Abstract
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 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.
Highlights
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
acyl-CoA oxidase 1 (ACOX1) gain-of-function mutations result in a progressive glial degeneration, due to enhanced oxidative stress caused by excessive H2O2 production, which can be pharmacologically attenuated by treatment with the antioxidant N-acetyl cysteine amide (NACA)[8]
To investigate a possible functional crosstalk between both organelles, we studied the effect of PEX proteins, which are key mediators of peroxisomal function, on lipolysis by utilizing a small-scale screen in immortalized brown adipocytes (iBAs) (Extended Data Fig. 1c)
Summary
PEX2/10/12 modulate lipolysis by regulating ATGL protein. Peroxisomal β-oxidation accounts for a substantial part of the overall cellular FA degradation within a cell[3] and the physical interaction between LDs and peroxisomes has been shown to facilitate LD-derived FA trafficking into peroxisomes[16]. To investigate a possible functional crosstalk between both organelles, we studied the effect of PEX proteins, which are key mediators of peroxisomal function, on lipolysis by utilizing a small-scale screen in iBAs (Extended Data Fig. 1c). We observed that both Pex2/12 depletion increased glycerol levels and FA release (Fig. 1a,b), suggesting an elevated lipolytic activity. This functional crosstalk between peroxisomes and lipolysis from LDs was confirmed in both HepG2 and HEK293T cells (Fig. 1e–g and Extended Data Fig. 2g–p), suggesting that it constitutes a conserved regulatory mechanism. To uncover the mechanism by which peroxisomal function is linked to the control of lipolysis through modulation of ATGL protein levels, we first analysed whether the effect was due to a direct interaction of Articles a
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