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.

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

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

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

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

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.

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

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H. Shimano Physiology and pathophysiology of the SREBP family
FEBS Journal 276 (2009) 616–621 ª 2008 The Author Journal compilation ª 2008 FEBS 621