Journal
NATURE METABOLISM
Volume 3, Issue 12, Pages 1648-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42255-021-00489-2
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Funding
- European Molecular Biology Organization long-term postdoctoral fellowship [ALTF 50-2017]
- Agence Nationale pour la Recherche [ANR-16-RHUS-0006-PreciNASH, ANR-10-LABX-46]
- ERC [694717]
- Swiss SNF
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The study elucidates a cellular mechanism for sensing cellular fatty acid levels and adjusting lipolysis as needed, involving peroxisomal degradation of fatty acids, production of reactive oxygen species, and post-translational regulation of adipose triglyceride lipase.
To liberate fatty acids (FAs) from intracellular stores, lipolysis is regulated by the activity of the lipases adipose triglyceride lipase (ATGL), hormone-sensitive lipase and monoacylglycerol lipase. Excessive FA release as a result of uncontrolled lipolysis results in lipotoxicity, which can in turn promote the progression of metabolic disorders. However, whether cells can directly sense FAs to maintain cellular lipid homeostasis is unknown. Here we report a sensing mechanism for cellular FAs based on peroxisomal degradation of FAs and coupled with reactive oxygen species (ROS) production, which in turn regulates FA release by modulating lipolysis. Changes in ROS levels are sensed by PEX2, which modulates ATGL levels through post-translational ubiquitination. We demonstrate the importance of this pathway for non-alcoholic fatty liver disease progression using genetic and pharmacological approaches to alter ROS levels in vivo, which can be utilized to increase hepatic ATGL levels and ameliorate hepatic steatosis. The discovery of this peroxisomal beta-oxidation-mediated feedback mechanism, which is conserved in multiple organs, couples the functions of peroxisomes and lipid droplets and might serve as a new way to manipulate lipolysis to treat metabolic disorders. Ding et al. report a mechanism that allows cells to sense cellular fatty acid levels and adjust lipolysis as needed, which involves peroxisomal degradation of fatty acids, production of reactive oxygen species and post-translational regulation of adipose triglyceride lipase.
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