Peroxisomal β-oxidation acts as a sensor for intracellular fatty acids and regulates lipolysis - Archive ouverte HAL Access content directly
Journal Articles Nature Metabolism Year : 2021

Peroxisomal β-oxidation acts as a sensor for intracellular fatty acids and regulates lipolysis

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Abstract

To liberate fatty acids (FA) from intracellular stores, lipolysis is driven by the activity of the lipases ATGL, HSL and MGL. Excessive FA release as a result of uncontrolled lipolysis causes lipotoxicity, which can cause metabolic disorders. However, whether cells can sense FA directly to regulate their levels to maintain cellular homeostasis is unknown. Here we report a sensing mechanism for cellular FA content, based on peroxisomal degradation of FA and coupled 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 NAFLD 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 β-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.
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Origin : Publication funded by an institution

Dates and versions

inserm-03507759 , version 1 (03-01-2022)

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Lianggong Ding, Wenfei Sun, Miroslav Balaz, Anyuan He, Manuel Klug, et al.. Peroxisomal β-oxidation acts as a sensor for intracellular fatty acids and regulates lipolysis. Nature Metabolism, 2021, 3 (12), pp.1648-1661. ⟨10.1038/s42255-021-00489-2⟩. ⟨inserm-03507759⟩
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