Lipid droplets in the nervous system

Abstract

Lipid droplets are dynamic intracellular lipid storage organelles that respond to the physiological state of cells. In addition to controlling cell metabolism, they play a protective role for many cellular stressors, including oxidative stress. Despite prior descriptions of lipid droplets appearing in the brain as early as a century ago, only recently has the role of lipid droplets in cells found in the brain begun to be understood. Lipid droplet functions have now been described for cells of the nervous system in the context of development, aging, and an increasing number of neuropathologies. Here, we review the basic mechanisms of lipid droplet formation, turnover, and function and discuss how these mechanisms enable lipid droplets to function in different cell types of the nervous system under healthy and pathological conditions.

Figure 1.

Schematic of lipid droplet formation and turnover. Reviewed in more detail in Olzmann and Carvalho (2019) and Walther et al. (2017). (A) Structure of a lipid droplet including two classes of binding proteins. Class I proteins, via their hydrophobic hairpin, insert into the phospholipid monolayer, while class II proteins bind to the surface of lipid droplets through an amphipathic helix or stretch of hydrophobic residues. (B) Neutral lipid synthesis. Free fatty acids and cholesterol are converted to triglycerides and cholesteryl esters, respectively, between the leaflets of the ER membrane and enter lipid droplets. Important enzymes in the process include glycerol-3 phosphate acyltransferase (GPAT); lysophosphatidic acid acyltransferase (LPAAT), also known as 1-acylglycerol-3-phosphate O-acyl-transferase (AGPAT); phosphatidic acid phosphatase (PAP1); diacylglycerol acyltransferase (DGAT); and acetyl-CoA acetyltransferase (ACAT). Seipin localizes to the ER–lipid droplet interface to facilitate lipid flow into lipid droplets. Lipid binding proteins such as perilipin-1 (PLIN1) prevent lipases from hydrolyzing neutral lipids, thereby promoting lipid droplet growth. (C) Lipolysis involves the hydrolysis of neutral lipids back into free fatty acids and cholesterol and their release into the cytosol. Important enzymes in the process include adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and monoacylglycerol lipase (MGL). (D) Lipophagy involves the autophagic degradation of lipid droplets and involves machinery common to macroautophagy such as microtubule-associated proteins 1A/1B light chain 3B (LC3). Hydrolysis of neutral lipids by lysosomal lipases liberates free fatty acids and cholesterol.

Figure 2.

Lipid droplet formation in the nervous system. Schematic summarizing the known and hypothesized triggers of lipid droplet formation within cells in the nervous system. ROS, reactive oxygen species.

Figure 3.

Lipid transfer in the nervous system. Schematic summarizing proposed pathways of lipid transfer between neurons and astrocytes. (1) Astrocytes secrete lipoprotein particles rich in cholesterol that are internalized by neurons (Lane-Donovan et al., 2014). (2) Lipoprotein particles are loaded with neuron-derived lipids through ABCA transporters. Lipoprotein particles are endocytosed by astrocytes (Moulton et al., 2021). (3) Fatty acids bound to albumin are transported from astrocytes to neurons during development (Tabernero et al., 2001). (4) Neuronal lipids are released, possibly as specialized lipid particles, and endocytosed by astrocytes (Ioannou et al., 2019a).