Current Biology

Review

Expanding Roles for Lipid Droplets

Michael A. Welte
Department of Biology, University of Rochester, RC Box 270211, 317 Hutchison Hall, Rochester, NY 14627, USA
Correspondence: [email protected]
http://dx.doi.org/10.1016/j.cub.2015.04.004

Lipid droplets are the intracellular sites for neutral lipid storage. They are critical for lipid metabolism and
energy homeostasis, and their dysfunction has been linked to many diseases. Accumulating evidence sug-
gests that the roles lipid droplets play in biology are significantly broader than previously anticipated. Lipid
droplets are the source of molecules important in the nucleus: they can sequester transcription factors and
chromatin components and generate the lipid ligands for certain nuclear receptors. Lipid droplets have also
emerged as important nodes for fatty acid trafficking, both inside the cell and between cells. In immunity, new
roles for droplets, not directly linked to lipid metabolism, have been uncovered, with evidence that they act as
assembly platforms for specific viruses and as reservoirs for proteins that fight intracellular pathogens. Until
recently, knowledge about droplets in the nervous system has been minimal, but now there are multiple links
between lipid droplets and neurodegeneration: many candidate genes for hereditary spastic paraplegia also
have central roles in lipid-droplet formation and maintenance, and mitochondrial dysfunction in neurons can
lead to transient accumulation of lipid droplets in neighboring glial cells, an event that may, in turn, contribute
to neuronal damage. As the cell biology and biochemistry of lipid droplets become increasingly well under-
stood, the next few years should yield many new mechanistic insights into these novel functions of lipid
droplets.

Introduction key recent findings into these emerging roles of lipid droplets,
Lipid droplets are the sites where cells store neutral lipids, such with the aim of sharing these exciting developments with re-
as triglycerides, steryl esters, and retinyl esters [1–3]. These searchers beyond the lipid-droplet field. Lipid droplets are still
stored lipids can then be used in times of need to generate relatively understudied organelles and, given the versatile func-
energy, membrane components, and signaling lipids. Impair- tions already revealed, it seems likely that further roles in new
ment of the machinery that makes or degrades lipid droplets areas of biology will be discovered.
has severe physiological consequences [1,4–6], demonstrating
that lipid droplets play central roles in cellular and organismal Some Basic Concepts in Lipid-Droplet Biology
energy homeostasis, in particular, and overall lipid metabolism In the last few years, there has been an explosive growth in our
in general. understanding of the structure, biogenesis, and turnover of lipid
Lipid droplets also allow cells to safely sequester otherwise droplets, which have been extensively covered in many excellent
toxic lipids. For example, as amphipathic molecules, overabun- recent reviews [1,5,10–15]. Among cellular organelles, lipid
dant fatty acids can severely compromise membrane integrity. droplets have a unique structure (Figure 1A): a central core of
Once turned into triglycerides and incorporated into lipid drop- hydrophobic (neutral) lipids is surrounded by a single layer of
lets (Figure 1A), they are relatively inert, stable, and harmless. amphipathic lipids and proteins (reminiscent of half a membrane
This protective function is probably the reason for the abundant bilayer). The triglycerides in the hydrophobic core are generated
accumulation of lipid droplets in many disease states character- by an elaborate biosynthetic pathway (for a summary, see [10]),
ized by aberrant lipid supply and metabolism, such as obesity, with the final step being catalyzed by the acyl-CoA:diacylgly-
atherosclerosis, and fatty liver disease [1,6,7]. cerol acyltransferases DGAT1 and DGAT2 (Figure 1A), convert-
Lipid droplets are particularly important in tissues specialized ing diacylyglycerol (DAG) and fatty acids, first activated to
for energy storage or lipid turnover, such as adipose tissue, acyl-CoA, into triglycerides. Both enzymes are located in the
the liver, and the intestine [2,3,8], yet they also accumulate in endoplasmic reticulum (ER), where triglycerides accumulate at
skeletal muscle, the adrenal cortex, macrophages, and mam- privileged sites that represent nascent lipid droplets [16]; mature
mary glands [1]. They control lipid signaling in immune cells lipid droplets are generated by continuous growth of these
and are the targets of attack by pathogens [9]. Finally, they structures and finally become distinct from the ER, likely via a
have been observed in most cell types and occur throughout process resembling budding [10,13]. DGAT2 is only inserted
the animal kingdom, in plants, and in unicellular organisms. into one leaflet of the ER membrane and can therefore diffuse
Recently, it has become apparent that lipid droplets play even onto the surface of lipid droplets, promoting triglyceride synthe-
broader cellular roles than previously appreciated. For example, sis and continued droplet growth locally [17]. The hydrophobic
they modulate the availability of proteins and signaling lipids in core can also contain steryl esters, the synthesis of which is
the nucleus, act as hubs for fatty acid trafficking, are used by catalyzed by acyl-CoA:cholesterol acyltransferases. Depending
viruses as assembly platforms, and their dysfunction in neurons on cell type and conditions, steryl esters or triglycerides may
and glia may lead to neurodegeneration. This review summarizes predominate.

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Current Biology

Review

ATGL Figure 1. Lipid droplet basics.

A B
(A) Top: Lipid droplets have a central core of
TAG FA
FA neutral lipids (triglycerides, steryl esters, retinyl
Steryl esters esters) surrounded by a single layer of amphi-
DAG TAG
Phospholipids Retinyl esters Lipid MAG pathic lipids (mostly phospholipids) and proteins.
droplet MGL Bottom: Lipid droplets arise from the ER,
where two enzymes (DGAT1, DGAT2) synthesize
HSL
triglycerides (triacylglycerol, TAG) from diac-
Glycerol FA
FA FA Lipid droplet ylglycerol (DAG) and acyl-CoA (ultimately derived
DAG
from fatty acids, FAs). Triglycerides initially
Acyl-CoA C
accumulate between the two leaflets of the ER;
Acyl-CoA DAG
these nascent droplets eventually give rise to
mature lipid droplets that may become detached
DGAT2 from the ER or remain connected by narrow
DGAT1
bridges. Accumulation of steryl and retinyl esters
TAG
also promotes lipid-droplet formation. Like tri-
ER Phagophore Autolysosome glycerides, these molecules are produced by ER-
resident transferases, but for simplicity these
enzymes are not included in the cartoon. (B) Tri-
glyceride breakdown via cytoplasmic lipases. The
Lipid droplet Mitochondrion Vesicle Lipase triglyceride lipase ATGL is droplet-bound and,
when activated, hydrolyzes TAG to DAG and FA.
DAG is further broken down, via hormone-sensi-
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tive lipase (HSL) and monoglyceride lipase (MGL)
to monoacylglycerol (MAG), glycerol, and FAs.
(C) Triglyceride breakdown via autophagy. A double membrane (phagophore) grows around various organelles (left), including lipid droplets, mitochondria, and
vesicles, and traps them inside an autophagosome. After fusion of the autophagosome with lysosomes to form autolysosomes, the organelles are broken down
by acid hydrolases, including lysosomal acid lipase (LAL, not shown).

Breakdown of the droplet triglycerides can occur by two Biochemical fractionation suggests that these structures differ
distinct pathways. Cytoplasmic triglyceride lipases bound to in their lipid composition from the lipid droplets in the cytoplasm
the surface of lipid droplets hydrolyze triglycerides to DAG and [20]; however, they resemble cytoplasmic lipid droplets in their
fatty acids. DAG can be further broken down, in two steps, into morphology and in the presence of neutral lipids and were thus
fatty acids and glycerol (Figure 1C). In adipose tissue and named ‘nuclear lipid droplets’. It is not yet known how these lipid
many other cells, the bulk of triglyceride hydrolysis is catalyzed droplets arise, what proteins they associate with, or what their
by a single lipase, adipose triglyceride lipase (ATGL) [5]. Lipid functional significance is. However, it is an intriguing possibility
droplets can also be turned over by autophagy (Figure 1C): that they contribute to nuclear lipid homeostasis and locally
like other cellular organelles, lipid droplets are taken up by auto- modulate the availability of signaling lipids.
phagosomes, which fuse with lysosomes to form autolyso- Exchange of Proteins between Lipid Droplets and Nuclei
somes. The hydrolytic enzymes delivered from lysosomes then Cytoplasmic lipid droplets can also profoundly affect nuclear
break down the autophagosome content; triglycerides, in partic- events. For example, lipid droplets have been implicated in sup-
ular, are predominantly hydrolyzed by lysosomal acid lipase pressing the activity of a transcription factor by keeping it out of
(LAL) [5]. Discovered in hepatocytes [18], autophagy of lipid the nucleus [21]. The lipid-droplet protein Fsp27, also known as
droplets (‘lipophagy’) appears to make varied contributions to CIDEC, is expressed in adipocytes and promotes fusion be-
triglyceride breakdown, depending on cell type and physiolog- tween droplets, causing the formation of a single droplet per
ical conditions [5]. cell [22,23]. A yeast two-hybrid screen revealed the transcription
factor NFAT5 (nuclear factor of activated T cells 5) as a potential
Lipid Droplets as Modulators of Nuclear Functions Fsp27 interaction partner. NFAT5 is cytoplasmic under hypo-
Lipid droplets arise from the ER and typically reside in the cyto- tonic conditions and translocates to the nucleus upon hypertonic
plasm, often at considerable distance from the nucleus. Never- stress to activate osmoprotective genes [24]. The physical inter-
theless, recent studies have uncovered intimate connections action between Fsp27 and NFAT5 was confirmed in vivo, and
between lipid droplets and nuclear events. There is emerging Fsp27 knockdown in adipocytes led to expression of NFAT5
evidence for a nuclear population of lipid droplets, which has target genes even in the absence of hypertonic stress [21]. To
been proposed to directly modulate lipid metabolism in the nu- examine the underlying mechanism, Fsp27 was ectopically ex-
cleus. In addition, lipid droplets in the cytoplasm can sequester pressed in the heterologous HEK293 cell line; under these con-
transcription factors, enzymes, and chromatin components — ditions, Fsp27 was observed broadly throughout the cytoplasm.
and possibly many other proteins — and thus control their avail- Fsp27 overexpression reduced the amount of nuclear NFAT5, as
ability in the nucleus. determined both by imaging and biochemistry, and blunted the
Nuclear Lipid Droplets expression of NFAT5 target genes when cells were exposed to
Two different groups have reported the presence of lipid droplets hypertonic stress [21]. These results suggest that Fsp27 is able
inside nuclei [19,20]. Using dyes specific for neutral lipids, small to sequester NFAT5 in the cytoplasm and interferes with its
spherical structures were identified in the nuclei of cultured cells nuclear trafficking; since endogenous Fsp27 is associated with
as well as in biochemically isolated nuclei [20]. Electron micro- lipid droplets in adipocytes, this interaction would retain
scopy of serial sections revealed that at least some of these NFAT5 at the droplet surface (Figure 2A), something that remains
structures truly reside inside the nuclear compartment [19]. to be demonstrated directly. It will be interesting to determine

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A B Figure 2. Protein exchange between lipid

Polysome droplets and the nucleus.
NFAT5 (A) The lipid-droplet protein Fsp27 can physically
Histones interact with the transcription factor NFAT5. This
interaction is proposed to keep NFAT5 out of the
Fsp27 nucleus, thus dampening transcriptional activation
of NFAT5 target genes. (B,C) Modulation of histone
metabolism by lipid droplets. Typically, newly
Lipid droplet Nucleus translated histones are either incorporated into
Protease chromatin in the nucleus or degraded (B). In
D Inactive CCT1 Drosophila embryos, newly synthesized histones
Nucleus can be sequestered on lipid droplets before being
imported into nuclei, shielding them from degra-
C dation (C). This sequestration allows long-term
storage of histones in the cytoplasm and also en-
Droplet Histones sures a consistent histone supply despite short-
static term fluctuations in histone production. (D) The
Nucleus phospholipid synthesis enzyme CCT1 is usually
present in both the nucleus and in the cytoplasm.
Active CCT1 These two pools exchange rapidly, with the ma-
jority of CCT1 present in the nucleus at any one
time (top). When lipid droplets are growing, CCT1 is
stably recruited to the droplet surface (bottom).
Droplet binding results in a conformational change
Lipid that activates the enzyme, boosting phospholipid
droplet synthesis, and thus allows the droplet surface layer
Droplet
to expand in concert with the growth of the core.
growing
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whether the interaction between Fsp27 and NFAT5 is regulated, here lipid droplets can trap histones produced in excess and
for example, by signaling pathways controlling lipolysis. prevent their unregulated entry into nuclei. Whether other
In Drosophila embryos, lipid droplets are associated with large species use similar droplet-based histone buffering remains
amounts of specific histones [25] via the histone anchor Jabba to be determined, although histones have also been detected
[26]. This association is first detected during oogenesis and on lipid droplets in housefly embryos, rat sebocytes, and
makes it possible for females to build up massive histone stores mouse oocytes [25,29,30]
in the developing eggs (Figure 2B,C). Wild-type embryos contain The enzyme CCT1 also displays dramatic exchange between
enough excess histones for thousands of diploid nuclei, whereas lipid droplets and nuclei. CCT1 is one of two isoforms of
mutants lacking Jabba have drastically reduced histone stores CTP:phosphocholine cytidylyltransferase, an enzyme that cata-
[26]; indirect evidence suggests that extranuclear histones not lyzes the rate-limiting step in the synthesis of the phospholipid
bound to lipid droplets are degraded. Transplantation experi- phosphatidylcholine. In cultured fly cells, CCT1 is usually present
ments revealed that in the embryo droplet-bound histones in the nucleus, but, under conditions in which cells synthesize
can transfer to nuclei [25] and presumably support chromatin new triglycerides and expand the hydrophobic core of droplets,
assembly. Surprisingly, embryos lacking this droplet-bound his- CCT1 accumulates at the droplet surface [31,32] (Figure 2D). The
tone supply develop largely normally [26,27]. This is possible presence at the droplet surface is critical to expand the droplet
because of the intricate regulation of histone metabolism in early surface in concert with growth of the core: droplet binding acti-
embryos (reviewed in [28]), which also contain abundant levels of vates the enzyme and thus leads to an increase in the cellular
histone messages deposited during oogenesis. When new syn- phosphatidylcholine supply. Whether CCT1’s presence in the
thesis of histones in the embryo is even mildly impaired, Jabba nucleus in the basal state is functionally important remains un-
mutants cannot sustain development and die very early [26]. clear. Nuclear accumulation is apparently not a mechanism to
Thus, in this case, lipid droplets sequester a nuclear protein for prevent access to the droplet surface: fluorescence recovery
long-term storage. This sequestration allows the organism to after photobleaching (FRAP) experiments revealed that CCT1
build up histone stores during oogenesis and keep them avail- is not immobilized inside nuclei, but rapidly exchanges with a
able for when they are needed later for chromatin assembly cytoplasmic pool. And overexpression of CCT2, an isoform
(Figure 2C). exchanging between the cytoplasm and droplets, can fully
Lipid droplets of early Drosophila embryos also appear rescue the effect of CCT1 depletion on droplet growth [31].
to affect histone metabolism in the short term, by buffering High nuclear accumulation and consequent low cytoplasmic
the histone supply [27]. When droplets are transplanted pools of CCT1 might possibly modulate the kinetics of relocaliza-
between embryos, the donor droplets can bind histones tion to droplets.
from the recipient embryo, suggesting that histones can be Prp19 is a subunit of the NineTeen Complex, which is involved
loaded onto droplets even in embryos. In Jabba mutants, in a number of nuclear events, including spliceosome activation
the synthesis of histone H2A and its variant H2Av are and transcription elongation [33]. In mouse adipocytes, Prp19
imbalanced, and H2Av overaccumulates in the nuclei, an was also found associated with lipid droplets, and Prp19 knock-
event linked to DNA damage [27]. This nuclear overaccumula- down resulted in reduced triglyceride accumulation [34]. It is not
tion does not occur in wild-type embryos, presumably because clear whether this dual localization to lipid droplets and to the

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Current Biology

Review

A Mitochondrion Nucleus Mitochondria fused Figure 3. Lipid droplets as hubs for fatty
B acid trafficking.
(A) During starvation, fatty acids from phospholipid
breakdown in autolysosomes are routed to lipid
droplets, building up triglyceride stores there. This
increase in triglycerides balances the loss of
ATGL-generated fatty acids from droplets to
mitochondria, where they are burned as fuel. Fatty
acids generated at lipid droplets by ATGL can also
activate the PPARa transcription factor in the
ATGL nucleus; the actual ligand for PPARa might be the
Mitochondria fragmented fatty acids themselves or lipids derived from those
fatty acids. (B) Mitochondrial fusion state controls
the usage of lipid-droplet-derived fatty acids.
In starved cells, mitochondria are usually highly
fused (top). The mitochondrial network thus
created allows fatty acids from lipid droplets to be
Lipid droplet Autolysosome evenly distributed throughout mitochondria, pro-
moting equal mitochondrial respiration. When
fusion is prevented (bottom), mitochondria are
fragmented, and efficient uptake of fatty acids and
their metabolic breakdown occurs only in the
mitochondria directly associated with lipid drop-
D High lipid cell Low lipid cell C lets. Unmetabolized fatty acids are re-exported,
either into lipid droplets or into the extracellular
ROS space. (C) Even in clonal populations of cells, there
ROS
is great heterogeneity in the numbers of lipid
droplets per cell. Cells with high lipid storage also
Mix have higher levels of reactive oxygen species
ROS (ROS), presumably as a result of more active fatty
ROS
acid metabolism. (D) When cells with high and low
ROS lipid-droplet content are cultured together, fatty
acids can be transferred from the high-lipid cells to
the low-lipid cells.

ROS ROS
FA

activation [37]. It was proposed that

ATGL-mediated triglyceride hydrolysis
generates the ligands for PPARa [37]
Lipid droplet Vesicle Mitochondrion Respiration Lipases FA flux (Figure 3A). This pathway may be tissue
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specific because liver-specific knock-
down of ATGL impaired the expression
nucleus represents distinct functions of Prp19, or whether the of PPARa target genes in this tissue, but PPARa agonists failed
two populations are connected. Initial experiments with inhibi- to reverse this effect [38].
tors of nuclear export revealed no changes in overall intracellular
Prp19 distribution [34]. Lipid Droplets as Hubs for Fatty Acid Trafficking
Modulation of Lipid Signaling Lipid droplets act as a sink for overabundant fatty acids, and they
Peroxisome proliferator-activated receptors (PPARs) are tran- can release lipids when needed for energy production, synthesis
scription factors bound and activated by lipid ligands, including of membrane components, or signaling. It is becoming increas-
fatty acids and their derivatives. In oxidative tissues, such as the ingly apparent that lipid trafficking to and from droplets is highly
mammalian heart and liver, PPARa promotes the expression of regulated in space (Figure 3A). Fatty acids from triglyceride hy-
proteins involved in lipid homeostasis [35]. In principle, fatty drolysis signal to nuclear receptors (as discussed above); fatty
acids from exogenous sources or synthesized de novo might acids released during autophagy are shuttled through lipid drop-
activate PPARa directly. However, free fatty acids are typically lets, as a way station before import into mitochondria for ATP
channeled, via activation to acyl-CoA, into specific metabolic production; production of steroid hormones in flies requires lipid
pathways [36] and thus are not readily available for signaling. exchange between the ER, lipid droplets, and mitochondria; and
Studies in mice uncovered that PPARa signaling is severely within a population of cells, high accumulation of droplets in a
compromised in the hearts of animals lacking ATGL [37]. Given subset of cells has been proposed to protect the rest of the cells
that lack of ATGL function in the heart causes many profound from fatty acid overload.
changes (such as massive lipid accumulation and mitochondrial Lipid Trafficking between Lipid Droplets and
dysfunction), the effect on PPARa signaling might conceivably Mitochondria
be indirect. Yet pharmacological stimulation of the PPARa In starved mammalian cells, fatty acids fuel ATP production, via
pathway is sufficient to reverse these phenotypes, establishing b-oxidation in mitochondria. These fatty acids could be derived
PPARa signaling as a primary defect in these mutant hearts from triglycerides (Figure 1B,C) or from various membranous
and suggesting a direct link between lipid droplets and PPARa organelles. To follow the flux of fatty acids through various

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compartments, mouse embryonic fibroblasts (MEFs) were associated regulatory factor (Marf), the fly ortholog of mamma-
allowed to incorporate fluorescently labeled lipids into either lipid lian mitofusins, is a small GTPase that promotes fusion of
droplets or membranes, and their fate during starvation was the outer mitochondrial membrane; thus, loss of Marf leads to
monitored by imaging and biochemistry [39]. Fatty acids present small, round mitochondria [44]. Marf-deficient flies show a
as triglycerides in lipid droplets moved to mitochondria fairly particularly dramatic phenotype in the ring gland, an endocrine
quickly and were readily broken down. When ATGL (Figure 1B) tissue responsible for hormone secretion [45]: mitochondrial
was knocked down, transfer of fatty acids was dramatically morphology is altered, the ER is fragmented, and lipid-droplet
reduced and mitochondrial oxygen consumption rates dropped. number is dramatically reduced [44]. Ring gland lipid droplets
Under the starvation conditions employed, lipophagy (Figure 1C) receive sterols from the ER and store them as steryl esters;
was not induced and autophagy made no detectable contribu- these, in turn, are the precursors for the production of the steroid
tion to the transfer of fatty acids from droplets to mitochondria hormone ecdysone in the mitochondrial matrix. Efficient storage
or to mitochondrial oxygen consumption rates. and turnover of steryl esters therefore presumably requires inti-
The rapid relocalization of fatty acids to mitochondria is pre- mate contacts between the three organelles; in Marf mutants
sumably accomplished by direct transfer. Lipid droplets and the contacts between all three organelles were severely reduced
mitochondria indeed display close physical associations [40– [44]. Lack of Marf in the ring gland also greatly impairs ecdysone
42], and direct channeling of fatty acids from their site of release production, with dramatic organism-wide consequences [44].
(droplets) to the site of consumption (mitochondria) would mini- Mitochondria may not be the only organelle for which close
mize the risk of toxic effects elsewhere, such as disruption of contacts with lipid droplets promote efficient transfer of fatty
cellular membranes or inappropriate nuclear signaling. acids. Breakdown of fatty acids is not restricted to mitochondria,
Curiously, during starvation, the number and size of lipid drop- but can also occur in peroxisomes. In the yeast Saccharomyces
lets increased and total cellular triglyceride levels went up [39]. cerevisiae, b-oxidation is even entirely restricted to peroxisomes.
Using fluorescently labeled phospholipids and inhibition of Here, lipid droplets and peroxisomes display intimate physical
autophagy pathways, this effect was traced to autophagic connections, which have been proposed to promote efficient
breakdown of membranous organelles. Presumably, fatty acids coupling of triglyceride breakdown with peroxisomal fatty acid
from phospholipid breakdown in autolysosomes are employed oxidation [46].
to replenish triglyceride stores in droplets upon starvation Lipid-Droplet Specialization across a Cell Population
(Figure 3A). The role of lipid droplets as buffers for fatty acid availability may
Mitochondria can be remodeled by fusion and fission [43], even extend to lipid exchange between cells in the same tissue.
allowing them to form highly interconnected networks or individ- A recent study identified a surprising heterogeneity in lipid-
ual fragments. In starved cells, mitochondria were highly fused, a droplet content in hepatocytes [47]: in mouse liver, some cells
state that is apparently critical for efficient fatty acid import: usu- have substantially larger numbers of lipid droplets than neigh-
ally labeled fatty acids from lipid droplets are homogenously boring cells (Figure 3C); this variability is especially apparent
distributed throughout the mitochondria, but when mitochondria under conditions of high overall lipid storage in the liver. Similar
were fragmented, the label was distributed unevenly [39]. As a variability was observed in primary hepatocytes in culture and
result, fatty acids could not be metabolized as efficiently; with a cultured cell line of liver origin (AML12), suggesting that
although cells with either fused or fragmented mitochondria up- it is due to cell-intrinsic properties, rather than a reflection of
regulate b-oxidation upon starvation, only those with fused mito- overall tissue structure.
chondria were able to maintain these levels of b-oxidation. For Such heterogeneity might arise if some cells have acquired
cells with fragmented mitochondria, levels of b oxidation and, mutations in lipid metabolism. However, a cell sorting strategy
as a result, total mitochondrial respiration, dropped off with demonstrated that heterogeneity is reversible and appears to
time, presumably because not all mitochondria had a sufficient be a population property. After growth on fatty-acid-rich media,
supply of fatty acids (Figure 3B). The likely reason is that there cells were separated by flow cytometry into a low-lipid and a
are many fewer lipid droplets than mitochondrial fragments, high-lipid subpopulation. After culture in standard media to pro-
and that only the mitochondria in direct physical contact with mote breakdown of the stored lipids, the two populations were
lipid droplets can take up fatty acids efficiently. In fused mito- again grown under fatty-acid-rich conditions. Remarkably,
chondria, those fatty acids can diffuse through the entire both cultures showed the same broad distribution in lipid con-
network. In support of this interpretation, when glutamine was tent. Inhibitor studies indicate that heterogeneity arises from
used as an alternative fuel, the fusion state of the mitochondria fluctuations in biochemical networks controlling lipolysis, fatty
did not matter; as glutamine diffuses through the cytoplasm, acid oxidation, and protein synthesis.
its import into mitochondria is not restricted to a limited number At the level of a whole organism, heterogeneity of lipid-droplet
of sites, unlike the supply of fatty acids from lipid droplets. Pre- content is very common. Many animals have adipose tissues
sumably because an oversupply of unmetabolized fatty acids is specialized for storing lipids. It was proposed that heterogeneity
dangerous, fatty acids were re-exported from the mitochondria, within a single cell population similarly sets aside a subpopula-
and either accumulated back in lipid droplets or were released tion of cells that collects lipids particularly well, stores them,
from the cells into the extracellular space [39]. and releases them to their neighbors when needed [47]. To
Efficiency of lipid exchange between mitochondria, ER, and test this idea, high-lipid cells were isolated in which lipid droplets
lipid droplets may also underlie a recent observation that had accumulated fluorescently labeled fatty acids. After co-cul-
promotion of mitochondrial fusion is important for lipid-droplet ture with low-lipid cells (marked with a different fluorescent dye
formation and steroid signaling in Drosophila. Mitochondrial to distinguish the two original populations), the high-lipid group

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had lost — and the low-lipid group had gained — some of the [55]. For the final maturation, the virus hijacks the pathway
labeled fatty acids. Thus, the high-lipid cells can indeed supply responsible for secretion of the very-low-density lipoprotein
lipids to their neighbors (Figure 3D). (VLDL) particles, and virions are released into the extracellular
But what is the point of setting aside a subpopulation of cells space as low-density lipoviroparticles [56], whose lipids may
with especially high lipid stores if — in the long run — the lipids ultimately be derived from lipid droplets. HCV is not unique in
are presumably needed equally across cells? One possibility its use of lipid droplets; several other viruses assemble with
has to do with the fact that overaccumulation of free fatty acids the help of lipid droplets [57,58].
is dangerous, both because of disruption of membranes and Droplet accumulation is a necessary step for virus maturation;
because of toxic metabolites generated by fatty acid break- if the interaction between core protein and lipid droplets is dis-
down. The high-lipid subpopulation indeed showed higher levels rupted, either with mutations in core protein or via pharmacolog-
of oxidative damage, as seen by levels of reactive oxygen spe- ical approaches, core protein stability is greatly reduced and
cies (ROS; Figure 3C). Importantly, when fluorescently marked virion assembly is impaired [59,60]. Thus, preventing the recruit-
low-lipid cells were co-cultured with either low-lipid or high-lipid ment of viral proteins to droplets is an attractive target for dis-
cells (unmarked) and challenged with fatty-acid-rich media, the rupting the viral life cycle. Droplet targeting requires cis-acting
marked cells displayed lower ROS levels in the presence of sequence motifs in both core protein and NS5A [61,62], but
high-lipid cells. Thus, the presence of high-lipid cells protected also trans-acting host factors. In particular, DGAT1, one of the
their low-lipid neighbors. High-lipid cells may remove fatty acids two enzymes mediating triglyceride synthesis (Figure 1A), plays
more efficiently from the media, and thus the flux of free fatty a crucial role: DGAT1 binds to both NS5A and core protein,
acids into the low-lipid cells is reduced. Remarkably, in the co- and this interaction mediates recruitment of both proteins to
culture experiment with high-lipid cells, ROS levels were not droplets and is required for efficient virion assembly [63,64].
only reduced for the marked low-lipid cells, but also for the pop- Interestingly, inhibiting the enzymatic activity of DGAT1 is suffi-
ulation as a whole. cient to prevent droplet targeting of these proteins. Since
Although the detailed mechanisms underlying these protec- DGAT1 generates only a subset of lipid droplets (the others
tive effects remain to be worked out, the reported experiments depend on DGAT2; Figure 1A), it was proposed that DGAT1 con-
nicely demonstrate a novel strategy, namely heterogeneity in centrates the viral proteins at the sites where it promotes lipid-
lipid-droplet accumulation, to alleviate risks from overabun- droplet formation and thus guides the viral proteins onto just
dance of lipids. By accumulating more lipid droplets and more these lipid droplets [64] (Figure 4A).
ROS, the high-lipid subpopulation reduces the overall risk of lip- Lipid Droplets as Stores for Antiviral and Antibacterial
otoxicity. It is not yet clear how the high-lipid population is able to Proteins
handle its increased risk: these cells may induce specific protec- Viperin (which stands for virus inhibitory protein, ER associated,
tive mechanisms, or they might repair their damage during the interferon inducible) is an interferon-induced protein with broad
time when they find themselves in the low-lipid state (which antiviral activity [65,66]. Viperin is targeted to the cytoplasmic
will occur sooner or later, due to the stochastic nature of the face of the ER and is also enriched around lipid droplets [62];
heterogeneity). Since heterogeneity has been observed in targeting to both locations is mediated by an amino-terminal
cultured cells of various origins [47], this protective strategy amphipathic a-helix [62]. Intriguingly, two of the viruses com-
may be employed not just by hepatocytes, but more generally batted by viperin, HCV and Dengue virus, employ droplets for
in other cell types. their assembly. Using confocal microscopy and fluorescence
resonance energy transfer (FRET), viperin was shown to interact
Lipid Droplets and the Fight against Pathogens with the HCV nonstructural protein NS5A at the droplet surface,
It has been long known that lipid droplets play important roles in via its carboxy-terminal region [67]. This interaction as well as the
the immune system. They are sites of synthesis of eicosanoids, amino-terminal droplet-targeting helix are required for viperin’s
signaling lipids important for inflammation, host defense against antiviral activity against HCV [67]. For Dengue virus, in contrast,
pathogens, and cancer [48]. Various pathogens have, in turn, while a physical interaction with the viral protein NS3 was impor-
evolved strategies to tap into the lipid droplets of the host tant, droplet binding was dispensable for the anti-viral effect [68].
to ensure a sufficient lipid supply [49,50]. Recent years have The amino-terminal a-helix in viperin was also important to
uncovered how certain viruses appropriate lipid droplets as restrict the replication of chikungunya virus, though presumably
assembly platforms and how cells use lipid droplets in novel through localization at the ER, rather than at lipid droplets [69].
ways to fight back. Thus, at least in some cases, viperin apparently targets a
Lipid Droplets and Viral Assembly droplet-dependent step of viral replication and its enrichment
Infection with hepatitis C virus (HCV) is a global public health on the droplet surface is necessary for its activity (Figure 4A).
threat and can lead to liver cirrhosis and liver cancer [51]. For As discussed earlier, lipid droplets can be associated with his-
part of its life cycle, HCV crucially depends on lipid droplets tones. This observation potentially has implications for immunity
(see [52,53] for recent reviews): after infection, two newly ex- since histones are increasingly recognized as antibacterial
pressed viral proteins transiently accumulate on lipid droplets: agents [70,71]: in vitro, histones have broad antibacterial activity
core protein, which is the major structural protein of the virus, [72], and histones present in extracellular secretions have been
and NS5A, a regulator of viral replication. Droplet-bound viral reported to contribute to protection against bacterial pathogens
proteins then interact with the sites of viral RNA replication, a [73,74]. Analysis in Drosophila suggests that histones bound to
process facilitated by the droplet-localized Rab18 [54] and lipid droplets can similarly provide a defense against intracellular
by dynein-mediated intracellular relocalization of lipid droplets bacterial invaders [75]. Droplets biochemically purified from

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 Current Biology

Review

A B Lipid droplets Lipid droplets Figure 4. Novel interactions between lipid

with histones without histones droplets and pathogens.
Injection of (A) During hepatitis C virus replication, newly
bacteria synthesized core and NS5A proteins are (after
processing) attached to the ER. Via physical in-
teractions with DGAT1, they are guided to nascent
Lipid droplet lipid droplets and thus accumulate on the lipid-
droplet surface. This accumulation is a necessary
step for later virion assembly. The antiviral protein
viperin also accumulates on lipid droplets, where it
NS5A physically interacts with NS5A. This interaction
Viperin suppresses NS5A’s function in viral replication.
Core (B) When bacteria are injected into the cytoplasm
of wild-type Drosophila embryos (left), they are
killed via lipid-droplet-associated histones, allow-
ing embryo survival. After injection into mutants
lacking droplet-bound histones (right), the bacteria
DGAT1 ER Bacteria die out Bacteria proliferate proliferate and kill the host.
Embryos live Embryos die
Current Biology

Drosophila embryos are associated with high levels of certain Hereditary Spastic Paraplegias and Lipid Droplets
histones [25] and are highly bactericidal in vitro [75]. A number Hereditary spastic paraplegias (HSPs) are inherited disorders
of independent approaches, including using histone antibodies characterized by motor-sensory axon degeneration, weakness
and mutations in the histone anchor Jabba [26], showed that in lower extremities, and spasticity [84]. Mutations in over 50
this killing activity of droplets was due to histones. loci can cause HSP, and the cellular functions of the encoded
To test whether droplet-bound histones are protective in vivo, proteins show a surprising heterogeneity. Recently, a number
wild-type and Jabba mutant embryos were injected with GFP- of HSP candidate genes have been shown to have crucial roles
labeled Escherichia coli; while bacterial numbers diminished in in lipid-droplet biology: atlastin, REEP1, seipin, spartin, spastin,
the wild type, they dramatically increased in the mutants [75] and kinesin-1. Atlastin mediates fusion of ER tubules and also
(Figure 4B). In the same injection assay, wild-type embryos controls the size of lipid droplets [85]. REEP1 maintains the
also showed significantly higher levels of survival when chal- high curvature of ER tubules and, when overexpressed together
lenged with a number of Gram-positive and Gram-negative bac- with atlastin, increases lipid-droplet size [85,86]. Seipin, an inte-
teria. This new immune mechanism may also operate at other gral membrane protein at the ER–droplet junction, is important
developmental stages: when adult flies were infected with the for lipid-droplet formation and maintenance [87,88]. Spartin
intracellular pathogen Listeria monocytogenes, Jabba mutants localizes to lipid droplets, interacts with E3 ubiquitin ligases,
were impaired in restricting bacterial titers and were killed and modulates the turnover of lipid-droplet proteins [89–91];
much more readily than wild-type flies [75]. Loading up lipid spartin knockout mice have increased lipid-droplet numbers in
droplets with histones to kill bacterial invaders may be a their adipose tissue [92]. Spastin is a microtubule-severing pro-
conserved innate immunity mechanism, since when mice were tein that mediates remodeling of the cytoskeleton; in mammalian
challenged with lipopolysaccharide — to mimic bacterial infec- cells, a particular spastin isoform harbors a lipid-droplet target-
tions — the levels of droplet-bound histone H1 increased in the ing sequence, and depletion of spastin in Drosophila or
liver [75]. C. elegans alters lipid-droplet number and cellular triglyceride
content [93]. KIF5A encodes the microtubule motor kinesin-1;
Lipid Droplets and the Nervous System the same motor powers the motion of lipid droplets in Drosophila
Lipid metabolism plays crucial roles in the nervous system, for [94]. Finally, several of the HSP candidate genes encode en-
many membrane functions and signaling events [76–78]. Yet un- zymes implicated in phospholipid or fatty acid metabolism
til recently, there has been only sparse and unconnected infor- [95,96]; their dysfunction might therefore alter the supply or
mation on the role of lipid droplets in neurons and other cells composition of the lipids stored in lipid droplets. These observa-
of the nervous system. For example, lipid droplets have been de- tions raise the intriguing possibility that aberrant lipid-droplet
tected in the axons of Aplysia neurons cultured in vitro [79] and in biogenesis or function might contribute to axonal degeneration.
cultured neurons and brain sections of Huntington’s disease However, since all of these proteins also have functions unre-
models [80]. There are also links between a-synuclein, a protein lated to lipid droplets (such as controlling ER structure or pro-
whose dysfunction or overexpression can cause Parkinson’s moting vesicle trafficking), the link between lipid droplets and
disease, and lipid droplets: a-synuclein has been reported to HSPs remains tentative.
bind to lipid droplets in vitro [81] and in cultured cells [82], and A much more direct connection to lipid droplets has recently
overexpression in yeast promotes droplet accumulation [83], emerged from the analysis of the HSP gene DDHD2 [97]. Patients
but the relevance of these observations for a-synuclein’s in vivo with mutations in DDHD2 exhibit very early onset of the disease
function and for neurodegeneration has yet to be explored. How- (<2 years) and are often intellectually disabled [98]. The DDHD2
ever, recent papers have identified the presence of lipid droplets gene is highly expressed in the brain and encodes a serine
in neurons and in glia under certain disease conditions and sug- hydrolase that displays phospholipase activity in vitro. To deter-
gest that disrupted lipid-droplet function can contribute to neu- mine its function in vivo, DDHD2 activity was abrogated geneti-
rodegeneration. cally, using knockout mice, as well as pharmacologically, with

R476 Current Biology 25, R470–R481, June 1, 2015 ª2015 Elsevier Ltd All rights reserved
Current Biology

Review
Figure 5. A link between lipid droplets and
A B C
Neuron neurodegeneration.
(A) In healthy neurons and glia, few (if any) lipid
ROS droplets are present. (B) High levels of ROS in
ROS neurons, due to mitochondrial dysfunction, lead to
neurodegeneration and to accumulation of lipid
Mitochondrion
droplets in glia. Droplet accumulation requires the
JNK SREBP Lipase JNK and SREBP pathways in neurons. (C) Over-
expression of triglyceride lipases in neurons or
glia or both reduces the number of glial lipid
droplets and delays neurodegeneration, indicating
a mechanistic role for lipid metabolism and glial
Lipid droplets Lipase
lipid droplets.

Glia
effect because CPT2 is expressed pre-
dominantly in glia and CPT2 expression
solely in glia is sufficient to reverse triglyc-
eride accumulation in the brain. Flies lack-
ing CPT2 have a dramatically reduced
Healthy Degeneration Degeneration slowed
Current Biology
lifespan, and glial-specific CPT2 expres-
sion was able to partially rescue this
defect, indicating that triglyceride meta-
selective inhibitors [97]. In both cases, adults accumulated large bolism in glia may make an important contribution to overall
amounts of triglycerides in the brain and the spinal cord, but organismal energy metabolism.
there was little to no effect in other tissues; brain phospholipid Lipid droplets can accumulate in glia also non-cell-autono-
content was unchanged. These observations suggest that mously, in response to mitochondrial dysfunction in neighboring
DDHD2 has a specific function in triglyceride metabolism of neurons [103]. For a subset of Drosophila mutants known to
the central nervous system. It likely acts as a triglyceride lipase cause neurodegeneration in adult photoreceptors [104], abun-
since recombinant DDHD2 expressed in cultured cells displays dant lipid droplets transiently accumulate in the glial cells next
triglyceride hydrolase activity and, compared with wild type, to photoreceptors, prior to or concomitant with the onset of
total triglyceride hydrolase activity is significantly reduced in neurodegeneration. No droplets were observed in the wild type
brain lysates of DDHD2 mutant mice [97]. Finally, the main tri- or in the neurons of mutant animals [103] (Figure 5A,B). The
glyceride hydrolase in the fat body of the moth Manduca sexta mutants that showed accumulation of droplets in glial cells all
shares extensive sequence homology with DDHD2 [99]. affect mitochondrial function and, in particular, cause increased
The brains of DDHD2 knockout mice displayed abundant lipid levels of ROS. Elevated ROS are indeed critical for droplet for-
droplets, while lipid droplets were only rarely detected in wild- mation in glia because pharmacological or genetic reduction of
type brains [97]. They accumulated predominantly in neurons ROS prevented droplet accumulation. Lipid droplets were also
and were present in cytoplasm, dendrites, and axons. The detected in glial cells in a mouse model of neurodegeneration
DDHD2 knockout mice also exhibited deficits in motor coordina- caused by mitochondrial dysfunction, suggesting an evolution-
tion and cognition [97], reminiscent of the defects in the human arily conserved pathway.
patients [98]. Intriguingly, in the patients, cerebral magnetic reso- How do ROS promote the accumulation of glial lipid droplets?
nance spectroscopy revealed an abnormal spectrum, with a The full pathway has yet to be worked out, but activation of
peak characteristic of lipid accumulation [98], though it is not c-Jun-N-terminal kinase (JNK) and sterol regulatory element
yet known whether this peak represents triglycerides. While binding protein (SREBP) pathways are critical; JNK mediates
the mechanisms that link droplet accumulation and neuronal stress responses [105] and SREBP controls transcription of
impairment remain obscure, one intriguing observation is that many metabolic genes and, in particular, promotes lipogenesis
in the DDHD2 knockout mice some of the large droplets [106,107]. Although droplets accumulate in glia, the trigger for
observed were associated with noticeable swellings of the accumulation originates in neurons: when the mitochondrial
neuronal processes and thus might present obstacles to intra- genes identified were knocked down in glia, there was no effect;
cellular trafficking in the relatively thin axons and dendrites. knockdown only in neurons was sufficient to promote glial lipid
Glial Lipid Droplets droplets. In addition, expression of an antioxidant enzyme or
Glial cells are non-neuronal cells that surround neurons and play knockdown of JNK solely in neurons was able to reduce glial
important supportive roles in the central and peripheral nervous droplet accumulation. Thus, mitochondrial dysfunction and
system. Lipid droplets have been observed in culture in primary elevated ROS in photoreceptors cause accumulation of lipid
glia as well as in glia-derived cell lines [100,101]. When carnitine droplets in glia in a non-cell-autonomous manner.
palmitoyltransferase 2 (CPT2), a mitochondrial enzyme neces- Damage to neurons resulting from mitochondrial dysfunction
sary for b-oxidation of long-chain fatty acids, is abolished in flies, therefore leads both to transient formation of lipid droplets in
massive amounts of triglycerides accumulate specifically in the glia and to neurodegeneration. Are these lipid droplets an ulti-
brain of adults; glial cells, but not neurons, accumulated abun- mately futile protective response, do they promote neurodegen-
dant lipid droplets [102]. This seems to be a cell-autonomous eration, or are they innocent bystanders? Activation of JNK or

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 Current Biology

Review

SREBP in neurons in the absence of ROS still leads to glial lipid some insights into the importance of direct contacts between
droplets, but not neurodegeneration [103]. Thus, glial lipid drop- lipid droplets and mitochondria [42], little is known about the
lets per se are not detrimental for neurons. The culprit might molecular mechanisms controlling this trafficking. For fatty
be lipids damaged by ROS, given that the mutants leading to acid trafficking modulated by droplet heterogeneity between
neurodegeneration displayed dramatically elevated levels of cells (Figure 3C,D), there are intriguing hints that heterogeneity
peroxidated lipids. Furthermore, expression of two different is a regulatable property since the extent of heterogeneity is
lipases, the ATGL homolog Brummer or the LAL homolog Lip4 different between cells of different origin [47], but the control
(Figure 1B,C), dramatically reduced both lipid-droplet accumula- pathways remain to be worked out.
tion and the levels of peroxidated lipids and also delayed neuro- For lipid droplets in the nervous system, it is now established
degeneration (Figure 5C) [103]. These observations strongly that both neurons and glia can accumulate lipid droplets under
suggest that neurodegeneration is driven by altered lipid meta- certain disease conditions. But what role they play under these
bolism, although the exact role of lipid droplets remains to be conditions and whether droplets are normally present in the ner-
elucidated. vous system is far from clear. For example, in the fly models of
The fatal neurodegenerative disease amyotrophic lateral scle- neurodegeneration (Figure 5), it was proposed that accumulation
rosis (ALS) has recently also been linked to lipid droplets. of lipid droplets in glia promotes neurodegeneration, as long as
A particular subtype of ALS is caused by mutations in the human high ROS levels provide a second insult [103]. However, lipase
VAMP (vesicle-associated membrane protein)-associated pro- overexpression in glia only mildly delayed neurodegeneration,
tein B (hVAPB). Equivalent mutations in the fly ortholog DVAP, whereas lipase overexpression in neurons, where no droplets
when ectopically expressed, lead to degeneration of fly photore- were detected, had a much stronger protective effect. It will be
ceptors. In genetic screens for enhancers and suppressors of this very interesting, in these examples and in the mouse models of
phenotype, one of the most represented functional categories HSP, to examine whether ablation of droplet biogenesis in spe-
was proteins linked to lipid droplets, including proteins involved cific cell types modulates the disease phenotypes, for better or
in droplet biogenesis and droplet motility [108]. The proteins for worse, and how these effects compare to disruption or upre-
such identified will provide a rich source for follow-up studies to gulation of turnover pathways (Figure 1B,C). Real-time imaging
dissect how lipid droplets might impact neurodegeneration. of the trafficking of labeled fatty acids (as in [39]) and character-
ization of the lipidomes and proteomes of these droplets will pro-
Perspective vide complementary information to characterize exactly how
The crucial roles of lipid droplets in energy homeostasis and lipid lipid metabolism is derailed in the disease conditions.
metabolism have focused a lot of recent attention on these still Given the diverse novel roles proposed for lipid droplets, drop-
relatively understudied organelles. Yet the examples discussed lets should be on the radar screen of many a biologist trying to
above show that lipid droplets play even broader roles and touch uncover the mechanistic basis of an ill-characterized process.
on biological processes only loosely connected to their tradition- With the recent insights into biogenesis and turnover of lipid
ally studied functions. droplets [14], one can now systematically determine how a pro-
In particular, lipid droplets contribute to protein trafficking and cess is affected if droplets are entirely absent, are structurally
protein maturation in the cell. They exchange proteins with the abnormal, or cannot be degraded. Because lipid droplets are
nucleus, modulate protein stability, and allow concentrated ubiquitous organelles but have been carefully studied in only a
accumulation of antiviral and antibacterial proteins. We do not few cell types, it seems likely that, as our understanding of these
know enough to judge whether these processes have indepen- unique and dynamic organelles deepens, their cellular and phys-
dently evolved and all just happen to take advantage of lipid iological roles will keep expanding.
droplets or whether they are indicative of a general cellular
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