Spatiotemporal contact between peroxisomes and lipid droplets regulates fasting-induced lipolysis via PEX5

Abstract

Lipid droplets (LDs) are key subcellular organelles for regulating lipid metabolism. Although several subcellular organelles participate in lipid metabolism, it remains elusive whether physical contacts between subcellular organelles and LDs might be involved in lipolysis upon nutritional deprivation. Here, we demonstrate that peroxisomes and peroxisomal protein PEX5 mediate fasting-induced lipolysis by stimulating adipose triglyceride lipase (ATGL) translocation onto LDs. During fasting, physical contacts between peroxisomes and LDs are increased by KIFC3-dependent movement of peroxisomes toward LDs, which facilitates spatial translocations of ATGL onto LDs. In addition, PEX5 could escort ATGL to contact points between peroxisomes and LDs in the presence of fasting cues. Moreover, in adipocytespecific PEX5-knockout mice, the recruitment of ATGL onto LDs was defective and fastinginduced lipolysis is attenuated. Collectively, these data suggest that physical contacts between peroxisomes and LDs are required for spatiotemporal translocation of ATGL, which is escorted by PEX5 upon fasting, to maintain energy homeostasis.

Peroxisomal Membrane Contact Sites in Mammalian Cells

“…These results suggest that the two organelles need to cooperate to maintain cellular homeostasis. Two recent studies find that they communicate through the peroxisome-lipid droplet (PO-LD)-MCSs as follows (Chang et al, 2019;Kong et al, 2020).…”

“…Another study revealed the role of PO-LD-MCS in regulating lipolysis, the hydrolysis of lipid metabolites stored in LDs (Kong et al, 2020). During fasting, the increase in PO-LD-MCSs facilitates the spatial translocation of adipose triglyceride lipase (ATGL) onto LDs for lipolysis.…”

“…In addition, other effector proteins may be enriched at the MCSs to regulate MCS formation or facilitate the exchange of metabolites (Scorrano et al, 2019). As discussed above, ATGL can be grouped as the effector protein that promotes lipolysis at the PO-LD-MCS during fasting (Kong et al, 2020).…”

“…The movement of peroxisomes in mammalian cells preferentially depends on the microtubular network and allows peroxisomes to be uniformly dispersed for metabolism (Neuhaus et al, 2016). PO-LD-MCS depends on the motility of peroxisomes along microtubules through the kinesin-like motor KifC3 to promote lipolysis under fasting stress conditions (Kong et al, 2020). Microtubule disruption by nocodazole treatment in COS-7 cells decreases peroxisome contacts with all the examined organelles (the ER, mitochondria, LDs, Golgi, and lysosomes) (Valm et al, 2017).…”

The Lipolysome—A Highly Complex and Dynamic Protein Network Orchestrating Cytoplasmic Triacylglycerol Degradation

“…Among those, PEX5, or peroxisome target sequence 1 receptor protein (PTS1R), which occurs predominantly in the cytoplasm, shuttles PTS1 binding peroxisomal proteins from the cytoplasm to the peroxisome [105,106]. Recently, PEX5 has been reported to regulate fasting-induced lipolysis by direct interaction with ATGL [107]. Using Caenorhabditis elegans, 3T3-L1 adipocytes, and mice, the authors demonstrate that peroxisome-LD interactions are enhanced upon fasting and necessary for fully activated fasting-mediated lipolysis.…”