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El complejo mTOR 1 regula la localización del lipin 1 para controlar la vía SREBP
Timothy R Peterson1, Shomit S Sengupta, Thurl E Harris
1Whitehead Institute for Biomedical Research, Koch Center for Integrative Cancer Research at MIT, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
Cell
|August 6, 2011
Resumen
El complejo mTOR 1 (mTORC1) de la nutriente quinasa controla el crecimiento mediante la regulación de la entrada nuclear de la lipina 1. Este mecanismo afecta la actividad de SREBP, influyendo en la transcripción génica y la resistencia a la enfermedad metabólica en ratones.
Área de la Ciencia:
- Biología celular Biología celular.
- El metabolismo es el metabolismo.
- Biología Molecular Biología Molecular
Sus antecedentes:
- El objetivo mecánico del complejo de rapamicina 1 (mTORC1) es un regulador clave del crecimiento celular y el metabolismo.
- Las proteínas de unión de los elementos reguladores de esteroles (SREBPs) son factores de transcripción cruciales para la síntesis de lípidos y colesterol.
- Los mecanismos precisos por los cuales mTORC1 influye en la actividad de SREBP siguen siendo incompletamente entendidos.
Objetivo del estudio:
- Para dilucidar el mecanismo molecular que vincula la señalización mTORC1 a la función SREBP.
- Investigar el papel de la lipina 1 en la mediación de la regulación dependiente del mTORC1 de la lipogénesis y la esterogénesis.
- Para determinar la relevancia in vivo de la vía mTORC1-lipina 1-SREBP en los trastornos metabólicos inducidos por la dieta.
Principales métodos:
- Utilizó ensayos bioquímicos para evaluar las interacciones de proteínas y la actividad enzimática.
- Se emplearon ensayos basados en células para monitorear la expresión génica objetivo de SREBP y la actividad del promotor.
- Estudios in vivo realizados con modelos de ratón con inhibición específica del hígado de mTORC1 y dietas altas en grasas y colesterol.
Principales resultados:
- Se demostró que mTORC1 controla la translocación nuclear de la lipina 1, una fosfatasa del ácido fosfatídico.
- Se demostró que la lipina nuclear 1 desfosforilada es esencial para mediar los efectos de mTORC1 en la actividad de SREBP y la expresión génica diana.
- Se encontró que la inhibición del mTORC1 hepático confiere resistencia a la esteatosis hepática inducida por la dieta y la hipercolesterolemia, dependiente de la lipina 1.
Conclusiones:
- Lipin 1 establecido como un mediador crítico en el eje de señalización mTORC1-SREBP.
- Identificó la entrada nuclear del lipin 1 como una etapa reguladora clave controlada por mTORC1.1.
- Destacó el potencial terapéutico de dirigirse a la vía mTORC1-lipina 1 para enfermedades metabólicas.
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