Tài liệu Báo cáo khoa học: SREBPs: physiology and pathophysiology of the SREBP family ppt

MINIREVIEW
SREBPs: physiology and pathophysiology of the
SREBP family
Hitoshi Shimano
Department of Internal Medicine (Endocrinoglogy and Metabolism), Graduate School of Comprehensive Human Sciences, University of
Tsukuba, Japan
SREBP-2 and sterol regulation
The sterol regulatory element-binding protein (SREBP)
family, originally identified as basic helix–loop–helix
(bHLH) leucine zipper transcription factors by Gold-
stein and Brown, is involved in the regulation of genes
participating in cholesterol biosynthesis and low-density
lipoprotein receptor synthesis [1,2]. They are now estab-
lished as global regulators of lipid synthesis. What
makes this bHLH family unique is that SREBPs are syn-
thesized and located on the endoplasmic reticulum (ER)
membrane in their precursor form. To exert transcrip-
tional activities, the active N-terminal region of the
bHLH needs to undergo proteolytic cleavage for nuclear
translocation. Sterol regulation is mainly attributed to
this cleavage activity, depending on cellular cholesterol
levels. The SREBP cleavage-activating protein (SCAP)
functions as a cholesterol sensor. When the cellular cho-
lesterol levels are depleted, SCAP binds to and escorts
SREBP in COPII vesicles to the Golgi apparatus, where
the site 1 and site 2 proteases cleave the SREBPs [3,4].
Upon restoration of cellular cholesterol, Insig, another
key regulator of ER membrane proteins, traps and
retains the SREBP–SCAP complex at the ER to inhibit
SREBP cleavage in the Golgi, thus downregulating
sterol and low-density lipoprotein receptor biosynthesis.

Keywords
cholesterol; diabetes; dyslipidemia; fatty
acids; fatty liver; insulin resistance;
lipotoxicity; metabolic syndrome; SREBP;
trigylcerides
Correspondence
H. Shimano, Department of Internal
Medicine (Endocrinoglogy and Metabolism),
Graduate School of Comprehensive Human
Sciences, University of Tsukuba,
1-1-1 Tennodai, Tsukuba, 305-8575, Japan
Fax: +81 29 853 3174
Tel: +81 29 853 3053
E-mail: ,

(Received 2 August 2008, revised 11
November 2008, accepted 18 November
2008)
doi:10.1111/j.1742-4658.2008.06806.x
Sterol regulatory element-binding proteins (SREBPs) have been established
as physiological regulators of lipid synthesis. The molecular mechanisms by
which cellular sterol balance and nutritional states regulate SREBP acti-
vities are the current research focus of this field. Meanwhile, it has been
shown that overnutrition or disturbed energy balance causes accumulation
of tissue lipids, leading to metabolic disorders, often referred to as ‘lipotox-
icity’. In this overview, I discuss the pathological aspects of SREBPs, which
contribute to lipotoxicity in a wide variety of organs, including hepatic
insulin resistance in hepatosteatosis, impaired insulin secretion in pancreatic
b-cells, diabetic nephropathy, cardiac arrythmiasis, and obesity.
Abbreviations

bHLH, basic helix–loop–helix; ER, endoplasmic reticulum; IRS-2, insulin receptor substrate-2; PUFA, polyunsaturated fatty acid; SCAP, sterol
regulatory element-binding protein cleavage-activating protein; SREBP, sterol regulatory element-binding protein.
616 FEBS Journal 276 (2009) 616–621 ª 2008 The Author Journal compilation ª 2008 FEBS
SREBP-1c and lipogenesis
The SREBP family consists of three isoforms: SREBP-
1a, SREBP-1c, and SREBP-2. Each isoform has a
different regulatory mechanism [5–8]. In contrast to
sterol regulation by SREBP-2 at the cleavage level as
described above, SREBP-1c activates transcription of
genes involved in fatty acid and triglyceride synthesis,
such as the genes encoding acetyl-CoA carboxylase,
fatty acid synthase, Elovl-6, and stearoyl-CoA desatur-
ase. These genes are regulated by SREBP-1c, depend-
ing on the nutritional conditions for triglyceride
storage. SREBP-1c is also subject to the SCAP–Insig
cleavage regulation system, but it is not strictly under
sterol regulation. Under conditions of overnutrition,
SREBP-1c expression is elevated, and consequently,
the levels of nuclear SREBP-1c protein and lipogenesis
are enhanced in the liver and adipose tissues. Intake of
energy molecules such as sugars, carbohydrates and
saturated fatty acids activates SREBP-1c expression,
which is eliminated under conditions of fasting and
starvation. SREBP-1c activates insulin-mediated lipo-
genesis, whereas starvation signals such as glucagon,
protein kinase A and AMP-activated protein kinase
inhibit SREBP-1c. Glucose metabolism and lipid
metabolism are highly linked, as depicted in Fig. 1.
The feedback system by SREBP-2 guarantees appro-
priate levels of cellular cholesterol. Meanwhile, excess

glucose cumulatively activates SREBP-1c and increases
triglyceride storage. This scenario explains the physio-
logical transcriptional regulation of energy storage in
response to the nutritional status. Under energy abun-
dance scenarios, acetyl-CoA is used as a substrate for
the synthesis of fatty acids and cholesterol. In contrast,
in an energy-depleted state, acetyl-CoA serves as fuel
for the tricarboxylic acid cycle and ATP production
via fatty acid oxidation. SREBP-1c is an upstream
regulator of genes for energy storage, and could
precipitate cardiovascular risks. Physiologically, this
system is important for surviving starvation. However,
in modern society, where obesity is a major health
problem, these thrifty genes exacerbate metabolic
disturbances such as diabetes, hyperlipidemia, and
metabolic syndrome [9]. Chronic activation of
SREBP-1c in cases of overnutrition can therefore lead
to obesity-related problems.
SREBP as the global lipid regulator
SREBP-1a is highly expressed in growing cells, and it
activates the synthesis of a variety of lipids, such as
fatty acids, triglycerides, and phospholipids, as well as
cholesterol, presumably for the supply of membrane
lipids. It has been reported that SREBP may play a role
in proliferation in a wide variety of human cancers [10–
13]. Recent reports also suggest that SREBP-1a could
be involved in lipid synthesis during the cell cycle [14].
Regulation of SREBP-1a in the cell cycle is mediated
through its phosphorylation and ubiquitin-dependent
degradation by the Fbw7 ubiquitin ligase, indicating a

new mechanism of SREBP regulation [15–18]. In con-
trast, we recently reported that overexpression of
SREBP-1a activates cyclin-dependent kinase inhibitors
such as p21, p27, and p16, and causes cell cycle arrest
Glucose
Glc6P 6PG
G6PD
Feedback
Pentose phosphate
pathway
NADPH
Pyruvate Malate
ME
PK
Cholesterol synthesis
Squalene
Cholesterol
HMG-CoA reductase
SREBP-2
NADPH
Pyruvate
Acetyl-CoA
Citrate
acetyl-CoA
Oxaloacetate
Oxaloacetate
ACL
ACC
HMG-CoA
HMG-CoA synthase

Citrate
Malonyl-CoA
Palmitate
Malate
Mitochondria
FAS
ACC
SCD
Fatty acid synthesis
Stearate
Elovl6
acyl-CoA
Glycerol-3-phosphate
1-acylglycerol-3-phosphate
CoA
Cytosol
GPAT
SCD
Feedforward
SREBP-1
Triglyceride
DGAT
Fig. 1. Regulation of glucose and lipid
metabolism by SREBPs. Acetyl-CoA is
produced from glycolysis of glucose, and
passed into the tricarboxylic acid cycle or
used for fatty acid synthesis or cholesterol
synthesis. SREBP-2 regulates cholesterol
synthetic genes in a sterol-regulatory feed-
back fashion, whereas SREBP-1c controls

lipogenic genes depending upon energy
states. Glc6P, glucose 6-phosphate; G6PD,
glucose-6-phosphate dehydrogenase; PK,
pyruvate kinase; ME, malic enzyme; ACL,
acetyl-CoA lyase; ACC, acetyl-CoA carboxyl-
ase; FAS, fatty acid synthase; SCD, stea-
royl-CoA desaturase; GPAT, glycerol
phosphate acyltransferase; DGAT, diacyl-
glycerol acyltransferase; 6PG, 6-phosphoglu-
conate.
H. Shimano Physiology and pathophysiology of the SREBP family
FEBS Journal 276 (2009) 616–621 ª 2008 The Author Journal compilation ª 2008 FEBS 617
at G
1
[19]. In particular, p21 is a direct target of
SREBP [20]. The role of SREBP-1a in the regulation of
cell growth and the cell cycle might be biphasic and
complex, and needs to be further investigated.
SREBP is evolutionarily conserved; however, the
key lipid molecules that control SREBP activation dif-
fer among species. Cellular cholesterol levels strictly
and partially determine SREBP-2 and SREBP-1 cleav-
age in mammalian cells for sterol regulation and
synthesis of other lipids, respectively. Intriguingly,
cleavage of SREBP homolog is regulated by cellular
phosphatidylethanolamine, the major phospholipid in
Drosophila, whereas hypoxia regulates SREBP activa-
tion in fission yeast [21,22]. Despite species-specific
roles, SREBP is linked to cell growth, which leads us
to speculate that SREBP cleavage in the membrane is

the cell’s sensory response to stress that manifests
through changes in membrane lipid composition. Dif-
ferential regulation of SREBP processing by different
lipids among species suggests that SREBP is a monitor
and controller of cell membrane composition.
Pathophysiological aspects of SREBPs
in various organs
Accumulation of lipids has been linked to functional
disturbances in various tissues and organs, often
referred to as lipotoxicity [23]. Fatty liver is associated
with hepatic insulin resistance and b-cell lipotoxicity
with impaired insulin secretion, both of which trigger
diabetes. SREBP-1c controls endogenous fatty acid
synthesis [24]. It is conceivable that positive energy
imbalance chronically activates SREBP-1c, causing
lipotoxicity in various tissues and organs. It has been
reported that SREBP-1c is involved in hepatosteatosis
and pancreatic b-cell dysfunction [25,26].
Insulin resistance in liver and impaired
insulin secretion in b-cells
Molecular dissection of the underlying mechanisms of
lipotoxicity due to cellular stresses such as reactive
oxygen species and ER stress caused by lipid peroxida-
tion has been conducted [27]. Meanwhile, we have
been focusing on the molecular mechanisms by which
SREBPs are involved in lipotoxicity. SREBPs directly
repress the transcription of insulin receptor substrate-2
(IRS-2), the main insulin signaling molecule in the liver
and pancreatic b-cells [8,26]. Suppression of IRS-2 by
SREBP-1c in the liver inhibits processes regulating

insulin signaling, such as glycogen synthesis, and con-
tributes to the physiological switching from glycogen
synthesis to fatty acid synthesis during energy reple-
tion. Chronic activation of hepatic SREBP-1c causes
fatty liver, hypertriglyceridemia, and insulin resistance,
leading to the development of metabolic syndrome.
SREBP-1c activation causes b-cell dysfunction, leading
to impaired insulin secretion [28]. IRS-2 is a key mole-
cule for pancreatic b-cell mass, through influencing cell
survival or possibly proliferation. Diminished b-cell
mass is crucial in the development of diabetes.
SREBP-1c inhibition of IRS-2 affects b-cell mass and
promotes diabetes. Besides affecting b-cell mass, the
other factors by which SREBP-1c could contribute to
diabetes include exocytosis of insulin-containing gran-
ules by uncoupling protein-2 through ATP consump-
tion, and granuphilin through inhibition of the vesicle
fusion machinery [29–31].
Fatty acids as modulators of SREBP-1c
The protective role of fish oil rich in polyunsaturated
fatty acids (PUFAs) against cardiovascular diseases has
been long known. In addition to antiplatelet and coagu-
lant actions, PUFAs also inhibit lipogenesis and lower
tissue and plasma triglyceride levels through inhibition
of SREBP-1c. The molecular mechanisms by which
PUFAs inhibit SREBP-1c are multiple and complex,
and still under investigation. Most importantly, PUFAs
inhibit SREBP-1c cleavage for nuclear translocation
[32,33], which highlights different regulators of the
SREBP cleavage system, SREBP-1c for lipogenesis and

SREBP-2 for cholesterol synthesis, although the precise
molecular basis is still under investigation. PUFAs also
suppress SREBP-1c expression [33–37]. They amelio-
rated insulin resistance along with hepatosteatosis in an
obese mouse model [38]. In pancreatic b-cells, palmitate
impairs and eicosapentaenoic acid restores insulin
secretion, and studies conducted on SREBP-1c-deficient
islets found that these effects are mediated through
regulation of SREBP-1c (Fig. 2) [39].
Chronic kidney diseases and SREBP-1c
SREBP-1c is also implicated in chronic kidney dis-
eases. Glomerular SREBP-1c has been suggested to be
involved in diabetic nephropathy and hyperlipidemia-
associated glomerulopathy through activation of
reactive oxygen species, NADPH oxidase and, thus,
transforming growth factor-b [40–43].
Adipogenesis and SREBP-1c
SREBP-1c is also known as ADD1, which has been
cloned as a regulator of adipogenesis [44]. The roles of
SREBP-1c in adipogenesis are currently controversial.
Physiology and pathophysiology of the SREBP family H. Shimano
618 FEBS Journal 276 (2009) 616–621 ª 2008 The Author Journal compilation ª 2008 FEBS
In 3T3L1 adipocytes, overexpression of ADD1 ⁄
SREBP-1c slightly enhances triglyceride accumulation.
However, chronic activation of SREBP-1c in adipose
tissues of transgenic mice with disrupted adipogenesis
caused lipodystrophy phenotypes [45], suggesting that
inappropriate activation of SREBP-1c impairs normal
adipogenesis. However, neither adipogenesis nor lipo-
genesis was affected in SREBP-1 knockout mice [46],

indicating that its chronic absence could be compen-
sated for by other factors, potentially SREBP-2.
SREBP-1c expression was unexpectedly suppressed in
hypertrophic adipose tissues of ob ⁄ ob mice [47]. These
data hamper a consistent evaluation of the role of
SREBP-1c in adipogenesis. Although it is likely that
SREBP-1c ⁄ ADD1 contributes to adipogenesis and
lipogenesis in normal adipocytes, the timing and levels
of SREBP-1c action are important for effects on adi-
pocyte functions. The gene encoding the cyclin-depen-
dent kinase inhibitor p21 is a target gene of SREBP
[20]. This finding suggests that the regulation of lipid
synthesis is linked to the regulation of cell growth.
Recently, we observed that in adipocytes, p21 is
involved in adipogenesis and obesity associated with
insulin resistance [48]. The exact roles of SREBP-1c ⁄
ADD1 are not yet fully defined.
SREBP and parasympathetic function
in heart
Parasympathetic stimulation of the heart involves
activation of GIRK1 ⁄ 4, a G-protein-coupled inward-
rectifying potassium channel, and results in an
acetylcholine-sensitive atrial potassium current.
GIRK1 is a newly identified SREBP target [49]. The
regulation of the cardiac parasympathetic response
and development of ventricular arrhythmia, especially
after myocardial infarction, could be regulated by
myocardial SREBP-1c, indicating a relationship
between lipid metabolism and the parasympathetic
response that may play a role in arrhythmogenesis.

Regulation of sulfonylurea channels and other potas-
sium channels by SREBPs was also observed in our
preliminary evaluation of SREBP-1c-overexpressing
b-cells, partially contributing to impaired insulin secre-
tion. These data imply that changes in lipid meta-
bolism could regulate the physiology of biomembranes
potentially through SREBPs, although it is yet to be
determined whether other ion channels are direct
targets of SREBP.
New aspects of SREBP functions
To summarize, SREBP-1c is a physiological regulator
of lipogenesis, and activation of SREBP could
contribute to obesity-related pathophysiology through
modification of tissue-specific gene expression as
shown in Fig. 3.
References
1 Brown MS & Goldstein JL (1997) The SREBP path-
way: regulation of cholesterol metabolism by proteolysis
of a membrane-bound transcription factor. Cell 89,
331–340.
2 Brown MS & Goldstein JL (1999) A proteolytic path-
way that controls the cholesterol content of membranes,
cells, and blood. Proc Natl Acad Sci USA 96, 11041–
11048.
3 Brown AJ, Sun L, Feramisco JD, Brown MS & Goldstein
JL (2002) Cholesterol addition to ER membranes alters
Disturbed energy balance
Abnormal activation of SREBP-1c
PDX1 IRS-2
p21 Granuphilin

Cell cycle arrest
Anti-apoptosis
Obesity
Diabetic
nephropathy
NA DP H
oxidase
GIRK
Parasympathetic
response
cardiac
arrt
y
thmo
g
enesis
Insulin
resistance
Loss of
β-cell mass
Impaired
insulin secretion
Fig. 3. Chronic activation of SREBP-1c and pathophysiology in
various tissues Indicated are genes responsible for pathological
mechanisms for lipotoxicity in various tissues. Granuphilin, p21
and G-protein-activated inwardly rectifying potassium (GIRK) chan-
nels are direct SREBP targets [49]. IRS-2 is directly repressed by
SREBP [8].
Saturated FA Poly unsaturated FA
Activation of SREBP-1c

Endogenous fatty acid synthesis
Lipotoxicity
Liver
Pancreatic β cells
Insulin resistance Impaired insulin secretion
Fig. 2. Regulation of SREBP-1c by saturated fatty acids and PU-
FAs. Saturated fatty acids activate, and PUFAs suppress, SREBP-
1c, leading to and protecting from hepatic insulin resistance and
pancreatic b-cell insulin secretion, respectively [39]. FA, fatty acid.
H. Shimano Physiology and pathophysiology of the SREBP family
FEBS Journal 276 (2009) 616–621 ª 2008 The Author Journal compilation ª 2008 FEBS 619
conformation of SCAP, the SREBP escort protein that
regulates cholesterol metabolism. Mol Cell 10, 237–245.
4 Espenshade PJ, Li WP & Yabe D (2002) Sterols block
binding of COPII proteins to SCAP, thereby controlling
SCAP sorting in ER. Proc Natl Acad Sci USA 99,
11694–11699.
5 Horton JD & Shimomura I (1999) Sterol regulatory ele-
ment-binding proteins: activators of cholesterol and
fatty acid biosynthesis. Curr Opin Lipidol 10, 143–150.
6 Shimano H (2001) Sterol regulatory element-binding
proteins (SREBPs): transcriptional regulators of lipid
synthetic genes. Prog Lipid Res 40, 439–452.
7 Shimano H (2002) Sterol regulatory element-binding
protein family as global regulators of lipid synthetic
genes in energy metabolism. Vitam Horm 65, 167–194.
8 Ide T, Shimano H, Yahagi N, Matsuzaka T, Nakakuki
M, Yamamoto T, Nakagawa Y, Takahashi A, Suzuki
H, Sone H et al. (2004) SREBPs suppress IRS-2-medi-
ated insulin signalling in the liver. Nat Cell Biol 6,

351–357.
9 Shimano H (2007) SREBP-1c and TFE3, energy tran-
scription factors that regulate hepatic insulin signaling.
J Mol Med 85, 437–444.
10 Swinnen JV, Heemers H, Deboel L, Foufelle F, Heyns
W & Verhoeven G (2000) Stimulation of tumor-associ-
ated fatty acid synthase expression by growth factor
activation of the sterol regulatory element-binding
protein pathway. Oncogene 19, 5173–5181.
11 Li JN, Mahmoud MA, Han WF, Ripple M & Pizer ES
(2000) Sterol regulatory element-binding protein-1 par-
ticipates in the regulation of fatty acid synthase expres-
sion in colorectal neoplasia. Exp Cell Res 261, 159–165.
12 Heemers H, Maes B, Foufelle F, Heyns W, Verhoeven
G & Swinnen JV (2001) Androgens stimulate lipogenic
gene expression in prostate cancer cells by activation of
the sterol regulatory element-binding protein cleavage
activating protein ⁄ sterol regulatory element-binding
protein pathway. Mol Endocrinol 15, 1817–1828.
13 Yang YA, Morin PJ, Han WF, Chen T, Bornman DM,
Gabrielson EW & Pizer ES (2003) Regulation of fatty
acid synthase expression in breast cancer by sterol regu-
latory element binding protein-1c. Exp Cell Res 282,
132–137.
14 Sundqvist A & Ericsson J (2003) Transcription-depen-
dent degradation controls the stability of the SREBP
family of transcription factors. Proc Natl Acad Sci USA
100, 13833–13838.
15 Bengoechea-Alonso MT & Ericsson J (2006) Cdk1 ⁄ -
cyclin B-mediated phosphorylation stabilizes SREBP1

during mitosis. Cell Cycle 5, 1708–1718.
16 Punga T, Bengoechea-Alonso MT & Ericsson J (2006)
Phosphorylation and ubiquitination of the transcription
factor sterol regulatory element-binding protein-1 in
response to DNA binding. J Biol Chem 281, 25278–
25286.
17 Bengoechea-Alonso MT, Punga T & Ericsson J (2005)
Hyperphosphorylation regulates the activity of SREBP1
during mitosis. Proc Natl Acad Sci USA 102, 11681–
11686.
18 Sundqvist A, Bengoechea-Alonso MT, Ye X, Lukiyan-
chuk V, Jin J, Harper JW & Ericsson J (2005) Control
of lipid metabolism by phosphorylation-dependent deg-
radation of the SREBP family of transcription factors
by SCF(Fbw7). Cell Metab 1, 379–391.
19 Nakakuki M, Shimano H, Inoue N, Tamura M, Matsu-
zaka T, Nakagawa Y, Yahagi N, Toyoshima H, Sato R
& Yamada N (2007) A transcription factor of lipid
synthesis, sterol regulatory element-binding protein
(SREBP)-1a causes G(1) cell-cycle arrest after accumu-
lation of cyclin-dependent kinase (cdk) inhibitors. FEBS
J 274, 4440–4452.
20 Inoue N, Shimano H, Nakakuki M, Matsuzaka T,
Nakagawa Y, Yamamoto T, Sato R, Takahashi A,
Sone H, Yahagi N et al. (2005) Lipid synthetic tran-
scription factor SREBP-1a activates p21WAF1 ⁄ CIP1, a
universal cyclin-dependent kinase inhibitor. Mol Cell
Biol 25, 8938–8947.
21 Rawson RB (2003) The SREBP pathway – insights
from Insigs and insects. Nat Rev Mol Cell Biol 4, 631–

640.
22 Hughes AL, Todd BL & Espenshade PJ (2005) SREBP
pathway responds to sterols and functions as an oxygen
sensor in fission yeast. Cell 120, 831–842.
23 Unger RH (1995) Lipotoxicity in the pathogenesis of
obesity-dependent NIDDM. Genetic and clinical impli-
cations. Diabetes 44, 863–870.
24 Shimano H, Yahagi N, Amemiya-Kudo M, Hasty AH,
Osuga J, Tamura Y, Shionoiri F, Iizuka Y, Ohashi K,
Harada K et al. (1999) Sterol regulatory element-bind-
ing protein-1 as a key transcription factor for nutri-
tional induction of lipogenic enzyme genes. J Biol Chem
274, 35832–35839.
25 Yahagi N, Shimano H, Hasty AH, Matsuzaka T, Ide
T, Yoshikawa T, Amemiya-Kudo M, Tomita S, Oka-
zaki H, Tamura Y et al. (2002) Absence of sterol regu-
latory element-binding protein-1 (SREBP-1) ameliorates
fatty livers but not obesity or insulin resistance in
Lep(ob) ⁄ Lep(ob) mice. J Biol Chem 277, 19353–19357.
26 Takahashi A, Motomura K, Kato T, Yoshikawa T,
Nakagawa Y, Yahagi N, Sone H, Suzuki H, Toyoshima
H, Yamada N et al. (2005) Transgenic mice overex-
pressing nuclear SREBP-1c in pancreatic beta-cells.
Diabetes 54, 492–499.
27 Unger RH (2003) Minireview: weapons of lean body
mass destruction: the role of ectopic lipids in the meta-
bolic syndrome. Endocrinology 144, 5159–5165.
28 Shimano H, Amemiya-Kudo M, Takahashi A, Kato T,
Ishikawa M & Yamada N (2007) Sterol regulatory ele-
ment-binding protein-1c and pancreatic beta-cell dys-

function. Diabetes Obes Metab 9(Suppl. 2), 133–139.
Physiology and pathophysiology of the SREBP family H. Shimano
620 FEBS Journal 276 (2009) 616–621 ª 2008 The Author Journal compilation ª 2008 FEBS
29 Zhang CY, Baffy G, Perret P, Krauss S, Peroni O, Grujic
D, Hagen T, Vidal-Puig AJ, Boss O, Kim YB et al.
(2001) Uncoupling protein-2 negatively regulates insulin
secretion and is a major link between obesity, beta cell
dysfunction, and type 2 diabetes. Cell 105, 745–755.
30 Yamashita T, Eto K, Okazaki Y, Yamashita S, Yamau-
chi T, Sekine N, Nagai R, Noda M & Kadowaki T
(2004) Role of uncoupling protein-2 up-regulation and
triglyceride accumulation in impaired glucose-stimulated
insulin secretion in a beta-cell lipotoxicity model overex-
pressing sterol regulatory element-binding protein-1c.
Endocrinology 145, 3566–3577.
31 Kato T, Shimano H, Yamamoto T, Yokoo T, Endo Y,
Ishikawa M, Matsuzaka T, Nakagawa Y, Kumadaki S,
Yahagi N et al. (2006) Granuphilin is activated by
SREBP-1c and involved in impaired insulin secretion in
diabetic mice. Cell Metab 4, 143–154.
32 Hannah VC, Ou J, Luong A, Goldstein JL & Brown
MS (2001) Unsaturated fatty acids down-regulate srebp
isoforms 1a and 1c by two mechanisms in HEK-293
cells. J Biol Chem 276, 4365–4372.
33 Yahagi N, Shimano H, Hasty AH, Amemiya-Kudo M,
Okazaki H, Tamura Y, Iizuka Y, Shionoiri F, Ohashi
K, Osuga J et al. (1999) A crucial role of sterol regula-
tory element-binding protein-1 in the regulation of
lipogenic gene expression by polyunsaturated fatty
acids. J Biol Chem 274, 35840–35844.

34 Kim HJ, Takahashi M & Ezaki O (1999) Fish oil feed-
ing decreases mature sterol regulatory element-binding
protein 1 (SREBP-1) by down-regulation of SREBP-1c
mRNA in mouse liver. A possible mechanism for
down-regulation of lipogenic enzyme mRNAs. J Biol
Chem 274, 25892–25898.
35 Xu J, Nakamura MT, Cho HP & Clarke SD (1999) Sterol
regulatory element binding protein-1 expression is sup-
pressed by dietary polyunsaturated fatty acids. A mecha-
nism for the coordinate suppression of lipogenic genes by
polyunsaturated fats. J Biol Chem 274, 23577–23583.
36 Nakatani T, Kim HJ, Kaburagi Y, Yasuda K & Ezaki
O (2003) A low fish oil inhibits SREBP-1 proteolytic
cascade, while a high-fish-oil feeding decreases SREBP-
1 mRNA in mice liver: relationship to anti-obesity.
J Lipid Res 44, 369–379.
37 Yoshikawa T, Shimano H, Yahagi N, Ide T, Amemiya-
Kudo M, Matsuzaka T, Nakakuki M, Tomita S, Oka-
zaki H, Tamura Y et al. (2002) Polyunsaturated fatty
acids suppress sterol regulatory element-binding pro-
tein 1c promoter activity by inhibition of liver X recep-
tor (LXR) binding to LXR response elements. J Biol
Chem 277, 1705–1711.
38 Sekiya M, Yahagi N, Matsuzaka T, Najima Y, Nak-
akuki M, Nagai R, Ishibashi S, Osuga J, Yamada N &
Shimano H (2003) Polyunsaturated fatty acids amelio-
rate hepatic steatosis in obese mice by SREBP-1
suppression. Hepatology 38, 1529–1539.
39 Kato T, Shimano H, Yamamoto T, Ishikawa M,
Kumadaki S, Matsuzaka T, Nakagawa Y, Yahagi N,

Nakakuki M, Hasty AH et al. (2008) Palmitate impairs
and eicosapentaenoate restores insulin secretion through
regulation of SREBP-1c in pancreatic islets. Diabetes
57, 2382–2392.
40 Sun L, Halaihel N, Zhang W, Rogers T & Levi M
(2002) Role of sterol regulatory element-binding pro-
tein 1 in regulation of renal lipid metabolism and glom-
erulosclerosis in diabetes mellitus. J Biol Chem 277,
18919–18927.
41 Jiang T, Liebman SE, Lucia MS, Li J & Levi M (2005)
Role of altered renal lipid metabolism and the sterol
regulatory element binding proteins in the pathogenesis
of age-related renal disease. Kidney Int 68, 2608–2620.
42 Wang Z, Jiang T, Li J, Proctor G, McManaman JL,
Lucia S, Chua S & Levi M (2005) Regulation of renal
lipid metabolism, lipid accumulation, and glomerulo-
sclerosis in FVBdb ⁄ db mice with type 2 diabetes. Diabe-
tes 54, 2328–2335.
43 Ishigaki N, Yamamoto T, Shimizu Y, Kobayashi K,
Yatoh S, Sone H, Takahashi A, Suzuki H, Yamagata
K, Yamada N et al. (2007) Involvement of glomerular
SREBP-1c in diabetic nephropathy. Biochem Biophys
Res Commun 364, 502–508.
44 Kim JB & Spiegelman BM (1996) ADD1 ⁄ SREBP1 pro-
motes adipocyte differentiation and gene expression
linked to fatty acid metabolism. Genes Dev 10, 1096–
1107.
45 Shimomura I, Hammer RE, Richardson JA, Ikemoto S,
Bashmakov Y, Goldstein JL & Brown MS (1998) Insu-
lin resistance and diabetes mellitus in transgenic mice

expressing nuclear SREBP-1c in adipose tissue: model
for congenital generalized lipodystrophy. Genes Dev 12,
3182–3194.
46 Shimano H, Shimomura I, Hammer RE, Herz J,
Goldstein JL, Brown MS & Horton JD (1997) Elevated
levels of SREBP-2 and cholesterol synthesis in livers of
mice homozygous for a targeted disruption of the
SREBP-1 gene. J Clin Invest 100, 2115–2124.
47 Soukas A, Cohen P, Socci ND & Friedman JM (2000)
Leptin-specific patterns of gene expression in white
adipose tissue. Genes Dev 14, 963–980.
48 Inoue N, Yahagi N, Yamamoto T, Ishikawa M,
Watanabe K, Matsuzaka T, Nakagawa Y, Takeuchi Y,
Kobayashi K, Takahashi A et al. (2008) Cyclin-depen-
dent kinase inhibitor, p21WAF1 ⁄ CIP1, is involved in
adipocyte differentiation and hypertrophy, linking to
obesity, and insulin resistance. J Biol Chem 283,
21220–21229.
49 Park HJ, Georgescu SP, Du C, Madias C, Aronovitz
MJ, Welzig CM, Wang B, Begley U, Zhang Y, Blau-
stein RO et al. (2008) Parasympathetic response in
chick myocytes and mouse heart is controlled by
SREBP. J Clin Invest 118, 259–271.
H. Shimano Physiology and pathophysiology of the SREBP family
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