Referencia

Garcia-Macia M*, Santos-Ledo A, Leslie J, Paish HL, Collins AL, Scott RS, Watson A, Burgoyne RA, White S, French J, Hammond J, Borthwick LA, Mann J, Bolaños JP, Korolchuk VI, Oakley F, Mann DA*. Hepatology. 2021 Jul 7. doi: 10.1002/hep.32048. Online ahead of print. PMID: 34233024

Autores

Marina Garcia-Macia*, Adrián Santos-Ledo, Jack Leslie, Hannah L. Paish, Amy L. Collins, Rebecca S. Scott, Abigail Watson, Rachel A. Burgoyne, Steve White, Jeremy French, John Hammond, Lee A. Borthwick, Jelena Mann, Juan P. Bolaños, Viktor I. Korolchuk, Fiona Oakley, Derek A. Mann*.

Resumen

Background and Aims: NAFLD is the most common hepatic pathology in western countries and no treatment is currently available. NAFLD is characterized by the aberrant hepatocellular accumulation of fatty acids in the form of lipid droplets (LDs). Recently, it was shown that liver LD degradation occurs through a process termed lipophagy, a form of autophagy. However, the molecular mechanisms governing liver lipophagy are elusive. Here, we aimed to ascertain the key molecular players that regulate hepatic lipophagy and their importance in NAFLD.
Approach and Results: We analyzed the formation and degradation of LD in vitro (fibroblasts and primary mouse hepatocytes), in vivo and ex vivo (mouse and human liver slices) and focused on the role of the autophagy master regulator mammalian target of rapamycin complex (mTORC) 1 and the LD coating protein perilipin (Plin) 3 in these processes. We show that the autophagy machinery is recruited to the LD on hepatic overload of oleic acid in all experimental settings. This led to activation of lipophagy, a process that was abolished by Plin3 knockdown using RNA interference. Furthermore, Plin3 directly interacted with the autophagy proteins focal adhesion interaction protein 200 KDa and autophagy-related 16L, suggesting that Plin3 functions as a docking protein or is involved in autophagosome formation to activate lipophagy. Finally, we show that mTORC1 phosphorylated Plin3 to promote LD degradation.
Conclusions: These results reveal that mTORC1 regulates liver lipophagy through a mechanism dependent on Plin3 phosphorylation. We propose that stimulating this pathway can enhance lipophagy in hepatocytes to help protect the liver from lipid-mediated toxicity, thus offering a therapeutic strategy in NAFLD.

Descripción

5. Descripción (en Español: 5 líneas aprox.)
La acumulación aberrante de gotas lipídicas puede causar enfermedades como el hígado graso, que es la patología hepática mas frecuente en los países occidentales. Las gotas lipídicas se caracterizan por un núcleo lipídico rodeado por una membrana decorado con proteínas, de las cuales las perilipinas (Plins) son específicas de este orgánulo. En este trabajo abordamos la degradación de las gotas lipídicas mediante autofagia, el proceso denominado lipofagia. Hemos descubierto como mTOR fosforila a la Plin3 que induce la activación de lipofagia. El estímulo de este mecanismo podría suponer una estrategia terapéutica para la enfermedad de hígado graso.

Marina García Macia2

REFERENCIA DEL GRUPO INVESTIGADOR

Dr. Garcia-Macia es contratada posdoctoral Sara Borrell (ISCIII) e investigadora del CIBERFES. Licenciada y Doctora en Biología por la Universidad de Oviedo. Tras un postdoc en el Albert Einstein College of Medicine (NY, USA) y otro en la Universidad de Newcastle (UK). En 2019 se incorporó al grupo de Juan Pedro Bolaños, en Salamanca, para continuar su carrera investigadora dirigiendo su línea de investigación en la Enfermedad de Batten. Forma parte de diferentes redes científicas, entre la que cabe destacar Women In Autophagy (WIA), SEBBM y SEFAGIA. Su trayectoria científica ha estado siempre ligada al estudio de la autofagia. En su estudio del reciclaje celular ha utilizado diferentes modelos desde la carne de ternera al ratón, pasando por el pez cebra, hámster, cultivos celulares, para entender desde el envejecimiento a la obesidad, incluyendo enfermedades neurodegenerativas o hepáticas.

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