Lipid droplet–organelle interactions: emerging roles in lipid metabolism

doi:10.1016/j.ceb.2015.04.017

Current Opinion in Cell Biology

Volume 35, August 2015, Pages 91-97

https://doi.org/10.1016/j.ceb.2015.04.017 Get rights and content

Cellular homeostasis depends on the precisely coordinated use of lipids as fuels for energy production, building blocks for membrane biogenesis or chemical signals for intra-cellular and inter-cellular communication. Lipid droplets (LDs) are universally conserved dynamic organelles that can store and mobilize fatty acids and other lipid species for their multiple cellular roles. Increasing evidence suggests that contact zones between LDs and other organelles play important roles in the trafficking of lipids and in the regulation of lipid metabolism. Here we review recent advances regarding the nature and functional relevance of interactions between LDs and other organelles — particularly the endoplasmic reticulum (ER), LDs, mitochondria and vacuoles — that highlight their importance for lipid metabolism.

Introduction

Cells have the ability to store metabolic energy in the form of nonpolar or ‘neutral’ lipids in ubiquitous organelles, lipid droplets (LDs). Unlike other organelles, LDs exhibit a unique topology consisting of a hydrophobic core, predominantly of triacylglycerol (TAG) and steryl esters (SE), and coated by a phospholipid monolayer, which solubilizes the LD in the cytoplasm and a set of proteins involved in LD function. In response to metabolic signals, mobilized fatty acids (FAs) and other precursors derived from stored neutral lipids are used for a striking variety of functions, including energy production via β-oxidation, membrane biogenesis for cell growth, protein modification, signalling, and even secretion within lipoproteins. Growth and consumption of LDs can occur via multiple pathways but ultimately both processes depend on the regulated exchange of lipid content between LDs and other organelles within an aqueous cytoplasm. Because LDs are not directly connected to the vesicular transport pathways, the neutral lipids and phospholipids required for their biogenesis must be generated either in situ or arrive from other organelles through physical interactions. Here we discuss recent advances and highlight open questions on how contacts between LDs and other organelles are established and how they regulate lipid metabolism. LD biogenesis will not be discussed in detail as it has been comprehensively reviewed elsewhere [1, 2, 3, 4, 5].

Section snippets

LD–ER contact sites

While it is widely thought that LDs emerge from the ER membrane, the mechanisms responsible for the initial stages of their formation are not well understood. A popular model proposes that accumulation of neutral lipids between the leaflets of the ER bilayer forms an oil droplet or ‘lens’ that eventually buds towards the cytoplasm [6], although there is still little direct evidence to support it. Whether this budding process is spontaneous or assisted by ER proteins is also not clear [7].

LD–LD contact sites

LDs tend to cluster together under certain conditions or when specific proteins are over-expressed [35, 36, 37, 38, 39]. However, for the most part these observations of changes in LD proximity do not conclusively document direct contact sites between adjacent LDs. Furthermore, the biological importance of this proximity to one another remains largely unknown; one notable exception is the role of Fsp27 (fat specific protein of 27 kDa, also known as Cidec) in mediating formation of the large

LD–mitochondria/peroxisome interactions

Catabolism of LD-derived fatty acids through β-oxidation takes place in mitochondria in metazoans, or peroxisomes in yeasts and plants. Extensive fatty acid trafficking is therefore likely to take place between LDs and these organelles (Figure 1). Increased fatty acid flux from LDs induces mitochondrial biogenesis, highlighting the close interplay between the two organelles [53]. Close association of LDs with mitochondria, or peroxisomes, has previously been described in many cell types. For

LD–vacuole/lysosome interactions

In addition to the activity of cytosolic lipases, fatty acids can be mobilized from LDs through macroautophagy in mammalian cells. This process is known as lipophagy and involves the sequestration of small, or portions of larger, LDs in the autophagosome [64]. Genetic and pharmacological inhibition of autophagy leads to accumulation of LDs in different cell types. Therefore, proteins that control autophagic flux and are also associated with LDs may specifically control lipophagy. The small

Conclusion and perspective

Lipid synthesis is highly compartmentalized in eukaryotic cells and therefore regulated contacts between LDs and other organelles are likely to be critical for cellular homeostasis. LD tethering to organelles may result in more efficient channeling of lipid intermediates from LDs explaining, perhaps, why lipolysis-derived FAs are used by cells more efficiently over other sources of FAs. How LD–organelle contacts are established, maintained and regulated in response to metabolic cues remains

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

This work was supported by an MRC Senior Non-Clinical Fellowship (to S.S.) and a Wellcome Trust Senior Clinical Fellowship (to D.B.S.). We thank Roger Schneiter and Alison Schuldt for critically reading the manuscript and Robert Parton, Charles Ferguson, Sepp Kohlwein and Maja Radulovic for providing electron micrographs.

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Lipid droplet–organelle interactions: emerging roles in lipid metabolism

Introduction

Section snippets

LD–ER contact sites

LD–LD contact sites

LD–mitochondria/peroxisome interactions

LD–vacuole/lysosome interactions

Conclusion and perspective

References and recommended reading

Acknowledgements

J Biol Chem

Chem Biol

Trends Biochem Sci

J Lipid Res

Dev Cell

Curr Opin Cell Biol

J Lipid Res

Biochim Biophys Acta

J Biol Chem

J Cell Sci

Cell Metab

Biochim Biophys Acta

PLoS Biol

J Cell Sci

J Biol Chem

J Biol Chem

J Lipid Res

J Cell Biol

Histochem Cell Biol

J Lipid Res

Nature

Hepatology

Autophagy

J Cell Biol

J Cell Biol

Curr Biol

The biophysics and cell biology of lipid droplets

Nat Rev Mol Cell Biol

Lipid droplets and peroxisomes: key players in cellular lipid homeostasis or a matter of fat—store ‘em up or burn’ em down

Genetics

Biogenesis of the multifunctional lipid droplet: lipids, proteins, and sites

J Cell Biol

Lipid droplets are arrested in the ER membrane by tight binding of lipidated apolipoprotein B-100

J Cell Sci

Adipophilin-enriched domains in the ER membrane are sites of lipid droplet biogenesis

J Cell Sci

Acyl-CoA synthetase 3 promotes lipid droplet biogenesis in ER microdomains

J Cell Biol

The yeast lipin orthologue Pah1p is important for biogenesis of lipid droplets

J Cell Biol

A role for seipin in lipid droplet dynamics and inheritance in yeast

J Cell Sci

Lipid droplets are functionally connected to the endoplasmic reticulum in Saccharomyces cerevisiae

J Cell Sci

Transport and retention mechanisms govern lipid droplet inheritance in Saccharomyces cerevisiae

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