SREBPs: physiology and pathophysiology of theSREBP family Hitoshi Shimano Department of Internal Medicine Endocrinoglogy and Metabolism, Graduate School of Comprehensive Human Sciences,
Trang 1SREBPs: 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: shimano-tky@umin.ac.jp,
hshimano@md.tsukuba.ac.jp
(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.
Trang 2SREBP-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
G6PD
Feedback
Pentose phosphate pathway NADPH
Pyruvate ME Malate
PK
Cholesterol synthesis
Squalene
Cholesterol
HMG-CoA reductase
SREBP-2 NADPH
Pyruvate Acetyl-CoA
Citrate acetyl-CoA
Oxaloacetate
ACC
HMG-CoA HMG-CoA synthase Citrate
Malonyl-CoA Palmitate Malate
Mitochondria
FAS ACC
SCD
Fatty acid synthesis
StearateElovl6
acyl-CoA Glycerol-3-phosphate
1-acylglycerol-3-phosphateCoA
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 synthcarboxyl-ase; SCD,
stea-royl-CoA desaturase; GPAT, glycerol
phosphate acyltransferase; DGAT,
diacyl-glycerol acyltransferase; 6PG,
6-phosphoglu-conate.
Trang 3at G1 [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
Trang 4In 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
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