Lipid droplet biogenesis

Abstract

Lipid droplets (LDs) are found in most cells, where they play central roles in energy and membrane lipid metabolism. The de novo biogenesis of LDs is a fascinating, yet poorly understood process involving the formation of a monolayer bound organelle from a bilayer membrane. Additionally, large LDs can form either by growth of existing LDs or by the combination of smaller LDs through several distinct mechanisms. Here, we review recent insights into the molecular process governing LD biogenesis and highlight areas of incomplete knowledge.

Figure 1

A step-wise model of lipid droplet formation. Lipid droplets form in at least three discrete steps. (a) Neutral lipids are synthesized in the ER and accumulate within the bilayer. Neutral lipids are highly mobile in the bilayer and may spontaneously aggregate based on thermal fluctuations and electrostatic interactions with integral membrane proteins or other lipids. (b) Once the local concentration of neutral lipid reaches a critical threshold, a lens will form as the oil phase coalesces. (c) As the lens accumulates additional neutral lipids, the bilayer deforms and a nascent lipid droplet buds into the cytoplasm, possibly via a de-wetting mechanism. The nascent droplet might remains attached to the ER or separate completely.

Figure 2

Features of lipid droplet growth (expansion) and fusion. Large LDs can form by at least two general mechanisms: growth of an LD or processes in which LDs combine to form a single, larger LD. Growth of LDs is triggered by relocalization of TG synthesis enzymes from the ER to the surface of LDs. (a) The COPI machinery buds small nano-LDs from a mature LD leading to a reduction of phospholipids on the LD surface. This leads to an increase in surface tension facilitating interactions of the LD with the ER. (b) Once connections are established, a subset of TG synthesis enzymes is able to relocalize to the LD surface to locally produce TG, which, in turn, leads to the growth of the LD. (c) Alternatively LDs can expand by a ripening process called permeation. Here neutral lipids are transferred from a smaller LD to a larger LD. In adipocytes, FSP27 is involved in this process. (d) Under certain conditions, for example when PC is limited and surface tension is relatively high, large LDs can form by fusion/coalescence of two or more LDs.