Triacylglycerols and sterol esters are the most abundant neutral lipids in eukaryotes 23.
Many models have been proposed for their biogenesis 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, with the most empirically supported version involving the synthesis, nucleation and cytoplasmic budding and growth of neutral lipids from the ER 5, 7, 8 (section 1 of Fig. Often used to refer generally to all lipid droplets, cytoplasmic lipid droplets are by far the most well characterized form of these increasingly recognized, diverse organelles. AGPAT, 1-acylglycerol-3-phosphate acyltransferase ApoB, apolipoprotein B-100 CIDE, cell death-inducing DFFA-like effector CYTOLD, cytoplasm to lipid droplet targeting DGAT, diacylglycerol transferase ERTOLD, ER to lipid droplet targeting FIT2, fat storage-inducing transmembrane protein 2 G-3-P, glycerol-3-phosphate GPAT, glycerol-3-phosphate acyltransferase LPA, lysophosphatidic acid MTP, microsomal lipid transfer protein PA, phosphatidic acid PAP, phosphatidic acid phosphatase Pi, inorganic phosphate PLIN3, perilipin 3.įull size image Cytoplasmic lipid droplets
MTP might connect cytoplasmic lipid droplets with the formation of luminal lipid droplets and might also mediate the lipid transfer between luminal lipid droplets and lipidated ApoB. Luminal lipid droplets are characterized as ApoB-free precursors. ( 4) Luminal lipid droplet biogenesis remains poorly characterized and confounded with VLDL biogenesis (lipidated ApoB represents nascent VLDL particles). During ER stress, degradation of ApoB but maintenance of MTP levels (top right) enable ApoB-free luminal lipid droplet accumulation in the ER lumen before entry into the nucleus through type I nucleoplasmic reticulum breakage. ( 3) In lipoprotein-secreting cells, nuclear lipid droplet biogenesis might also occur via the engulfment of luminal lipid droplets. While the role of seipin remains controversial, increased phosphatidic acid levels are hypothesized to be pivotal. ( 2) De novo nuclear lipid droplet biogenesis is similar to cytoplasmic lipid droplet formation but occurs at the inner nuclear membrane. Ostwald ripening, coalescence, membrane bridges and both ERTOLD and CYTOLD proteins might then contribute to the growth of cytoplasmic lipid droplets. Regulated by monolayer tension asymmetry, budding towards the cytosol might then occur spontaneously or be promoted by both proteins and lipids, including seipin, FIT2 or diacylglycerol (DAG). DGAT1 and DGAT2 catalyse the formation of triacylglycerols (TAG see inset for the biosynthesis pathway), which, once accumulated beyond 2.8–10.0 mol%, form lens structures at sites putatively defined by proteins, such as seipin and its interacting partners.
( 1) Cytoplasmic lipid droplet biogenesis involves the synthesis, nucleation, cytoplasmic budding and growth of neutral lipids from the endoplasmic reticulum (ER). We also discuss therapeutic strategies of targeting lipid droplet biogenesis, growth or degradation that could be applied in the future to common diseases, such as cancer, hepatic steatosis and viral infection.
Lumen biology update#
Here, we provide an update on the current understanding of the biogenesis and functions of lipid droplets in health and disease, highlighting a key role for lipid droplet biogenesis in alleviating cellular stresses. Moreover, the causal relationship between the biogenesis and function of lipid droplets and human diseases is poorly resolved. Despite these insights, the mechanisms governing the biogenesis and functions of lipid droplets remain incompletely understood. Advances uncovering the intricacies of their biogenesis and the diversity of their physiological and pathological roles have yielded new insights into lipid droplet biology. Ubiquitous yet unique, lipid droplets are intracellular organelles that are increasingly being recognized for their versatility beyond energy storage.
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