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Identificación de un ligando endógeno fisiológicamente relevante para PPARalpha en el hígado
Manu V Chakravarthy1, Irfan J Lodhi, Li Yin
1Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, Campus Box 8127, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
Cell
|August 4, 2009
Resumen
La síntesis de ácidos grasos (FAS) ayuda a crear un fosfolípido, 1-palmitoyl-2-oleoyl-sn-glycerol-3-fosfocolina (16:0/18:1-GPC), que actúa como un ligando endógeno para el receptor nuclear PPARalpha, lo que afecta el metabolismo de los lípidos.
Área de la Ciencia:
- La bioquímica es la bioquímica.
- Biología Molecular Biología Molecular
- Enfermedades Metabólicas Las enfermedades metabólicas.
Sus antecedentes:
- El receptor nuclear PPARalpha es un objetivo farmacológico para los trastornos del metabolismo lipídico.
- El ligando endógeno para PPARalpha sigue sin ser identificado.
- La inactivación de la síntesis de ácidos grasos (FAS) deteriora la expresión génica dependiente de PPARalpha, lo que sugiere su papel en la generación de ligandos.
Objetivo del estudio:
- Para identificar el ligando endógeno de PPARalpha.
- Para investigar el papel de la sintasa de ácidos grasos (FAS) en la producción de ligandos PPARalpha.
- Para caracterizar la interacción del ligando identificado con PPARalpha y su efecto sobre la expresión génica y la esteatosis hepática.
Principales métodos:
- Aislamiento y análisis de fosfolípidos unidos a PPARalpha de hígado de ratón.
- Espectrometría de masas para la identificación de las especies de fosfolípidos enlazados.
- Análisis de la expresión génica después de la eliminación de las enzimas de síntesis de fosfatidilcolina (Cept1).
- Ensayos de unión in vitro con el PPARalpha, el PPARdelta y el PPARgamma.
- Estudios in vivo que incluyen infusión en vena portal del ligando identificado.
Principales resultados:
- Un fosfolípido, 1-palmitoyl-2-oleoyl-sn-glycerol-3-fosfocolina (16:0/18:1-GPC), fue identificado como unido a PPARalpha en el hígado de ratón.
- La actividad de FAS se correlacionó con la presencia de 16:0/18:1-GPC unido a PPARalpha.
- Knockdown de Cept1, una enzima de síntesis de fosfatidilcolina, redujo la expresión génica dependiente de PPARalpha.
- 16:0/18:1-GPC demostró potentes interacciones con PPARalpha, comparables con los agonistas conocidos.
- La infusión de 16:0/18:1-GPC activó la expresión génica PPARalpha-dependiente y redujo la esteatosis hepática in vivo.
Conclusiones:
- 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC) es un ligando endógeno fisiológicamente relevante para el PPARalpha.
- La síntesis de ácidos grasos sintasa (FAS) y fosfatidilcolina son cruciales para generar este ligando PPARalpha.
- Este descubrimiento ofrece nuevos conocimientos sobre la regulación del metabolismo lipídico y posibles estrategias terapéuticas dirigidas a PPARalpha.
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