Lipid droplets (LDs) are multi-functional cellular organelles that store energy, and regulate many aspects of cell physiology. However, our understanding of the biogenesis of LDs remains very limited. Originating from the endoplasmic reticulum (ER), LDs are highly unique organelles in that each LD is bounded by a monolayer of amphipathic lipids. Recent progress has unveiled critical roles of non-bilayer lipids in LD formation. For instance, non-bilayer lipids such as lysophospholipids, diacylglycerol and phosphatidic acid (PA) can impact the curvature, surface and line tension of the ER, thereby impacting LD biogenesis. Two well-known regulators of LD formation, FIT2/FITM2 and seipin, have both been implicated in controlling the metabolism and/or distribution of non-bilayer lipids. We summarize and integrate these recent advances and propose that non-bilayer lipids may play a critical role in each step of LD biogenesis.
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