Lipid droplet biogenesis and functions in health and disease

Abstract

Ubiquitous yet unique, lipid droplets are intracellular organelles that are increasingly being recognized for their versatility beyond energy storage. Advances uncovering the intricacies of their biogenesis and the diversity of their physiological and pathological roles have yielded new insights into lipid droplet biology. Despite these insights, the mechanisms governing the biogenesis and functions of lipid droplets remain incompletely understood. Moreover, the causal relationship between the biogenesis and function of lipid droplets and human diseases is poorly resolved. 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. 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.

Fig. 1. Proposed mechanisms of eukaryotic lipid droplet biogenesis.

(1) Cytoplasmic lipid droplet biogenesis involves the synthesis, nucleation, cytoplasmic budding and growth of neutral lipids from the endoplasmic reticulum (ER). 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. 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). Ostwald ripening, coalescence, membrane bridges and both ERTOLD and CYTOLD proteins might then contribute to the growth of cytoplasmic lipid droplets. (2) De novo nuclear lipid droplet biogenesis is similar to cytoplasmic lipid droplet formation but occurs at the inner nuclear membrane. While the role of seipin remains controversial, increased phosphatidic acid levels are hypothesized to be pivotal. (3) In lipoprotein-secreting cells, nuclear lipid droplet biogenesis might also occur via the engulfment of luminal lipid droplets. 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. (4) Luminal lipid droplet biogenesis remains poorly characterized and confounded with VLDL biogenesis (lipidated ApoB represents nascent VLDL particles). Luminal lipid droplets are characterized as ApoB-free precursors. 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. 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.

Fig. 2. Postulated chronology of cellular stress-induced lipid droplet biogenesis.

Cellular stress, including endoplasmic reticulum (ER), oxidation and starvation might trigger increased lipogenesis, autophagy, lysosomal phospholipid turnover or the activity of phospholipases. In turn, increased flux of free fatty acids and other lipid intermediates to the ER might induce lipotoxicity. Lipid droplet biogenesis, which is initiated by increased neutral lipids at the ER, might then be promoted to sequester toxic free fatty acids. Through their various roles, including maintaining energy and membrane homeostasis and enabling protein storage and degradation, lipid droplets might further support stress alleviation.