Biochimica et Biophysica Acta 1831 (2013) 575581

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Biochimica et Biophysica Acta

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Review

Phospholipid metabolism and nuclear function: Roles of the

lipin family of phosphatidic acid phosphatases
Symeon Siniossoglou
Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge, CB2 0XY, United Kingdom

a r t i c l e

i n f o

Article history:
Received 31 July 2012
Received in revised form 19 September 2012
Accepted 24 September 2012
Available online 29 September 2012
Keywords:
Phosphatidic acid
Phosphatidic acid phosphatase
Lipin
Nucleus
Nuclear envelope
Nuclear lipids

a b s t r a c t
Phospholipids play important roles in nuclear function as dynamic building blocks for the biogenesis of the
nuclear membrane, as well as signals by which the nucleus communicates with other organelles, and regulate
a variety of nuclear events. The mechanisms underlying the nuclear roles of phospholipids remain poorly understood. Lipins represent a family of phosphatidic acid (PA) phosphatases that are conserved from yeasts to
humans and perform essential functions in lipid metabolism. Several studies have identied key roles for lipins
and their regulators in nuclear envelope organization, gene expression and the maintenance of lipid homeostasis
in yeast and metazoans. This review discusses recent advances in understanding the roles of lipins in nuclear
structure and function. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.
2012 Elsevier B.V. All rights reserved.

1. Introduction
The nucleus is traditionally the focus of studies of DNA and RNA
metabolism. It often appears detached from the world of lipid metabolism, commonly thought of as a cytoplasmic function. However, it
is now becoming increasingly clear that phospholipid metabolism is an
important player in nuclear physiology. A signicant number of phospholipid metabolic enzymes have been localized in the nucleus and
phospholipids or their water-soluble metabolites can regulate gene
expression, nucleocytoplasmic transport and nuclear organization.
These observations raise some fascinating questions with respect to nuclear biology. Are these enzymes active in the nucleus, and if so, what
are the molecular mechanisms by which their intranuclear lipid products
regulate nuclear functions? Since many of these enzymes are also active
on cytoplasmic membranes, is their function in the two compartments
somehow coordinated and if so, what are the underlying mechanisms?
And, given the emerging view of the nuclear envelope as a master

Abbreviations: CDP-DAG, cytidine diphosphate diacylglycerol; DAG, diacylglycerol; ER,

endoplasmic reticulum; mTORC, mammalian target of rapamycin complex; NES, nuclear
export signal; NLS, nuclear localization signal; NEBD, nuclear envelope breakdown; PA,
phosphatidic acid; PC, phosphatidylcholine; PE, phosphatidylethanolamine; PGC, peroxisome proliferator-activated receptor gamma co-activator; PI, phosphatidylinositol; PI-PLC,
phosphatidylinositol-specic phospholipase C; PPAR, peroxisome proliferator-activated repressor; SREBP, sterol regulatory element-binding protein; TAG, triacylglycerol; UASINO,
inositol-responsive upstream activating sequence
This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.
Corresponding author. Tel.: +44 1223 762641; fax: +44 1223 762640.
E-mail address: ss560@cam.ac.uk.
1388-1981/$ see front matter 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.bbalip.2012.09.014

regulator of nuclear function, do nuclear lipid metabolic enzymes have a

role in growth and development by controlling nuclear architecture?
Here, I will discuss some of these issues focusing on the lipin family of
PA phosphatases, the latest addition to the list of phospholipid metabolic
enzymes with a dual nuclear and cytoplasmic life. Since the identication
of the lipin family [1] and the demonstration of their PA phosphatase
activity in yeast [2] and mammals [2,3], lipins have emerged as key
players in lipid metabolism with roles in multiple organellar membranes.
Although their enzymology and regulation have been intensively studied
(reviewed in [4], this issue), the physiological roles of lipins in the nucleus and how their activity is connected to nuclear structure and function
are less well explored. This review will summarize relevant ndings
from yeast and metazoans, highlighting similarities in function as well
as the differences, which are characteristic of each model system.
2. Enzymes of phospholipid metabolism in the nucleus
The basic design of the phospholipid biosynthetic pathway is conserved from yeast to mammals [5,6]. In both cases, the glycerol backbone of the central phospholipid precursor, phosphatidic acid (PA),
partitions between the two major branches of the pathway (Fig. 1). In
one branch, PA is dephosphorylated to diacylglycerol (DAG) that is
then used for the synthesis of the most abundant phospholipids phosphatidylethanolamine (PE) and phosphatidylcholine (PC), through the
CDP-ethanolamine and the CDP-choline arms of the Kennedy pathway,
respectively. In the other branch, PA is converted to CDP-DAG that gives
rise to phosphatidylinositol (PI), phosphatidylglycerol and cardiolipin.
Yeast cells synthesize also phosphatidylserine (PS), PE and PC via

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different phosphoinositides that are at the heart of a complex signaling

network regulating several aspects of growth and development [19]. In
addition to their cytoplasmic signaling roles, many of these enzymes are
also found in the nucleus where they regulate cell cycle progression,
gene expression and pre-mRNA processing [9,20]. A key reaction in
nuclear lipid signaling is mediated by PI-specic phospholipase C
(PI-PLC) that cleaves the inositol headgroup of one of these PIPs,
phosphatidylinositol 4,5-bisphosphate (PIP2), and releases DAG and
water-soluble inositol (1,4,5)P3 (IP3) [20,21]. The latter, through the
action of inositol phosphate kinases (IPKs) in the nucleus, is used as a
precursor for the generation of higher inositol polyphosphate species,
with established roles in transcription, DNA repair and mRNA export
through the nuclear pore complex [22]. For example, in yeast, chromatin remodeling by nucleosome movement is regulated by inositol
polyphosphates [23,24]. Additionally, six kinases that phosphorylate
DAG to generate PA (DGKs) have been found in the nucleus, although
their nuclear functions have not been dened to the same extent as
their PI/PIP counterparts [25,26]. An intriguing aspect of nuclear lipid
metabolism is the evidence that some of these phospholipids exist not
only within the inner nuclear membrane, but in compartmentalized
pools in the nucleus as well. These lipid pools have been detected
both by biochemical and imaging approaches [2731], however, the
molecular mechanisms responsible for their intranuclear distribution
remain largely elusive.
3. Lipins in the nucleus
3.1. Lipins and the regulation of lipid homeostasis

Fig. 1. Simplied scheme of the role of lipins in the de novo phospholipid biosynthetic
pathways. Glycerol 3-phosphate (G3P) is converted though a series of acylations with
fatty acids (FA, not depicted here) into phosphatidic acid (PA). PA is a key precursor
that is used, through its conversion to diacylglycerol (DAG), and in the presence of ethanolamine (Etn) and choline (Cho), for the synthesis of the major phospholipids phosphatidylethanolamine (PE) and phosphatidylcholine (PC), respectively (Kennedy
pathway). In the other major branch of the pathway, PA is converted to cytidine diphosphate diacylglycerol (CDP-DAG) which then gives rise to phosphatidylinositol
(PI). In yeast CDP-DAG is also used for the synthesis of PE and PC (shaded box). DAG
can be also acylated to generate triacylglycerol (TAG).

CDP-DAG (Fig. 1). The last step in this pathway, the production of PC by
the methylation of PE, is also conserved in mammalian hepatocytes. The
endoplasmic reticulum (ER) is the main organelle that produces the
bulk of structural phospholipids and sterols, which are then distributed
for the biogenesis of the other membrane-bound organelles via vesicular and non-vesicular pathways [7].
A surprising aspect of phospholipid metabolism is the presence of a
number of key enzymes in the nucleus [8,9]. One well studied case is
CTP:phosphocholine cytidylyltransferase (CCT), the enzyme that
catalyzes the rate-limiting step in the CDP-choline pathway for PC synthesis. CCT is ubiquitously expressed in mammalian tissues [10]. In
many cell types, including the evolutionarily distant budding yeast
(where it is known as Pct1p), CCT localizes in the nucleus via a classic
nuclear localization signal (NLS) [1113] but is known to translocate to
the cytoplasm when there is increased demand for PC production
[14,15]. Given that the enzymes catalyzing the nal step in PC synthesis,
after the CCT step, localize to the ER and Golgi [16,17], it is possible
that nuclear CCT functions as a reserve for a rapid response to cellular
PC needs. However, puried nuclei can support synthesis of PC [18], so
nuclear CCT may also have a role in the production of a phospholipid
pool in the nucleus with a structural or signaling function.
In addition to CCT, the nucleus contains an extensive panoply of
lipid kinases and phosphatases. Phosphorylation of the PI polar inositol
headgroup through the action of PI or phosphoinositide (PIP) kinases at
a single or multiple hydroxyl groups, respectively, generates seven

Lipins catalyze the Mg2+-dependent dephosphorylation of PA to

DAG [2,3], which can then be used for the production of phospholipids
through the Kennedy pathway (Fig. 1). Because PA is also used for phospholipid synthesis via CDP-DAG, the regulation of lipin activity determines the distribution of the glycerol backbone between the two
branches of the pathway (Fig. 1). In addition, DAG produced by lipins
can be acylated to form TAG stored in lipid droplets.
Lipins are well conserved in eukaryotes. Fungi, nematodes and insects express one lipin, whereas mammals express three paralogues
called lipin 1 (with three described isoforms, 1, 1 and 1), lipin 2
and lipin 3 that display distinct but overlapping expression in many
mouse and human tissues [3,32,33]. All lipins exhibit similar overall primary organization (Fig. 2): they contain a conserved amino-terminal
domain (N-LIP) of unknown function and a carboxy-terminal catalytic
domain (C-LIP) with a DXDXTV motif required for PA dephosphorylation. The yeast enzyme contains an amino-terminal amphipathic helix
mediating its membrane recruitment [34]. Consistent with their
key lipid metabolic roles, loss of lipin function disrupts phospholipid
synthesis, membrane organization, lipid droplet biogenesis and TAG
production in several model organisms [reviewed in 35]. A mouse carrying deleterious mutations in lipin 1 lacks white and brown adipose
tissue depots, due to inhibition of adipogenesis [1,36], and displays defects in myelin sheath formation in peripheral nerves resulting in severe
neuropathy [1]. In both cases, there is evidence that defects in TAG production as well as accumulation of PA and deregulation of downstream
signaling contribute to the observed phenotypes [1,3739]. In addition,
a rat model carrying a lipin 1 allele lacking the catalytic site exhibits reduced white fat size and decreased levels of adipogenic markers [40].
Yeast and mammalian lipins are regulated by multisite phosphorylation mediated by several kinases, including cyclin-dependent
kinases and the mTOR kinase [4147]. Phosphorylation induces lipin
membrane dissociation while their dephosphorylation takes place
onto membranes where the enzymes must be active in order to access their substrate PA. The rst lipin phosphatase was identied in
budding yeast [48,49]. Pah1p dephosphorylation by the transmembrane complex consisting of a catalytic phosphatase subunit, Nem1p
and a regulatory subunit, Spo7p increases its PAP phosphatase

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Fig. 2. Domain and motif organization of the yeast (S. cerevisiae) Pah1p and mammalian (M. musculus) lipin 1. All members of the lipin family contain a conserved
amino-terminal domain (N-LIP) of an unknown function and a C-terminal catalytic domain that contains a HAD-like phosphatase motif (DxDxT). The yeast enzyme contains
an amino-terminal amphipathic helix mediating its membrane recruitment, a predicted bipartite NLS (but with no published evidence yet that it directs nuclear transport of
Pah1p) and a short carboxy-terminal acidic stretch of unknown function. Lipin 1 contains a polybasic sequence (PBs) with a dual function as a NLS and PA binding motif. A
serine rich domain (SRD) mediates interaction of lipin 1 with 14-3-3 proteins and is
responsible for its cytosolic retention. Within its C-LIP domain, lipin 1 contains a
LxxIL transcriptional co-activator motif that is required for its interaction and activation with transcription factors. The multiple phosphorylation sites on both yeast
Pah1p and mammalian lipins are not shown here.

activity and correlates with its membrane translocation [34,41,42,49].

The mammalian orthologue complex of Nem1pSpo7p has been recently identied as the Dullard-TMEM188 transmembrane complex
(now renamed as CTDNEP1-NEP1R1) [50,51], suggesting that the
lipin recruitment pathway could be conserved across eukaryotes.
3.2. Nucleocytoplasmic transport of lipins
The rst evidence that lipins can be found in the nucleus came
from the study describing the lipin gene family, where it was shown
that overexpressed mouse lipin 1 is nuclear in HEK293 cells and mutation of a conserved residue within its N-LIP domain, responsible for
lipodystrophy in mice, blocked nuclear import [1]. Most lipins contain
predicted NLS's and display both cytoplasmic and nuclear localization in
ies [52,53], worms [54,55] and mammals. At least for lipin 1, the most
extensively studied mammalian member of the family, mutation of its
NLS impairs its nuclear import in several different cell types [5658].
In addition, there is evidence that lipin 1 is exported from the nucleus
via an exportin 1/XPO1-dependent pathway [58], although no nuclear
export signal (NES) has been identied on any lipin yet.
In yeasts, genetic interaction data in yeasts link lipins to the nuclear
pore complex: the Schizosaccharomyces pombe lipin orthologue, Ned1, interacts with a component of the nuclear pore complex (nucleoporin) and
shows genetic interactions with factors involved in nucleocytoplasmic
transport [59], while in Saccharomyces cerevisiae loss of Nem1pSpo7p
is synthetically lethal with nucleoporin mutations [48]. The steady
state localization of a Pah1GFP fusion is cytoplasmic but a pool of the
enzyme localizes dynamically in the nucleus (Karanasios and
Siniossoglou, unpublished data), and an overexpressed plant lipin is nuclear in yeast cells treated with oleic acid [60].
The regulation of the steady state distribution of lipins appears to be
complex and is probably mediated by multiple factors that could inuence cytoplasmic retention, nuclear import or nuclear export rate. The
physiological stimuli that control nuclear import of lipins are largely
unknown and have only started to emerge. Inhibition of pro-growth
signals, like nutrient availability and growth factors, induce lipin 1
translocation to the nucleus where it represses expression of lipogenic
genes [47] (see also below). A recent study reported that hypoxia
causes also nuclear accumulation of lipin 1 [61]. How nuclear

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translocation of lipin relates to cellular PA levels and phospholipid biosynthesis is currently not known.
The complexity of the signals that govern nucleocytoplasmic transport of lipins is highlighted by the distribution of lipin 1 isoforms:
although lipin 1 and lipin 1 contain the same NLS, the former is predominantly nuclear while the latter is predominantly cytoplasmic in a
number of different cell lines [32,56,62,63]. In primary mouse embryonic broblasts (MEFs), these distinct localizations correlate with distinct
functions of the two isoforms: lipin 1 is required for the induction of
adipogenic transcription factors (adipocyte differentiation) while lipin
1 is required for the induction of lipogenic genes (lipid biosynthesis)
[32]. As lipins are amphitropic proteins that partition between a soluble
and a membrane-bound pool that is active in PA dephosphorylation, an
important determinant of nucleocytoplasmic transport could be their
membrane occupancy. Consistent with this hypothesis, deletion of the
lipin 1 NLS impairs both its nuclear import and the membrane association, suggesting that the same sequence may be involved in these two
processes [56]. Both NLS's and PA binding motifs consist of short stretches
of basic residues [64]. Moreover, the NLS of lipin 1 was shown to function also as a PA binding motif suggesting that interaction with PA may
antagonize nuclear import [58]. A link between PA binding and nuclear
import has been made previously in yeast where the PA binding sequences of Opi1p and Spo20p, two proteins moving between the nucleus
and the cytoplasm in response to changes in PA levels, overlap with their
NLS's [65,66]. How a protein, once in the nucleus, can sense changing PA
levels on cytoplasmic membranes, is not clear but continuous shuttling
between the two compartments with the protein being trapped in the
latter when PA levels reach a threshold may provide a mechanism.
Post-translational modications inuence the nucleocytoplasmic
distribution of lipin 1. Sumoylation of lipin 1 in neuronal cells has
been shown to promote nuclear import of lipin 1 [62]. In addition,
studies have highlighted a key role for phosphorylation in the
nucleocytoplasmic transport of lipin 1. In mouse adipocytes, insulindependent phosphorylation of lipin 1 on multiple sites correlates with
an increase of its soluble pool [45] and inhibits its nuclear import
through interactions with 14-3-3 proteins [57]. More recently it was
demonstrated that mTORC1-dependent phosphorylation of lipin 1
inhibits its nuclear import and that a 17-site phosphorylation decient
lipin 1 accumulates in the nucleus [47]. Consistent with this, ectopic
expression of the mammalian lipin 1 phosphatase complex CTDNEP1NEP1R1 led to lipin 1 nuclear accumulation [51]. Given that dephosphorylation of lipins promotes their membrane binding as well, these
observations raise again the possibility of a link between ER membrane
recruitment and nuclear import of lipins. Dephosphorylation and
recruitment at the inner nuclear membrane could be also necessary
for their intranuclear retention, if lipins are active as PA phosphatases
in the nucleus as well (see below). Indeed, two studies have reported
that CTDNEP1 localizes to the inner nuclear membrane [50,67].
4. Lipins and transcriptional regulation of lipid metabolic genes
An intriguing property of lipins that distinguishes them from many
other lipid biosynthetic enzymes is their functional duality: in addition
to their role in lipid homeostasis through the control of PA and DAG
levels, lipins also control transcription of genes encoding lipid metabolic
enzymes. Gene regulation by lipins can be exerted through three, not
mutually exclusive, mechanisms: (a) directly, mediated by the interaction of lipins with the transcriptional machinery (b) indirectly, mediated
by the signaling function of lipin-dependent PA pools and (c) indirectly,
mediated by lipin-dependent structural remodeling of the nuclear envelope as described in Section 5.2.
4.1. Lipins as transcription co-factors
A direct role for lipins as transcriptional regulators was rst established in mouse hepatocytes where lipin 1 was shown to interact

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directly with the peroxisome proliferator-activated repressor (PPAR), a

key transcription factor of lipid metabolism in the liver, and its
co-activator PGC-1 [68]. Lipin 1 co-activates PPAR-PGC-1 target
genes involved in fatty acid oxidation and mitochondrial oxidative phosphorylation in a manner that depends on a LXXIL nuclear receptor interaction motif but, importantly, is independent of its DXDXT catalytic motif
[68]. Because the co-activation is enhanced during fasting, when hepatocytes are challenged with increased fatty acid delivery, lipin 1 was proposed to potentiate the hepatic capacity for fatty acid oxidation [68].
An analogous function in nuclear receptor activation was also demonstrated in mouse adipocytes where lipin 1 co-activates PPAR, a factor
essential for both adipogenesis and mature adipocyte function, via a direct physical interaction [69]. In addition, lipin 1 co-activates PGC1
and myocyte enhancer factor 2 (MEF2) in neuronal cells [62]. Interestingly, lipin 1 functions also as a transcriptional repressor in mouse adipocytes where it inhibits the activity of nuclear factor of activated T cells c4
(NFATc4), a factor involved in cytokine expression and adipogenesis
[70]. Therefore, depending on the cellular context, lipin 1 can either activate or repress gene expression. On the other hand, there is less information about the transcriptional roles of the other lipins: lipin 2 co-activates
PPAR in hepatocytes [71] and lipin 3 binds to PPAR [68] although the
functional signicance of these interactions has not been addressed so
far. Because all lipins lack recognizable DNA-binding sequences, their
interaction with chromatin must be indirect through either scaffold
proteins like histones or components of multiprotein transcriptional
complexes.
Such a role for metabolic enzymes as transcriptional regulators in
the nucleus is not unprecedented (reviewed in [72]). Examples include Arg5,6 involved in ornithine biosynthesis and regulating
promoters of both nuclear and mitochondrial genes [73] or GAPDH
which as a component of the OCA-S complex co-activates the transcription of the histone H2B gene [74]. How the metabolic and transcription roles of these enzymes relate to each other is not well
dened and lipins are no exception to this. By coupling an enzyme
to transcription, cells may monitor directly their metabolic status to
regulate homeostasis. As discussed before, membrane binding and
nuclear import of lipins might be linked. Because PA is the earliest
precursor in phospholipid synthesis, lipins could function as sensors
of the lipid metabolic state of the cells, coordinating membrane biogenesis with transcription of lipid metabolic enzymes. In addition,
import of lipid-bound lipins could control the intranuclear levels of
PA and inuence the function of other transcriptional regulators,
such as nuclear receptors whose ligands may be phospholipids [75].
According to this hypothesis, lipins would mediate lipid transport in
the nucleus and could be involved in the maintainance of the compartmentalized intranuclear lipid pools described previously [2731].
4.2. Regulation of transcription by PA-dependent lipin pools
Previous work supports a signaling role for a lipin-dependent PA
pool in a transcriptional cascade of early mouse adipogenesis, which
is normally under the control of the master transcriptional regulator
PPAR. Lipin 1 deciency blocks adipogenesis at an early stage that
precedes TAG accumulation [36]. Lipin 1-decient MEFs exhibit impaired adipogenesis that cannot be rescued by a catalytically dead
but still active co-activator lipin 1 [39]. This correlates with elevated
PA in adipose tissue of the lipin1-decient animals and activation of
the ERK-signaling pathway [39]. Taken together, these results suggest
an inhibitory role of PA in adipogenesis [39,76].
In yeast cells, lipid homeostasis is maintained by a PA-sensing pathway. Here, the levels of PA control the expression of genes encoding
enzymes of the CDP-DAG and the Kennedy pathways [77]. Transcription of these genes is regulated by a promoter element known as UASINO
[7880] that is induced by the Ino2pIno4p complex and repressed by
the PA-binding protein Opi1p that normally resides onto ER membranes.
When the PA levels are low, Opi1p translocates in the nucleus where it

represses UASINO-transcription [65]. Conditions affecting PA levels, such

as inositol availability or growth phase inuence UASINO -dependent
transcription [77]. A link between nutrient sensing and lipid biosynthesis
has been reported in yeast, where a drop in glucose availability represses
phospholipid biosynthesis through Opi1p [81].
Phosphorylation of Pah1p [49], or mutations in Pah1p itself
[49,82], cause transcriptional derepression of UASINO-containing
genes, while overexpression of the more active dephosphorylated
Pah1p represses UASINO genes in an Opi1p-dependent manner [41].
The fact that the transcription of UASINO genes responds to changes in
the catalytic activity of Pah1p is consistent with Pah1p-derived PA regulating transcription via the Opi1p signaling pathway. However, when
compared with the single opi1 mutant, the pah1 opi1 double mutant
exhibits a synergistic effect on the transcriptional derepression of two
UASINO-containing genes, INO1 and OPI3, suggesting that Pah1p regulates the transcription of these genes through an Opi1p-independent
mechanism as well [41]. Interestingly, Pah1p can be immunoprecipitated
in association with the promoters of three UASINO-containing genes in a
phosphorylation-dependent manner [49], although so far there is no evidence that Pah1p has a direct role in transcription, similar to the one described for mammalian lipins. The identication of mutants that separate
the catalytic activity of Pah1p from its nuclear import will be crucial to
address further the role of Pah1p in the nucleus.
5. Lipins and nuclear architecture
The temporal and spatial control of lipin activity can have a major
impact in organelle biogenesis due to the multiple functions of PA and
DAG as metabolic intermediates, signaling molecules and regulators
of the physical properties of membranes. Emerging evidence from
various model systems supports important roles for lipins in the control of nuclear structure and ER membrane organization.
5.1. Nuclear shape, nuclear envelope dynamics and lipin activity
An important role for lipins in nuclear organization was rst demonstrated in yeasts, where inactivation of the Nem1pSpo7p phosphatase complex [48], Ned1 [59], or Pah1p [49] (then known as Smp2p),
was shown to cause nuclear membrane expansion. This expansion
takes place at the nucleolar-associated membrane, a nuclear envelope
subdomain in yeast that is in close association with the nucleolus,
lacks underlying chromatin binding and can function as a exible
membrane sink during cell cycle delay [83,84]. Among the other
major phospholipid biosynthetic enzymes in yeast, only inactivation
of Pah1p results in this defect [85]. Nuclear membrane expansion is
caused by a catalytically dead Pah1p [82] and can be phenocopied by
the overexpression of a catalytically competent Dgk1p, a nuclear/ER
transmembrane DAG kinase that generates PA [85,86]. How direct is
the role of PA in nuclear remodeling is not known. Genetic analysis
shows that the PA-dependent derepression of phospholipid biosynthesis via the CDP-DAG pathway, resulting from the inactivation of Pah1p,
is necessary but not sufcient for nuclear expansion in pah1, nem1 or
spo7 cells [49]. Therefore, in addition to increased phospholipid
synthesis, other factors must be involved. Since inactivation of Pah1p
results in membranes with a signicantly altered phospholipid composition, such as an increase in PA and the PE:PC ratio [2,82], it is possible
that qualitative changes in the composition of nuclear membrane and/
or ER are also involved in promoting nuclear expansion.
Under more physiological conditions, the nuclear envelope also undergoes dramatic structural changes during the cell cycle [87]. Because
yeast undergo closed mitosis, the nuclear envelope remains intact and
the nuclear membrane needs to expand signicantly, in order to allow
sister chromatid separation within a single nuclear compartment. Regulation of the phospholipid quantity and quality at the nuclear/ER
membrane by Pah1p may play an important role in this process. Consistent with this, constitutive dephosphorylation of Pah1p represses de

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novo phosholipid synthesis [84] and inhibits nuclear membrane expansion during mitosis [49]. The underlying mechanisms by which Pah1p
activity regulates this process remain to be determined.
Metazoan cells display some key differences from yeast with respect
to nuclear organization: their inner nuclear membrane, that faces the nucleoplasm, is coated by a meshwork of intermediate laments, the nuclear
lamina [87]. In addition, metazoan cells undergo nuclear envelope breakdown (NEBD) during their open mitosis, an event that is accompanied
by nuclear lamina and nuclear pore disassembly, and allows chromosome
separation within the cytoplasm [87]. In Drosophila and Caenorhabditis
elegans, lipin is required for proper nuclear structure [5355]. In addition,
downregulation of lipin 1 in C. elegans causes defects in lamina depolymerization, NEBD and chromosome segregation as well as altered ER
membrane organization with the appearance of large membrane sheets
[54,55]. Given that ER membrane structure can inuence nuclear envelope dynamics [88], the role of lipin in NEBD may be an indirect consequence of its function on ER organization [55]. Alternatively, as the lipin
1-mediated defects in NEBD are signicantly rescued by co-depletion of
lamins without affecting the ER defects, the functions of lipin 1 in NEBD
may be distinct from those in peripheral ER [54]. Consistent with this, a
very recent study reported a role for lipins in promoting mitotic lamin disassembly in cultured mammalian cells [89].
5.2. Lipin-mediated nuclear remodeling and gene regulation
Recently, a role for nuclear lipin 1 linking nuclear envelope remodeling and gene regulation was reported in mammals [47]. mTORC1 is a
nutrient-responsive kinase that promotes growth by positively regulating
many anabolic processes including protein and lipid synthesis, the latter
in part through SREBP [90]. The SREBP transcription factors are normally
present as inactive ER-bound precursors that are cleaved in response to
sterol depletion (SREBP-2) or insulin (SREBP-1) and translocate in the nucleus where they induce expression of genes involved in lipid biosynthesis [91]. Inhibition of mTORC1 causes translocation of dephosphorylated
lipin 1 in the nucleus concurrent with an increase in nuclear eccentricity,
dened as the ratio of horizontal to vertical axes of the nucleus [47]. Interestingly, this structural reorganization of the nucleus requires the catalytic
activity of lipin 1 inside the nucleus [47] and is therefore likely depending
on DAG and/or PA in the inner nuclear membrane. In addition, the lipin
1-dependent nuclear remodeling coincided with a downregulation of
the protein pool of SREBP in the nucleus, by a yet unknown mechanism,
and the inhibition of the expression of SREBP targets [47]. Lipin 1 itself
is an SREBP transcriptional target [92], suggesting the operation of a feedback loop that could turn lipin 1 levels off. How direct is the involvement
of nuclear envelope remodeling in the transcriptional response remains
to be determined.
In budding yeast, a role of the nuclear periphery in the regulation of
lipid homeostasis has been also reported, where repositioning of the
PA-regulated INO1 gene to the nuclear envelope upon inositol depletion
is important for its derepression [93]. Although the underlying mechanisms are most likely different, these examples highlight how changes
in nuclear architecture can inuence cellular lipid homeostasis.
While the molecular details of how lipins remodel nuclear architecture are not known, one could envision both signaling and structural mechanisms involved. Given the evidence for multiple DAG
pools in the nucleus, one of which depends on the nuclear PI-PLC
pathway [94], lipin 1-derived nuclear DAG may have a function in nuclear envelope remodeling, via its effector PKC, which is known to
translocate in the nucleus in response to DAG [9597] and mediate
phosphorylation and lamin disassembly [98,99]. Indeed, lipins promote lamin disassembly [89] and therefore their temporal and spatial
regulation in the nucleus may have important implications in nuclear
envelope structure.
Lipins may also regulate nuclear structure through the effects of
the conical shaped PA and DAG that are known to promote membrane deformation [100]. Curvature and tubulation of the inner

579

nuclear membrane induce invagination and expansion of the nuclear

envelope within the nucleoplasm (also known as nucleoplasmic reticulum) with possible functions in calcium signaling, nuclear growth
or gene expression [101]. Lipin-derived DAG may also play an analogous structural role during nuclear pore biogenesis and the formation of the highly curved nuclear pore membrane domains that link
the inner and outer nuclear membranes. In analogy to the roles of
PA and DAG in cytoplasmic membrane budding and fusion, it will
also be interesting to consider the roles of lipins and these lipids in
the nucleus in light of new data suggesting that budding from the
inner nuclear membrane is an alternative mechanism for export of
nuclear cargoes to the cytoplasm in a pathway that appears to also
depend on lamin remodeling and PKC activity [102,103].
6. Concluding remarks
Lipins are a prime example of how lipid biosynthetic enzymes,
sometimes regarded by cell biologists as uninteresting, can be used
in cells to regulate not only metabolism, but also membrane dynamics,
organelle shape and gene expression. The interplay between structure
and function, so fundamental in cell biology, is particularly relevant
when considering the roles of lipins in the nucleus. By remodeling nuclear envelope organization, lipins may not only control nuclear shape
changes during the cell cycle or development, but also impact upon
gene regulation. Interestingly, many lipin-regulated genes encode metabolic enzymes that can themselves inuence membrane biogenesis
through downstream pathways, establishing a cross-talk between nuclear organization and gene expression.
Unlike other lipid metabolic enzymes, lipins lack transmembrane
domains and can thus be rapidly and reversibly recruited onto membranes or translocated from the cytoplasm to the nucleus where they
inuence many aspects of nuclear physiology. It will be important to
dene the stimuli that dictate the movement of lipins on and off
membranes, how these inuence their nucleocytoplasmic transport,
their effects on the transcription of lipid metabolic enzymes and
their contribution to cellular membrane homeostasis. It will also be
interesting to examine the involvement of lipins in nuclear lipid metabolism and how their activities impact on PI and DAG nuclear signaling. These analyses should include lipins 2 and 3 for which there
is currently very little information available. Because lipins have multiple roles in organelle membrane biogenesis, it may be difcult to
separate direct from indirect effects using lipin deletion/knock-down
approaches. The identication of the sequences and signals that govern the nucleocytoplasmic transport of lipins and the analysis of the
corresponding mutants, while maintaining an active enzyme, will be
important in order to elucidate their specic nuclear roles.
The identication of the lipin PA phosphatases that are amenable
to biochemical characterization, model organism structure/function
analysis and play key roles in several aspects of mammalian physiology, offers a unique opportunity to explore the largely unknown functions of nuclear phospholipid metabolism in health and disease.
Acknowledgements
I am grateful to George Carman, Jenny Hirst, Nicholas Ktistakis,
Helena Santos-Rosa and George Simos for the critical reading of the
manuscript. Work in my laboratory is funded by the Medical Research
Council (Fellowship G0701446).
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