Adipose triglyceride lipase acts on neutrophil lipid droplets to regulate substrate availability for lipid mediator synthesis

Abstract

In humans, mutations in ATGL lead to TG accumulation in LDs of most tissues and cells, including peripheral blood leukocytes. This pathologic condition is called Jordans’ anomaly, in which functional consequences have not been investigated. In the present study, we tested the hypothesis that ATGL plays a role in leukocyte LD metabolism and immune cell function. Similar to humans with loss-of-function mutations in ATGL, we found that global and myeloid-specific Atgl−/− mice exhibit Jordans’ anomaly with increased abundance of intracellular TG-rich LDs in neutrophil granulocytes. In a model of inflammatory peritonitis, lipid accumulation was also observed in monocytes and macrophages but not in eosinophils or lymphocytes. Neutrophils from Atgl−/− mice showed enhanced immune responses in vitro, which were more prominent in cells from global compared with myeloid-specific Atgl−/− mice. Mechanistically, ATGL−/− as well as pharmacological inhibition of ATGL led to an impaired release of lipid mediators from neutrophils. These findings demonstrate that the release of lipid mediators is dependent on the liberation of precursor molecules from the TG-rich pool of LDs by ATGL. Our data provide mechanistic insights into Jordans’ anomaly in neutrophils and suggest that ATGL is a potent regulator of immune cell function and inflammatory diseases.

Role for formin-like 1-dependent acto-myosin assembly in lipid droplet dynamics and lipid storage

“…Together, these findings provide the first evidence that NMIIa dysfunction in man causes a lipid imbalance, possibly contributing to the pathogenesis of MYH9-RD. For instance, neutrophil LDs can modulate the immune response, as impaired LD lipolysis was found to be accompanied by reduced lipid mediator release26.…”

HILPDA Uncouples Lipid Droplet Accumulation in Adipose Tissue Macrophages from Inflammation and Metabolic Dysregulation

“…Indeed, the elevated triglyceride accumulation in ATGL À/À macrophages is accompanied by mitochondrial dysfunction and apoptosis, ER stress, reduced macrophage migration, and decreased phagocytosis ability (Chandak et al, 2010;Aflaki et al, 2011aAflaki et al, , 2011bAflaki et al, , 2012, suggesting that proper macrophage function is dependent on the liberation of free fatty acids from intracellular triglyceride stores. The ATGL-mediated release of fatty acids is also necessary for the production of lipid mediators, at least in neutrophils (Schlager et al, 2015). Similar to ATGL À/À macrophages, macrophages deficient in the ATGL activator CGI-58 (also known as (C) Corrected TNF-a and IL-6 secretion of adipose tissue macrophages from Hilpda flox/flox and Hilpda DMF mice fed a HFD for 20 weeks (n = 10-12 per group, pooled per 3-4).…”

Lipid droplet functions beyond energy storage

“…The lipase ATGL can release AA from these triglycerides and thus promote the production of eicosanoids [77, 78]. Inhibition of ATGL, genetically or pharmacologically, also impairs eicosanoid release in other types of immune cells, such as neutrophils [79]. In the intracellular parasites Leishmania and Trypanosoma , LDs can also act as a source of immunomodulatory prostaglandins implicated in improving the survival of the parasite within its host [80, 81].…”