Cide Proteins and Lipid Metabolism

ATVB in Focus
New Developments in Hepatic Lipoprotein Production and Clinical Relevance
Series Editor: Zemin Yao
CIDE Proteins and Lipid Metabolism
Li Xu, Linkang Zhou, Peng Li
Abstract—Lipid homeostasis is maintained through the coordination of lipid metabolism in various tissues, including adipose
tissue and the liver. The disruption of lipid homeostasis often results in the development of metabolic disorders such as
obesity, diabetes mellitus, liver steatosis, and cardiovascular diseases. Cell death–inducing DNA fragmentation factor 45like effector family proteins, including Cidea, Cideb, and Fsp27 (Cidec), are emerging as important regulators of various
lipid metabolic pathways and play pivotal roles in the development of metabolic disorders. This review summarizes the
latest cell death–inducing DNA fragmentation factor 45-like effector protein discoveries related to the control of lipid
metabolism, with emphasis on the role of these proteins in lipid droplet growth in adipocytes and in the regulation of very
­low-­density lipoprotein lipidation and maturation in hepatocytes. (Arterioscler Thromb Vasc Biol. 2012;32:1094-1098.)
Key Words: cell death–inducing DNA fragmentation factor 45-like effector  lipid droplet  lipid metabolism
 metabolic disorders  very ­low-­density lipoprotein
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T
he cell death–inducing DNA fragmentation factor 45-like
effector (CIDE) proteins, including Cidea, Cideb, and
Cidec (or Fsp27 in mice), have been shown to play important roles in the development of metabolic disorders.1,2 Mice
with a deficiency in CIDE proteins exhibit a lean phenotype,
resistance to ­high-­fat diet–induced obesity, improved insulin
sensitivity, and an increased w
­ hole-­body metabolic rate.1,3–6
Cidea and Cidec are expressed in the white adipose tissue of
humans, and their expression positively correlates with the
development of insulin sensitivity in obese people.7,8 A patient
who expresses a prematurely terminated Cidec protein develops k­ etosis-­prone insulin resistance and partial lipodystrophy.9 In addition, increased Cidea and Fsp27 expression have
been observed in the livers of ­high-­fat diet-fed and ob/ob mice
and under the condition of hepatic steatosis in humans.10,11 The
levels of hepatic expression of Cidea and Cidec also positively
correlate with body mass index.12 Furthermore, hepatic Cidec
mRNA levels are decreased in obese patients who lose weight
as a result of gastric bypass surgery.12 Fsp27 has been identified as a peroxisome proliferator–activated receptor-g target
and plays a crucial role in peroxisome proliferator–activated
receptor-g–induced hepatic steatosis.10 In addition, Cidea is
identified as a sensor of dietary saturated fatty for the development of hepatic steatosis.11 Cideb is expressed at high levels in
the liver, and modulates very ­low-­density lipoprotein (VLDL)
lipidation and cholesterol homeostasis in hepatocytes.4,13–15
Recently, the levels of Cideb and Cidec have been found to
be upregulated in macrophages in the presence of oxidized
­low-­density lipoprotein, suggesting potential roles of Cideb
and Cidec in foam cell formation and the development of
atherosclerosis.16 Intriguingly, Cidea is observed to be highly
expressed in lactating mammary gland and regulates milk
lipid secretion by acting as a potential cofactor of CCAAT/­
enhancer-­binding protein beta.17 Therefore, CIDE proteins are
crucial factors to control multiple lipid metabolic pathways
and maintain lipid homeostasis. The roles of CIDE proteins in
cell death, energy metabolism and metabolic disorders, their
transcriptional regulation, and their posttranslational modification have been extensively discussed previously.1,2 We will
summarize the roles of CIDE proteins in the regulation of
lipid metabolism, focusing on lipid droplet (LD) growth and
VLDL lipidation.
CIDE Proteins in Lipid Storage and LD Growth
Despite their diverse tissue expression patterns, deficiencies
in all CIDE proteins result in 1 common phenotype: the accumulation of small LDs in the respective cell types.3,4,8,18–21 For
example, brown adipocytes with a Cidea deficiency contain
significantly smaller LDs.3 In addition, white adipocytes from
Fsp27-deficient mice5,6 or from humans with Cidec mutations9
all exhibit the accumulation of smaller LDs. Therefore, CIDE
proteins appear to play a unique role in the control of the sizes
of cytosolic LDs in various cell types. Interestingly, CIDE
proteins are localized to the surface of cytosolic LDs and the
endoplasmic reticulum (ER)1,2 where nascent LDs are synthesized. LDs are important subcellular organelles responsible
for neutral lipid storage in all cell types. Recently, LDs were
shown to regulate viral assembly and intracellular protein
and lipid trafficking.22,23 More importantly, white adipocytes
contain a giant unilocular LD, and the sizes of LDs in adipocytes reflect the lipid storage capacity and have been linked
to the development of obesity and insulin resistance.9,24–26
Genetic screens in Drosophila and yeast cells have uncovered
links between factors involved in phospholipid synthesis,27,28
vesicular transport,29,30 and seipin/Fldp28,31,32 and regulation of
LD size and morphology. However, the mechanisms of LD
Received on: February 1, 2012; final version accepted on: March 12, 2012.
From the ­Tsinghua-­Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China (L.X., L.Z., P.L.); Key Laboratory for
Feed Biotechnology of the Ministry of Agriculture, Feed Research Institute, Chinese Academy of Agricultural Sciences, Beijing, China (L.X.).
Correspondence to Dr Peng Li, School of Life Sciences, Tsinghua University, Beijing 100084, China. ­E-­mail [email protected]
© 2012 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.orgDOI: 10.1161/ATVBAHA.111.241489
1094
Xu et al CIDE Proteins and Lipid Metabolism 1095
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growth and the formation of unilocular LDs in adipocytes
remain elusive.
Our recent research on the roles of Fsp27 and Cidea in the
control of LD growth uncovered a novel molecular mechanism for LD growth and the formation of unilocular LDs in
adipocytes.33 We have observed that both Fsp27 and Cidea are
enriched at a particular ­sub-­LD location: the L
­ D-­LD contact
site (LDCS). The enrichment of Fsp27 at LDCSs is a critical first step for Fsp27-mediated LD growth. Interestingly, we
observed that once Fsp27 and Cidea are enriched at LDCSs,
rapid lipid exchange among contacted LD pairs is detected. In
addition, a directional net transfer of neutral lipids from smaller
to larger LDs occurs at Fsp27-positive LDCS, resulting in the
merging of smaller LDs to form large LDs. The phenomenon of Fsp27 facilitating LD clustering was also observed in
another study.34 Intriguingly, Fsp27-mediated directional lipid
transfer can be observed in vitro in an autonomous or cytosolic ­factor-­independent manner. In addition, we observed a
50-fold higher lipid exchange activity in differentiated adipocytes than in preadipocytes overexpressing Fsp27, suggesting
that additional ­adipocyte-­specific factors are required to accelerate Fsp27-mediated LD growth in adipocytes.33
Fsp27- and C
­ idea-­mediated lipid transfer and LD growth is
a unique process that is distinct from other membrane fusion
processes, including vesicle fusion,35,36 ER fusion,37,38 and mitochondria fusion.39 Vesicle fusion involves the merging of lipid
bilayers, the formation of an interconnected membrane structure and a fusion pore in a short period of time, and the mixing
of the internal contents of the 2 vesicles. However, Fsp27- and
­Cidea-­mediated lipid transfer and LD growth require these
proteins to first be clustered and enriched at LDCSs. The clustering of Fsp27 and Cidea may provide a tethering force for
stable LD attachment. In addition, the clustering of Fsp27 at
LDCSs may recruit other proteins that deform the monolayer
phospholipids at the LDCS to form a pore or a lipid transfer
channel to initiate neutral lipid exchange among LDs that are
in contact, resulting in net lipid transfer from smaller to larger
LDs due to the difference in internal pressure (Figure). Fsp27mediated LD growth is a relatively slow process that depends
on the size of the LDs that are in contact, whereas vesicle
fusion usually proceeds very rapidly, and a size requirement
is not observed. Therefore, Fsp27-mediated lipid transfer and
LD growth can be defined as a special LD fusion process that
involves a localized and defined boundary (LDCS) and the
directional transfer of lipids gradually from smaller to larger
LDs. Such a slow process is likely favorable in adipocytes
because the 1-step mixing of the LD cores of large LDs due to
fusion pore expansion may generate mechanical stress in cells.
The presence of phospholipid monolayer in LDs may lower
the energy barrier for Fsp27-mediated LD growth relative to
the energy barriers for other bilayer membrane fusion mechanisms. Further analyses including the complete identification
of protein complex that facilitates Fsp27- or ­Cidea-­mediated
lipid transfer at the LDCS, structural characterization of Fsp27
and its associated proteins, and in vitro biochemical reconstitution of Fsp27-mediated lipid transfer will be needed to
elucidate the molecular basis of CIDE proteins in controlling
LD growth in adipocytes.
Regulation of LD size and lipid storage by Fsp27 and Cidea
may also be mediated by its activity in controlling lipolysis, as Fsp27 and Cidea deficiencies result in an increased
lipolysis,3,5,6 whereas overexpression of Cidea and Fsp27
leads to reduced lipolysis.7,8,20,40,41 The mechanism by which
CIDE proteins control lipolysis is unclear. Several sequence
homologous regions between CIDE proteins and perilipin are
identified,2,8,42 raising the possibility that CIDE proteins could
play dual roles in lipolysis as perilipin does.43 Alternatively,
CIDE proteins may act as physical barriers to protect LDs from
lipolysis, similar to that of adipose differentiation–related protein and TIP47 in contributing to LD stabilization.43,44
Interestingly, Cidea and Fsp27 are also reported to be markedly upregulated in the livers of h­ igh-­fat diet–fed and ob/ob
mice. Overexpression of Cidea and Fsp27 in hepatocytes
promotes the formation of larger LDs in hepatocytes.10,11,45
In contrast, Cidea and Fsp27 deficiency leads to reduced
hepatic triacylglycerol (TAG) levels, the accumulation of
smaller sized LDs, and alleviation of ob/ob or ­high-­fat dietinduced hepatic steatosis.10,11,45 Therefore, Cidea and Fsp27
are likely to play similar roles in promoting LD growth in
hepatocytes. However, the expressions of Cidea and Fsp27 in
hepatocytes are differentially regulated upon fat challenge as
Cidea is upregulated in the presence of dietary saturated fatty
acids, which is mediated by ­sterol-­regulatory-­element-­bindin
g protein-1c, whereas Fsp27 gene expression is controlled by
peroxisome proliferator–activated receptor-g pathway.10,11,45
Therefore, these 2 proteins may play different roles at the
Figure. The proposed model of Fsp27-mediated lipid transfer and lipid droplet (LD) growth. When clustering and enriching at the LD
contacting site (LDCS), Fsp27 may provide a tethering force for stable LD attachment and recruit unidentified proteins (X, Y, Z) to form a
complex at the LDCS. Fsp27-initiated protein complex may deform phospholipid monolayer to generate a pore (or channel-like) structure
at the LDCSs, resulting in neutral lipid exchange among contacted LDs and net lipid transfer from smaller to larger LDs due to the internal
pressure difference.33
1096 Arterioscler Thromb Vasc Biol May 2012
different stages of LD growth in hepatocytes. In addition, the
sizes of LDs in hepatocytes are much smaller than those of
adipocytes, possibly due to the lack of some crucial cofactors
required to accelerate the activity of Fsp27 and Cidea.
CIDE Proteins in VLDL Lipidation and Maturation
in Hepatocytes
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The assembly and maturation of VLDL in hepatocytes is
generally thought to involve 2 steps.43,46 The first step of
VLDL assembly occurs in the ER with the formation of lipid-­
poor lipoprotein particles (pre-VLDL),46 which is dependent on MTP to transfer locally synthesized TAG to
apoB-100.47 L
­ ipid-­poor ­pre-­VLDL particles are then further
lipidated to generate ­TAG-­rich and mature VLDL particles
for secretion.43,48 The subcellular location of VLDL lipidation and maturation, the source of the lipids, and the factors
promoting VLDL lipidation remain subjects of intense debate
and investigation. Some researchers suggest that the ER may
be the site of VLDL lipidation because the majority of TAG
is synthesized in the ER, and apoB-100 has been shown to
be localized to the ER membrane.49–51 Other researchers have
demonstrated that ­pre-­VLDL particles exit the ER and that
VLDL lipidation occurs primarily in the Golgi apparatus or
­post-­ER compartments.43,52–54 The factors affecting VLDL
assembly and maturation in hepatocytes have recently been
reviewed.55
Two types of LDs, cytosolic LDs and E
­ R-­lumenal LDs,
have been identified using the biochemical method.56–59 Two
hypotheses regarding the source of the lipids involved in VLDL
lipidation have been proposed. First, TAG is directly transferred through the fusion of ­ER-­lumenal LDs to T
­ AG-­poor
VLDL particles.51,60 Second, TAG from cytosolic LDs has
been reported to be hydrolyzed to yield free fatty acids that are
then r­ e-­esterified on the lumenal side of secretory apparatuses,
such as the Golgi, generating ­lipid-­rich VLDL particles.61 The
fusion of ­ER-­lumenal LDs with VLDL particles during VLDL
lipidation and maturation is proposed to be mediated by ApoC
III.62,63 One remaining question is whether TAG from cytosolic
LDs, which are the most abundant source of neutral lipids,
can be directly transferred to T
­ AG-­poor VLDL particles to
form ­lipid-­rich VLDL particles. Many factors, including ADP
ribosylation factor 1 (ARF1, a small GTPase involved in
vesicular trafficking),64 phospholipase D,64 the phospholipase
iPLA2b,65 phosphoinositide-3 kinase,66 and coat protein complex II,53 are involved in VLDL lipidation and secretion. In
addition, the synthesis of phosphatidylcholine and phosphatidylethanolamine, and their ratio regulate the VLDL assembly
and secretion.67,68
Cideb, a member of the CIDE family of proteins, is
expressed at higher levels in the liver and kidney.4 Cideb2/2
mice exhibit an increased ­whole-­body metabolic rate and
reduced serum TAG levels and are resistant to d­ iet-­induced
obesity.4 Further analyses reveal that the VLDL particles
secreted from Cideb2/2 mice or isolated Cideb2/2 hepatocytes contain significantly less TAG but have similar levels of
apoB-100/-48, indicating an impairment in VLDL lipidation
in ­Cideb-­deficient hepatocytes. In addition, Cideb is localized
to LDs and the ER and interacts with apoB-100/-48. The interaction between Cideb and apoB-100 is required for VLDL
lipidation in hepatocytes.13 Interestingly, the overexpression
of Plin2, another ­LD-­associated protein, has also been shown
to decrease the production and secretion of ­lipid-­rich VLDL
particles and to increase cytosolic TAG accumulation in McARH7777 cells.69 In contrast, mice with Plin2 and leptin double
deficiency exhibit increased VLDL lipidation,70 suggesting
that Plin2 negatively controls VLDL lipidation. Therefore,
­LD-­associated proteins appear to play important roles in
controlling VLDL lipidation and maturation. However, the
mechanisms of ­Cideb-­mediated VLDL lipidation and maturation remain elusive. Future studies will focus on the following
questions: (1) Where does ­Cideb-­mediated VLDL lipidation
occur? ER, p­ ost-­ER compartments, or the Golgi apparatus?
(2) Does ­Cideb-­mediated VLDL lipidation require the cooperation of Cideb with other LD- or ­ER-­associated proteins?
(3) Does C
­ ideb-­mediated VLDL lipidation involve direct
neutral lipid transfer from cytosolic (or ER-associated) LDs
to ­TAG-­poor VLDL particles? Alternatively, ­Cideb-­mediated
VLDL lipidation may require the hydrolysis of TAGs in
cytosolic LDs. Genetically modified animal models and
aw
­ ell-­established cell model will be good tools to address
these questions.71 The function of Cideb in hepatocytes may
be dependent on its subcellular localization. When localized
to LDs, Cideb mediates lipid transfer and LD growth using
similar mechanism to that of Cidea and Fsp27. When in close
contact with ­pre-­VLDL particles, Cideb promotes VLDL lipidation and maturation possibly by mediating direct transfer of
TAG from cytosolic LDs to ­pre-­VLDL particles or the second
step, bulk TAG pool.71
Conclusion
CIDE proteins are important modulators of diverse lipid
metabolic pathways, including lipolysis, fatty acid oxidation,
VLDL lipidation, and LD growth in adipocytes and hepatocytes. By localizing to LDs and the ER, Cideb controls VLDL
lipidation and maturation in hepatocytes. Furthermore, Fsp27
and Cidea are enriched at LDCSs and promote lipid exchange
and lipid transfer between LDs that are in contact, resulting
in the final growth and enlargement of LDs in adipocytes.
However, our understanding of the mechanistic details of
CIDE protein functions in controlling lipid metabolism is still
in its early stages. Much effort will be needed to determine
how CIDE proteins modulate the processes involved in lipid
homeostasis, including VLDL lipidation and LD growth in
hepatocytes and adipocytes and perhaps in other cells. CIDE
proteins may be new drug targets for the treatment of metabolic disorders.
Sources of Funding
The work that formed the basis for opinions expressed in this
review was supported by grants from the National Basic Research
Program (2011CB910800) and National High Technology Research
and Development program (2010AA023002) from the Ministry of
Science and Technology of China and National Natural Science
Foundation of China (30800555 to L.X. and 31030038 to P.L.). Dr Li
is a professor and investigator for ­Tsinghua-­Peking Center for Life
Sciences.
Disclosures
None.
Xu et al CIDE Proteins and Lipid Metabolism 1097
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CIDE Proteins and Lipid Metabolism
Li Xu, Linkang Zhou and Peng Li
Arterioscler Thromb Vasc Biol. 2012;32:1094-1098
doi: 10.1161/ATVBAHA.111.241489
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