV function as monomers and bind a single consensus motif. This class includes NGFI_B, Nur1, SF-1, LRH-1 and RORs.

Note that some receptors might function as monomer or as dimers, such as rev-erb NRs.

During the first ~12 years of my career, I have mostly focused on better understanding the role played by the class II nuclear receptors PPARalpha annd RXR on the regulation of gene expression in the liver.

The liver plays central roles in the detoxification of xenobiotics, including drugs and toxicants, but also in energy metabolism, notably via its roles in lipid and lipoprotein metabolism. As such, it represents both a relevant drug target and a tissue which dysfunction can have broad, systemic consequences.

During my PhD, I studied the activation of the PPARalpha-RXR heterodimer through nutritional (dietary fatty acids; Martin et al., Hepatology, 2007), pharmacological (RXR and PPARalpha activating-drugs; Martin et al., Gene Expr, 2006) and physio-pathological cues (fasting; Déjean et al., 2010, Blavy et al., 2009) and the corresponding impacts on gene expression and lipid storage in the liver (hepatic steatosis). See my PhD manuscript for further details

Later, I shared my experience in the analysis of the transcriptome by qPCR and microarrays by developping a transcriptomic facility in my research department: the GeT-TRiX facility. With the development of the ToxAlim INRA unit, I went on to address research questions in molecular food toxicology.

Publications

(2018). Dual extraction of mRNA and lipids from a single biological sample. Sci Rep. 2018 May;8(1):7019..

Project PubMed

(2017). NO synthesis from arginine is favored by alpha-linolenic acid in mice fed a high-fat diet.. Amino Acids. 2016 Sep;48(9):2157-68..

Project PubMed

(2017). Dietary oleic acid regulates hepatic lipogenesis through a liver X receptor-dependent signaling.. PLoS One. 2017 Jul 21;12(7):e0181393..

Project PubMed

(2014). Essential fatty acids deficiency promotes lipogenic gene expression and hepatic steatosis through the liver X receptor.. J Hepatol. 2013 May;58(5):984-92..

Project PubMed

(2013). A systems biology approach to the hepatic role of the oxysterol receptor LXR in the regulation of lipogenesis highlights a cross-talk with PPARalpha.. Biochimie. 2013 Mar;95(3):556-67..

Project PubMed

(2012). A role for PPARalpha in the regulation of arginine metabolism and nitric oxide synthesis.. Amino Acids. 2011 Oct;41(4):969-79..

Project PubMed

(2012). Liver X Receptor: an oxysterol sensor and a major player in the control of lipogenesis.. Chem Phys Lipids. 2011 Sep;164(6):500-14..

Project PubMed

(2011). Consequences of PPAR(alpha) Invalidation on Glutathione Synthesis: Interactions with Dietary Fatty Acids.. PPAR Res. 2011;2011:256186..

Project PubMed

(2011). The Peroxisomal 3-keto-acyl-CoA thiolase B Gene Expression Is under the Dual Control of PPARalpha and HNF4alpha in the Liver.. PPAR Res. 2010;2010:352957..

Project PubMed

(2011). A minimal model for hepatic fatty acid balance during fasting: application to PPAR alpha-deficient mice.. J Theor Biol. 2009 Nov 21;261(2):266-78..

Project PubMed

(2010). Clustering time-series gene expression data using smoothing spline derivatives.. EURASIP J Bioinform Syst Biol. 2007:70561..

Project Project PubMed

(2009). Di-(2-ethylhexyl)-phthalate (DEHP) activates the constitutive androstane receptor (CAR): a novel signalling pathway sensitive to phthalates.. Biochem Pharmacol. 2009 Jun 1;77(11):1735-46..

Project Project PubMed

(2008). Transcriptional regulation of hepatic fatty acid metabolism.. Subcell Biochem. 2008;49:3-47..

Project PubMed

(2008). Increased entropy production in diaphragm muscle of PPAR alpha knockout mice.. J Theor Biol. 2008 Jan 7;250(1):92-102..

Project PubMed

(2007). PPARalpha transcriptionally induces AhR expression in Caco-2, but represses AhR pro-inflammatory effects.. Biochem Biophys Res Commun. 2007 Dec 28;364(4):896-901..

Project PubMed

(2007). Novel aspects of PPARalpha-mediated regulation of lipid and xenobiotic metabolism revealed through a nutrigenomic study.. Hepatology. 2007 Mar;45(3):767-77..

Project PubMed

(2006). Transcriptional modulations by RXR agonists are only partially subordinated to PPARalpha signaling and attest additional, organ-specific, molecular cross-talks.. Gene Expr. 2005;12(3):177-92..

Project PubMed

(2005). Phenylbutyrate up-regulates the adrenoleukodystrophy-related gene as a nonclassical peroxisome proliferator.. J Cell Biol. 2005 Apr 11;169(1):93-104..

Project PubMed

(2005). Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia.. J Clin Invest. 2005 Jan;115(1):177-86..

Project PubMed

(2004). Effects of peroxisome proliferator-activated receptor alpha activation on pathways contributing to cholesterol homeostasis in rat hepatocytes.. Biochim Biophys Acta. 2004 Jul 5;1683(1-3):49-58..

Project PubMed

(2004). Pharmacological induction of redundant genes for a therapy of X-ALD: phenylbutyrate and other compounds.. Adv Exp Med Biol. 2003;544:281-91..

Project PubMed

(2004). Tissue-specific expression of two peroxisomal 3-ketoacyl-CoA thiolase genes in wild and PPAR alpha-null mice and induction by fenofibrate.. Adv Exp Med Biol. 2003;544:55-6..

Project PubMed

(2004). Molecular cloning, gene structure and expression profile of two mouse peroxisomal 3-ketoacyl-CoA thiolase genes.. BMC Biochem. 2004 Mar 25;5:3..

Project PubMed

(2004). Comparative effect of fenofibrate on hepatic desaturases in wild-type and peroxisome proliferator-activated receptor alpha-deficient mice.. Lipids. 2002 Oct;37(10):981-9..

Project PubMed