Chapter Three - Lipid Droplets as Organelles

https://doi.org/10.1016/bs.ircmb.2017.12.007Get rights and content

Abstract

Long considered inert fat storage depots, it has become clear that lipid droplets (LDs) are bona fide organelles. Like other organelles, they have a characteristic complement of proteins and lipids, and undergo a life cycle that includes biogenesis, maturation, interactions with other organelles, and turnover. I will discuss recent insights into mechanisms governing the life cycle of LDs, and compare and contrast the LD life cycle with that of other metabolic organelles such as mitochondria, peroxisomes, and autophagosomes, highlighting open questions in the field.

Introduction

Lipid droplets (LDs) are cellular structures that store fat in the form of neutral lipids. Nearly all eukaryotic cells can make LDs, which are composed of a core of triglycerides and sterol esters. Because the core of the LD is hydrophobic, LDs are surrounded by a phospholipid monolayer, with the hydrophobic phospholipid tails oriented toward the neutral lipid core (Thiam et al., 2013). This is different from most other cellular organelles, which have aqueous lumens and are surrounded by phospholipid bilayers. Despite their unique structure, it has become clear that LDs are bona fide organelles. Like other organelles, LDs have a characteristic complement of proteins and lipids. Over 100 LD-associated proteins have been identified (Bersuker and Olzmann, 2017; Krahmer et al., 2013). These include proteins involved in lipid synthesis and metabolism, as well as proteins involved in membrane trafficking and organelle transport (Bersuker and Olzmann, 2017). LDs undergo a life cycle that includes biogenesis, maturation, and turnover (Hashemi and Goodman, 2015; Fig. 1). Under certain conditions LDs can undergo fusion and fission (Thiam et al., 2013), and LDs also make close contacts with many other organelles, presumably to exchange lipids (Barbosa et al., 2015; Schuldiner and Bohnert, 2017; Fig. 1). In this review, I will discuss these aspects of the LD life cycle, highlighting similarities and differences with other cellular organelles, as well as open questions in this exciting field.

Section snippets

Mechanism of LD Biogenesis

LDs can form in response to various stimuli, including excess lipids or a variety of stresses (Gubern et al., 2009). There is evidence that LD biogenesis occurs in the endoplasmic reticulum (ER), which is the site of many lipid synthesis enzymes (Pol et al., 2014; Walther et al., 2017). In the prevailing models of LD biogenesis, neutral lipid synthesis occurs within the ER membrane, at ER microdomains enriched in acyl-CoA synthetase 3, an enzyme involved in the first step of triacylglycerol

LD Maturation and Heterogeneity

LDs show remarkable heterogeneity in protein and lipid composition. Some of this heterogeneity may reflect subpopulations of LDs with different functions. For example, when cells are loaded with excess fatty acids and sterols, they form distinct populations of LDs enriched either in sterol esters or in triglycerides (Hsieh et al., 2012). However, it has also been proposed that LDs undergo a maturation process over time. Organelle maturation and heterogeneity is an emerging theme in cell biology

LD Fusion

LDs can undergo fusion via two separate mechanisms. During the differentiation of adipocytes, many small LDs combine to form one large LD (Gao et al., 2017). The resulting LD occupies much of the volume of the adipocyte and allows for efficient lipid storage by minimizing the surface area to volume ratio of the hydrophobic neutral lipids. This type of fusion occurs by Ostwald ripening, in which lipids are transferred from the smaller to larger LD by diffusion (Thiam et al., 2013). The close

Interactions Between LDs and Other Organelles

LDs can make close contacts with a variety of other organelles (Barbosa et al., 2015; Schuldiner and Bohnert, 2017). Membrane contact sites are increasingly understood to be key sites of communication and metabolite exchange between organelles. A recent study using multispectral imaging to simultaneously image six organelles found that LDs frequently moved within 1 pixel (~ 100 nm) of every other labeled organelle, namely, the ER, mitochondria, peroxisomes, lysosomes, and the Golgi (Valm et al.,

LD Turnover

Like other organelles, LDs have a life cycle that involves LD turnover and breakdown. As the organelle responsible for lipid storage, LDs must be able to respond rapidly to changes in the energetic needs of the cell. The best-characterized mechanism for the release of fatty acids from triglycerides within LDs is via cytoplasmic lipases, called lipolysis (Zechner et al., 2017). However, pieces of LDs and even whole LDs can also be degraded via autophagy, in a process termed lipophagy (Singh et

Conclusions and Future Perspectives

LDs are bona fide organelles that undergo a life cycle including biogenesis, maturation, and turnover. They may also undergo fusion and fission, and they interact with and exchange materials with other organelles. Many aspects of the LD life cycle remain incompletely understood. LDs have unique biophysical properties, due to their hydrophobic core and phospholipid monolayer membrane (Thiam and Foret, 2016; Thiam et al., 2013). Therefore, certain aspects of the LD life cycle are unique to LDs.

Acknowledgments

This work was supported by the University of North Carolina at Chapel Hill, and by the National Institute on Aging of the National Institutes of Health, under award number K99AG052570.

References (123)

  • N. Kory et al.

    Protein crowding is a determinant of lipid droplet protein composition

    Dev. Cell

    (2015)
  • N. Kory et al.

    Targeting fat: mechanisms of protein localization to lipid droplets

    Trends Cell Biol.

    (2016)
  • N. Krahmer et al.

    Phosphatidylcholine synthesis for lipid droplet expansion is mediated by localized activation of CTP:phosphocholine cytidylyltransferase

    Cell Metab.

    (2011)
  • N. Krahmer et al.

    Protein correlation profiles identify lipid droplet proteins with high confidence

    Mol. Cell. Proteomics

    (2013)
  • A. Lass et al.

    Adipose triglyceride lipase-mediated lipolysis of cellular fat stores is activated by CGI-58 and defective in Chanarin-Dorfman syndrome

    Cell Metab.

    (2006)
  • J.P. Layerenza et al.

    Nuclear lipid droplets: a novel nuclear domain

    Biochim. Biophys. Acta

    (2013)
  • A. Marcinkiewicz et al.

    The phosphorylation of serine 492 of perilipin a directs lipid droplet fragmentation and dispersion

    J. Biol. Chem.

    (2006)
  • D.F. Markgraf et al.

    An ER protein functionally couples neutral lipid metabolism on lipid droplets to membrane lipid synthesis in the ER

    Cell Rep.

    (2014)
  • O. Moldavski et al.

    Lipid droplets are essential for efficient clearance of cytosolic inclusion bodies

    Dev. Cell

    (2015)
  • T.B. Nguyen et al.

    Lipid droplets and lipotoxicity during autophagy

    Autophagy

    (2017)
  • H.M. Ni et al.

    Mitochondrial dynamics and mitochondrial quality control

    Redox Biol.

    (2015)
  • M. Ouimet et al.

    Autophagy regulates cholesterol efflux from macrophage foam cells via lysosomal acid lipase

    Cell Metab.

    (2011)
  • M. Paar et al.

    Remodeling of lipid droplets during lipolysis and growth in adipocytes

    J. Biol. Chem.

    (2012)
  • A.S. Rambold et al.

    Fatty acid trafficking in starved cells: regulation by lipid droplet lipolysis, autophagy, and mitochondrial fusion dynamics

    Dev. Cell

    (2015)
  • M. Schuldiner et al.

    A different kind of love—lipid droplet contact sites

    Biochim. Biophys. Acta

    (2017)
  • J. Seelig

    Thermodynamics of lipid-peptide interactions

    Biochim. Biophys. Acta

    (2004)
  • M. Shibata et al.

    The MAP1-LC3 conjugation system is involved in lipid droplet formation

    Biochem. Biophys. Res. Commun.

    (2009)
  • M. Shibata et al.

    LC3, a microtubule-associated protein1A/B light chain3, is involved in cytoplasmic lipid droplet formation

    Biochem. Biophys. Res. Commun.

    (2010)
  • J.R. Skinner et al.

    Diacylglycerol enrichment of endoplasmic reticulum or lipid droplets recruits perilipin 3/TIP47 during lipid storage and mobilization

    J. Biol. Chem.

    (2009)
  • S.J. Stone et al.

    The endoplasmic reticulum enzyme DGAT2 is found in mitochondria-associated membranes and has a mitochondrial targeting signal that promotes its association with mitochondria

    J. Biol. Chem.

    (2009)
  • A.R. Thiam et al.

    The physics of lipid droplet nucleation, growth and budding

    Biochim. Biophys. Acta

    (2016)
  • B.M. Abell et al.

    Role of the proline knot motif in oleosin endoplasmic reticulum topology and oil body targeting

    Plant Cell

    (1997)
  • Q.M. Anstee et al.

    Mouse models in non-alcoholic fatty liver disease and steatohepatitis research

    Int. J. Exp. Pathol.

    (2006)
  • M.A. Aon et al.

    Mitochondrial and cellular mechanisms for managing lipid excess

    Front. Physiol.

    (2014)
  • E.L. Axe et al.

    Autophagosome formation from membrane compartments enriched in phosphatidylinositol 3-phosphate and dynamically connected to the endoplasmic reticulum

    J. Cell Biol.

    (2008)
  • D. Binns et al.

    An intimate collaboration between peroxisomes and lipid bodies

    J. Cell Biol.

    (2006)
  • D. Binns et al.

    Seipin is a discrete homooligomer

    Biochemistry

    (2010)
  • A.V. Bulankina et al.

    TIP47 functions in the biogenesis of lipid droplets

    J. Cell Biol.

    (2009)
  • B.R. Cartwright et al.

    Seipin performs dissectible functions in promoting lipid droplet biogenesis and regulating droplet morphology

    Mol. Biol. Cell

    (2015)
  • R. Chakrabarti et al.

    INF2-mediated actin polymerization at the ER stimulates mitochondrial calcium uptake, inner membrane constriction, and division

    J. Cell Biol.

    (2018)
  • C. Chitraju et al.

    Triglyceride synthesis by DGAT1 protects adipocytes from lipid-induced ER stress during lipolysis

    Cell Metab.

    (2017)
  • V. Choudhary et al.

    A conserved family of proteins facilitates nascent lipid droplet budding from the ER

    J. Cell Biol.

    (2015)
  • M. Eisenberg-Bord et al.

    Identification of seipin-linked factors that act as determinants of a lipid droplet subpopulation

    J. Cell Biol.

    (2018)
  • R.V. Farese et al.

    Lipid droplets go nuclear

    J. Cell Biol.

    (2016)
  • W. Fei et al.

    Fld1p, a functional homologue of human seipin, regulates the size of lipid droplets in yeast

    J. Cell Biol.

    (2008)
  • J.R. Friedman et al.

    ER tubules mark sites of mitochondrial division

    Science

    (2011)
  • L. Galluzzi et al.

    Molecular definitions of autophagy and related processes

    EMBO J.

    (2017)
  • L. Ge et al.

    The ER-Golgi intermediate compartment is a key membrane source for the LC3 lipidation step of autophagosome biogenesis

    Elife

    (2013)
  • J. Gong et al.

    Fsp27 promotes lipid droplet growth by lipid exchange and transfer at lipid droplet contact sites

    J. Cell Biol.

    (2011)
  • A. Grippa et al.

    The seipin complex Fld1/Ldb16 stabilizes ER-lipid droplet contact sites

    J. Cell Biol.

    (2015)
  • Cited by (0)

    View full text