Lysosomal lipid hydrolysis provides substrates for lipid mediator synthesis in murine macrophages

Abstract

Degradation of lysosomal lipids requires lysosomal acid lipase (LAL), the only intracellular lipase known to be active at acidic pH. We found LAL to be expressed in murine immune cells with highest mRNA expression in macrophages and neutrophils. Furthermore, we observed that loss of LAL in mice caused lipid accumulation in white blood cells in the peripheral circulation, which increased in response to an acute inflammatory stimulus. Lal-deficient (-/-) macrophages accumulate neutral lipids, mainly cholesteryl esters, within lysosomes. The cholesteryl ester fraction is particularly enriched in the PUFAs 18:2 and 20:4, important precursor molecules for lipid mediator synthesis. To investigate whether loss of LAL activity affects the generation of lipid mediators and to eliminate potential systemic effects from other cells and tissues involved in the pronounced phenotype of Lal-/- mice, we treated macrophages from Wt mice with the LAL-specific inhibitor LAListat-2. Acute inhibition of LAL resulted in reduced release of 18:2- and 20:4-derived mediators from macrophages, indicating that lipid hydrolysis by LAL is an important source for lipid mediator synthesis in macrophages. We conclude that lysosomes should be considered as organelles that provide precursor molecules for lipid mediators such as eicosanoids.

Cell type-resolved human lung lipidome reveals cellular cooperation in lung function

“…Traditionally, phospholipids are thought to serve as the major source of fatty acids which upon cleavage by phospholipases, are oxidized enzymatically (e.g., lipoxygenases and cyclooxygenase) or non-enzymatically (e.g., reactive oxygen species), resulting in the formation of potent bioactive lipid mediators (LM). Recent work demonstrated that TGs are a potential source of these fatty acids 44 , 45 . Lysosomal acid lipase (LICH_Human), located in lysosomes, break down TGs and cholesterol esters into their associated fatty acids.…”

“… 10 ) studies. Lysosomal acid lipase is highly expressed in lung macrophages 46 , where it generates lipid mediators 45 . Lipid mediators have many signaling functions regulating inflammation 47 .…”

Targeting Foam Cell Formation in Atherosclerosis: Therapeutic Potential of Natural Products

“…After uptake and internalization by macrophage SRs, modified LDL is transported to the late endosome/ lysosomes where the cholesteryl esters (CEs) are further hydrolyzed to free cholesterol (FC) and free fatty acids by lysosomal acid lipase [LAL, also known as lipase A (LIPA)] (Du et al, 2004;Ouimet et al, 2011;Dubland and Francis, 2015;Schlager et al, 2017). To prevent the potential cell toxicity caused by an excessive FC accumulation, FC can be re-esterified by acetyl-CoA acetyltransferases (ACAT) at the endoplasmic reticulum (ER) to form CE, which is stored in cytoplasm in the form of lipid droplets (LD).…”

Rewiring of Lipid Metabolism in Adipose Tissue Macrophages in Obesity: Impact on Insulin Resistance and Type 2 Diabetes

“…The contribution of the lysosomal pathway to inflammatory signaling and lipid handling has been the subject of numerous studies. Lipid catabolism, as it occurs in lysosomes, is mainly achieved by the action of LIPA, whose deficiency and overexpression have been shown to alter immune (efferocytosis, T cell and macrophage function) and metabolic (insulin signaling, VLDL metabolism, ATM lipid content, polyunsaturated fatty acid (PUFA) release and lipid mediator synthesis) homeostasis [52][53][54]. In ATMs, the lysosomal program has been associated with the MMe phenotype, as evidenced by the enrichment of lysosome-relates genes Lipa and Lamp2, among others, in both obese mice [5,32] and humans [36].…”