Unraveling the metabolic significance of the nuclear receptor co-activator rap250 (la relevancia metabólica del co-activador de receptores nucleares rap250)
- Autores: Sónia Rosa Pereira Da Veiga
- Directores de la Tesis: Antonio Zorzano Olarte (dir. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2011
- Idioma: español
- Tribunal Calificador de la Tesis: Diego Haro Bautista (presid.), Marc Claret Carles (secret.), Julián Aragonés López (voc.)
- Materias:
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- Resumen
The Nuclear coactivator RAP250 is believed to interact with a great number of transcription factors, including those belonging to the Nuclear Receptor family. These are responsible for sensing a variety of small molecules such as endocrine hormones, faty acids, cholesterol derivates and products of lipid metabolism, which act as ligands. In general, NRs are involved in growth and development, maintenance of cellular homeostasis, energy metabolism, inflammation, obesity and insulin resistance.
The increase prevalence of obesity and associated metabolic syndrome has driven intense interest in nuclear receptors (and their modulators) that can favorable alter body composition, lipid profiles and insulin sensitivity. However the interaction of these molecules and the side effects of their pharmacologic activation are complex and require additional explanation before long term treatments are implemented.
The biological role of RAP250 as an essential, non-redundant coactivator are evident from the studies involving RAP250 Knockout mice.
The main aim of these project was to evaluate the role of RAP250 in mice metabolism.
To that end, we have studied the impact of RAP250 loss of function in a heterozygous knockout mice model.
We found that the the RAP250 heterozygous male mice are leaner, with lower adiposity index, and have slightly enhanced food intake. Both can coincide due to an higher energy expenditure. They are more glucose tolerant and insulin sensitive. Overall glucose oxidation was increased, specially in both brown and white adipose tissues. RAP250 seems to have a role in modulating hepatic gluconeogenesis and adipose tissue glucose oxidation, such, may deeply impact on mice glucose homeostasis and energy usage.
RAP250 plays a relevant role in the establishment of the adipogenic lineage, and confers pre-adipocytes maximum capacity to conduct adipogenesis. Our data supports the concept that RAP250 is important to achieving PPAR¿'s full activity. The lack of RAP250 protects mice against diet-induced hepatic steatosis, probably through lowering PPAR¿'s activity.
RAP250 impacts on cholesterol levels by controlling De novo cholesterol synthesis (through modulation of SREBP2) and secretion in the form bile acids (through SHP, independently of FXR or not). RAP250 controls SHP gene expression (through FXR or not), and may be responsible for the hepatic regulation of Sirt1, in a cascade that involves the microRNA mir34.
Female's show a milder phenotype upon lack of RAP250, comparing to males. There must be a sex-related role for RAP250, and that impacts on the metabolic profile of mice, and how relevant RAP250 may be.
Overall, our data suggests that RAP250 has an energy saving and fat storage role.
RAP250 es un coactivador de Receptores Nucleares y se ha implicado en diversos procesos celulares. Esta tesis tenía como objetivo definir su relevancia en el contexto metabólico. Para tal utilizamos un modelo heterocigoto knock-out murinico. El modelo animal revelo varias características asociadas a su genotipo. Los machos heterocigotos para RAP250 son más delgados, con un índice de adiposidad bajo, y presentan un ligero aumento en la ingesta de comida. Estas características se deben a un aumentado consumo energético. RAP250 parece modular la oxidación de glucosa por parte de tejidos adiposo, sensibilidad a la insulina. RAP250 es importante en el proceso adipogenico y en la homeostasis lipida y de colesterol. En general, RAP250 parece tener un papel relacionado con el genero, en el sentido de ahorrar energía y promover su deposición en forma de grasa.
