Macrophage lipid droplets: Inert? Eicosa' not!

Lipidomics Gateway (22 July 2009) [doi:10.1038/lipidmaps.2009.17]

Lipid droplets are sites of eicosanoid production, implicated in atherosclerosis.

Electron micrograph of lipid droplets in adipocytes

The dynamic, active nature of lipid droplets is increasingly recognized, and the list of associated proteins is growing. The more these 'fat sacks' of old emerge as metabolically active, regulatable organelles, the more remains to be understood about their roles in different cell types. Macrophages accumulate lipid droplets through the uncontrolled uptake of modified low-density lipoprotein (LDL), becoming foam cells which are deposited beneath the endothelial layer of arteries in the first sign of atherosclerosis. Macrophages, lipid droplets and atherosclerotic plaques have all been associated with eicosanoid production but the functional significance of foam cell lipid droplets is not well understood. Two new studies address this: Weibel et al. show in the Journal of Lipid Research that macrophage lipid droplets contain active 15-lipoxygenase, and in BBA —Molecular and Cell Biology of Lipids, Silva et al. report that leukotriene production by macrophage lipid droplets is highly regulated by chemokine signaling.

Macrophages differentiate from monocyte precursor cells. Weibel et al. grew human THP-1 monocytes and induced their differentiation. The mature macrophages, and not the precursors, expressed 15-lipoxygenase (15-LO) and the protein was associated with the lipid droplet fraction. To investigate whether the enzyme is active in droplets, the authors turned to murine RAW macrophages that overexpress human 15-lipoxygenase, and confirmed that that this mainly cytoplasmic protein also co-localizes with lipid droplets. The cells, and the isolated droplet fraction, produced the major 15-LO product 15-hydroxyeicosatetraenoic acid (15-HETE) when incubated with the 15-LO substrate, arachidonic acid. The production was dependent on intact enzymatic activity, and was increased when the RAW cells were loaded with acetylated LDL. As well as demonstrating that lipid droplet-associated 15-LO is active, the authors suggest that its activity on lipid droplets might provide a mechanism for storage of 15-HETE and related metabolites by sequestering them after production. Eicosanoids are generally produced on demand but the fractional efflux of 15-HETE was diminished in the presence of lipid droplets, indicating that the lipophilic environment within might provide a cellular storage space for these potent lipid mediators.

Leukotrienes are a sub class of eicosanoids that are also associated with lipid droplets. Two members, produced by 5-lipoxygenase (5-LO), are LTB₄ and LTC₄ . Silva et al. found that LTB₄ and LTC₄ are both produced at lipid droplets in macrophages stimulated with oxidized LDL, and this was dependent on the oxLDL treatment and the activity of 5-LO. Both 5-LO and its activator were localized to lipid droplets, as shown by co-localization with bodipy-labeled lipid droplets and confocal microscopy. The biogenesis of lipid droplets in the macrophages was triggered by oxidized, but not native, LDL and this required MCP-1 (monocyte chemotactic protein-1, also called CC ligand 2, CCL2) chemokine signaling via extracellular signal-regulated kinase (ERK).The use of neutralizing antibodies to MCP-1 inhibited lipid droplet formation and prevented oxLDL-mediated induction of expression of adipose differentiation related protein (ADRP), a key lipid droplet biosynthetic protein. The link between oxLDL-induced lipid droplet formation, MCP-1 activity and leukotriene production was confirmed in mice lacking the MCP-1 receptor, which failed to form lipid droplets or produce leukotrienes in response to oxLDL.

Eicosanoids, including 15-HETE, LTB₄ and LTC₄, are signaling molecules implicated in inflammation and atherosclerosis. Understanding the role of lipid droplet-laden macrophages in the progression of atherosclerosis is a key target in tackling vascular disease. These studies add to the contemporary view of lipid droplets as dynamic organelles, actively participating in physiology and pathology, and are a further step towards full characterization of atherosclerotic progression.

Emma Leah