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Garcia-Macia M, Santos-Ledo A, Leslie J, et al. A Mammalian Target of Rapamycin-Perilipin 3 (mTORC1-Plin3) Pathway is essential to Activate Lipophagy and Protects Against Hepatosteatosis. Hepatology. 2021;74(6):3441-3459doi: 10.1002/hep.32048.
Garcia-Macia, M., Santos-Ledo, A., Leslie, J., Paish, H. L., Collins, A. L., Scott, R. S., Watson, A., Burgoyne, R. A., White, S., French, J., Hammond, J., Borthwick, L. A., Mann, J., Bolaños, J. P., Korolchuk, V. I., Oakley, F., & Mann, D. A. (2021). A Mammalian Target of Rapamycin-Perilipin 3 (mTORC1-Plin3) Pathway is essential to Activate Lipophagy and Protects Against Hepatosteatosis. Hepatology (Baltimore, Md.), 74(6), 3441-3459. https://doi.org/10.1002/hep.32048
Garcia-Macia, Marina, et al. "A Mammalian Target of Rapamycin-Perilipin 3 (mTORC1-Plin3) Pathway is essential to Activate Lipophagy and Protects Against Hepatosteatosis." Hepatology (Baltimore, Md.) vol. 74,6 (2021): 3441-3459. doi: https://doi.org/10.1002/hep.32048
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. A Mammalian Target of Rapamycin-Perilipin 3 (mTORC1-Plin3) Pathway is essential to Activate Lipophagy and Protects Against Hepatosteatosis. Hepatology. 2021 Dec;74(6):3441-3459. doi: 10.1002/hep.32048. Epub 2021 Sep 21. PMID: 34233024.
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Hepatology. 2021 Dec;74(6):3441-3459. doi: 10.1002/hep.32048. Epub 2021 Sep 21.

A Mammalian Target of Rapamycin-Perilipin 3 (mTORC1-Plin3) Pathway is essential to Activate Lipophagy and Protects Against Hepatosteatosis.

Hepatology (Baltimore, Md.)

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

Affiliations

  1. Newcastle Fibrosis Research Group, Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.
  2. Institute of Biomedical Research of Salamanca, University Hospital of Salamanca, Salamanca, Spain.
  3. Institute of Functional Biology and Genomics, University of Salamanca, CSIC, Salamanca, Spain.
  4. Centro de Investigación Biomédica en Red sobre Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain.
  5. E.U.E Dacio Crespo (Universidad de Valladolid), Palencia, Spain.
  6. FibroFind Ltd, William Leech Building, Medical School, Newcastle University, Newcastle upon Tyne, United Kingdom.
  7. Department of Hepatobiliary Surgery, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
  8. Biosciences Institute, Newcastle University, Newcastle upon Tyne, United Kingdom.

PMID: 34233024 DOI: 10.1002/hep.32048

Abstract

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.

© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

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