The (social) lives, deaths, and biophysical phases of lipid droplets

Abstract

Lipid droplets (LDs) are major lipid storage organelles, sequestering energy-rich triglycerides and serving as nutrient sinks for cellular homeostasis. Observed for over a century but generally ignored, LDs are now appreciated to play key roles in organismal physiology and disease. They also form numerous functional contacts with other organelles. Here, we highlight recent studies examining LDs from distinct perspectives of their life cycle: their biogenesis, "social" life as they interact with other organelles, and deaths via lipolysis or lipophagy. We also discuss recent work showing how changes in LD lipid content alter the biophysical phases of LD lipids, and how this may fine-tune the LD protein landscape and ultimately LD function.

Figure 1:

Cartoon schematic of the phases of the lipid droplet (LD) lifecycle. a) LD conception is depicted as the de-mixing of triglyceride (TG) in the endoplasmic reticulum (ER) bilayer when it surpasses a local concentration. b) LD birth depicted by the formation of the LD ‘lens’ which attracts canonical LD proteins. c) LD growth shown via the flow of TG into the growing LD as it ripens. Seipin oligomers promote LD biogenesis and proper growth. d) LD social life is dictated by functional and physical interactions with other cellular organelles. P: peroxiosome, M: mitochondrion, PM: plasma membrane, Endo: endosome, Lyso: lysosome. e) LD death is depicted through two mechanisms, lipolysis of TG and lipophagy (LD macro-autophagy). f) LD phase transitions depicting the phase transition of cholesterol-ester (CE) in red from a disordered liquid phase to a smectic liquid-crystalline phase.

Figure 2:

Cartoon depiction of LD ‘social’ interactions with other organelles, and some of the protein machinery that governs these interactions. SNX-RGS proteins are depicted tethering the endoplasmic reticulum (ER), LDs, and components of the plasma membrane (PM)/endosome/lysosome endomembrane system. MIGA2 is depicted tethering mitochondria to the LD. VPS13-class proteins are also depicted tethering LDs to the PM/endosome/lysosome endomembrane system.

Figure 3:

Schematic of the lipid phase transitions of LD neutral lipids. Prior to triglyceride (TG) lipolysis, both TG and sterol-ester (SE) are in disordered liquid-like phases in the LD hydrophobic core. Following TG lipolysis, TG and SE demix and the SE phase transitions into a smectic liquid-crystalline lattice in the periphery of the LD core underneath of the LD surface monolayer. This correlates with changes in LD protein targeting.