Etude des cofacteurs de récepteurs nucléaires impliqués dans la régulation du métabolisme lipidique

Les organismes répondent aux modifications de la quantité et de la composition des aliments qu'ils absorbent en modifiant l'expression de leur information génétique. Les récepteurs nucléaires impliqués dans le métabolisme lipidique sont des molécules clés qui permettent l'intégration de ces stimuli. Ils sont le plus souvent activés par des dérivés du cholestérol et des acides gras ainsi que par des acides biliaires. Les produits du métabolisme eux-mêmes sont ainsi capables de contrôler leur propre synthèse et leur devenir. Afin de moduler l'expression génique, les récepteurs nucléaires interagissent le plus souvent avec des cofacteurs qui remanient la structure de la chromatine par des modifications enzymatiques et/ou jouent le rôle de pont entre le récepteur et la machinerie transcriptionnelle de base. Ces cofacteurs peuvent activer (coactivateurs) ou réprimer (corépresseurs) la transcription. Un cofacteur donné peut interagir avec de multiples récepteurs nucléaires et un récepteur avec de multiples cofacteurs ; la détermination des conséquences physiologiques de ce partage est donc un des prochains enjeux de l'étude des cofacteurs. Ce travail de recherche a porté sur l'étude de deux cofacteurs de récepteurs nucléaires impliqués dans la régulation du métabolisme lipidique, le coactivateur MBF-1 et le corépresseur SHP. Tous deux sont capables d'interagir avec les récepteurs LRH-1, LXR et PPAR. La nature de l'interaction établie avec ces cofacteurs, l'effet de ces corégulateurs sur l'activité transcriptionnelle des récepteurs et leur mécanisme fonctionnel ont été analysés. Le MBF-1 permettrait le recrutement du complexe TFIID alors que le SHP interagirait avec l'ARN polymérase II. Ces nouvelles données s'avéreront sans doute très précieuses à l'avenir dans l'élaboration de thérapies innovantes pour le traitement de pathologies telles que l'athérosclérose, l'obésité, les dyslipidémies et le diabète non insulino-dépendant.Nuclear receptors implicated in the regulation of lipid metabolism establish a link between nutrition and gene expression. They are activated by cholesterol and fatty acids derivatives, as well as by bile acids. They interact with cofactors which can either activate (coactivators) or repress (corepressors) transcription. One cofactor can interact with several receptors and one receptor can interact with many cofactors. Two cofactors of nuclear receptors implicated in lipid metabolism have been studied, i.e. MBF-1, a coactivator, and SHP, a corepressor. Both of them are able to interact with receptors like LRH-1, LXR and PPAR. The type of interaction created between these cofactors and receptors, the influence of these coregulators on the transcriptional activity of the receptors, and their exact function have been assessed. MBF-1 might recrut the TFIID complex whereas SHP seems to interact with the RNA polymerase II. These new data should be helpful in the future for the elaboration of innovative therapies for treatment of pathologies such as atherosclerosis, obesity, dyslipidemia and non insulino-dependent diabetes.STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Multiprotein bridging factor-1 (MBF-1) is a cofactor for nuclear receptors that regulate lipid metabolism

Multiprotein bridging factor (MBF-1) is a cofactor that was first described for its capacity to modulate the activity of fushi tarazu factor 1, a nuclear receptor originally implicated in Drosophila development. Recently, it has been shown that human MBF-1 stimulates the transcriptional activity of steroidogenic factor 1, a human homolog of fushi tarazu factor 1, which is implicated in steroidogenesis. Here we show that this cofactor enhances the transcriptional activity of several nonsteroid nuclear receptors that are implicated in lipid metabolism, i.e. the liver receptor homolog 1, the liver X receptor alpha, and PPARgamma. MBF-1 interacts with distinct domains in these receptors, depending on whether the receptor binds DNA as a monomer or as a heterodimer with RXR. MBF-1 does not possess any of the classical histone modifying activities such as histone acetyl- or methyl transferase activities, linked to chromatin remodeling, but interacts in vitro with the transcription factor IID complex. MBF-1 seems therefore to act as a bridging factor enabling interactions of nuclear receptors with the transcription machinery

Sterols and gene expression: control of affluence

International audienceIntracellular and extracellular cholesterol levels are tightly maintained within a narrow concentration range by an intricate transcriptional control mechanism. Excess cholesterol can be converted into oxysterols, signaling molecules, which modulate the activity of a number of transcription factors, as to limit accumulation of excess of cholesterol. Two key regulatory pathways are affected by oxysterols. The first pathway involves the uptake and de novo synthesis of cholesterol and is controlled by the family of sterol response element binding proteins, whose activity is regulated by a sterol-dependent feedback mechanism. The second pathway, which only recently has become a topic of interest, involves the activation by a feedforward mechanism of cholesterol utilization for either bile acid or steroid hormone synthesis by oxysterol-activated nuclear receptors, such as liver X receptor and steroidogenic factor-1. Furthermore, biosynthesis and enterohepatic reabsorption of bile acids are regulated by the farnesol X receptor, a receptor activated by bile acids. Both the feedback inhibition of cholesterol uptake and production and the stimulation of cholesterol utilization will ultimately result in a lowering of the intracellular cholesterol concentration and allow for a fine-tuned regulation of the cholesterol concentration

Sterols and gene expression: control of affluence

Intracellular and extracellular cholesterol levels are tightly maintained within a narrow concentration range by an intricate transcriptional control mechanism. Excess cholesterol can be converted into oxysterols, signaling molecules, which modulate the activity of a number of transcription factors, as to limit accumulation of excess of cholesterol. Two key regulatory pathways are affected by oxysterols. The first pathway involves the uptake and de novo synthesis of cholesterol and is controlled by the family of sterol response element binding proteins, whose activity is regulated by a sterol-dependent feedback mechanism. The second pathway, which only recently has become a topic of interest, involves the activation by a feedforward mechanism of cholesterol utilization for either bile acid or steroid hormone synthesis by oxysterol-activated nuclear receptors, such as liver X receptor and steroidogenic factor-1. Furthermore, biosynthesis and enterohepatic reabsorption of bile acids are regulated by the farnesol X receptor, a receptor activated by bile acids. Both the feedback inhibition of cholesterol uptake and production and the stimulation of cholesterol utilization will ultimately result in a lowering of the intracellular cholesterol concentration and allow for a fine-tuned regulation of the cholesterol concentratio

The small heterodimer partner interacts with the liver X receptor alpha and represses its transcriptional activity

The small heterodimer partner SHP (NR0B2) is an unusual nuclear receptor that lacks the typical DNA binding domain common to most nuclear receptors. SHP has been reported to act as a corepressor for several nuclear receptors, but its exact mechanism of action is still elusive. Here we show that SHP can interact with the liver X receptors LXRalpha (NR1H3) and LXRbeta (NR1H2), as demonstrated by glutathione-S-transferase pull-down assays, mammalian two-hybrid, and coimmunoprecipitation experiments. In transfection assays, SHP inhibits the expression of an artificial reporter driven by an LXR-response element and represses the transcriptional activation by LXR of the human ATP-binding cassette transporter 1 (ABCA1) promoter. Treatment of Caco-2 cells with bile acids, which activate farnesoid X receptor and subsequently induce SHP, leads to the repression of the human ABCG1 gene, an established LXR target gene. These results demonstrate that SHP is able to interact with LXR and to modulate its transcriptional activity