From the Departments of Physiology, Biochemistry, and Molecular Biology, Michigan State University, East Lansing, Michigan 48824
Received for publication, December 17, 2002
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ABSTRACT |
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Sterol regulatory element-binding
protein-1c (SREBP-1c) plays a major role in hepatic lipogenic gene
expression. In adult animals, insulin and oxysterols induce SREBP-1c
gene transcription, whereas polyunsaturated fatty acids suppress the
nuclear content of SREBP-1c through pre-translational regulatory
mechanisms. A decline in nuclear SREBP-1 is associated with suppression
of hepatic lipogenesis. In contrast to adult rats, hepatic lipogenesis
in preweaned neonatal rats is low. Ingestion of milk fat by the neonate may contribute to low hepatic lipogenesis. In this report, we tested
the hypothesis that low lipogenic gene expression prior to weaning
correlates with low mRNASREBP-1c, as well as low
precursor and nuclear forms of SREBP-1. In contrast to expectations,
levels of mRNASREBP-1c and the 125-kDa SREBP-1
precursor in livers of preweaned rats was comparable with adult levels.
Despite high levels of SREBP-1 precursor, mature (65 kDa) SREBP-1 was
not detected in rat liver nuclei prior to 18 days postpartum. Weaning
rats at 21 days postpartum was accompanied by a rise in nuclear SREBP-1 levels as well as increased lipogenic gene expression. In contrast, SREBP-2 was present in rat liver nuclei, and its target gene, HMG-CoA reductase, was expressed above adult levels
prior to weaning. These studies indicate that, prior to weaning,
SREBP-2 but not SREBP-1 is proteolytically processed to the mature
form. As such, SREBP-2-regulated genes are active. Failure of SREBP-1
to be processed to the mature form <18 days postpartum correlates with
low hepatic lipogenic gene expression. This mechanism differs from the
hormonal and fatty acid-mediated pre-translational control of SREBP-1c in adult liver.
Hepatic de novo lipogenesis is under complex hormonal
and dietary regulation in adult animals (1). Lipogenic gene expression is induced by insulin, thyroid hormone, and dexamethasone and is
suppressed by hormones elevating hepatocellular cAMP levels (1, 2).
Dietary carbohydrate induces lipogenic genes, whereas dietary
polyunsaturated fatty acids
(PUFAs)1 suppress
transcription of hepatic lipogenic genes. One of the key transcription
factors controlling hepatic de novo lipogenesis is sterol
regulatory element-binding protein-1c (SREBP-1c) (3, 4). SREBP-1c is a
member of a family of basic helix-loop-helix leucine zipper
transcription factors involved in fatty acid, triglyceride, and
cholesterol synthesis.
SREBPs are translated as ~125-kDa precursors (pSREBP) attached to the
endoplasmic reticulum (ER) (4, 5). After proteolytic processing in the
Golgi, the nuclear form, nSREBP (~65 kDa), accumulates in nuclei
where it binds sterol regulatory elements in promoters of many genes
involved in fatty acid, triglyceride, and cholesterol synthesis. The
proteolytic processing of SREBP is mediated by at least three proteins,
i.e. SREBP-cleavage activating protein (SCAP), site-1
protease (S1P), and site-2 protease (S2P) (4). The escort of SREBP from
the ER to the Golgi by SCAP is inhibited by the accumulation of sterols
in cells, thus preventing maturation of SREBP to a form regulating gene
transcription. Germline modification of mice has shown that SCAP and
S1P are important for the processing of both SREBP-1 and SREBP-2 (4, 6,
7).
Whereas SREBP-2 is involved in cholesterol synthesis, SREBP-1 plays a
central role in lipogenesis (3, 4). SREBP-1c is the predominant SREBP-1
subtype expressed in adult rodent liver (3, 4). Transcription of the
SREBP-1c gene is induced by oxysterols through LXR (8, 9,11)
as well as insulin (12-15). Insulin induction of LXR Unsaturated fatty acids have been reported to suppress nuclear SREBP
levels in HepG2 cell, rat primary hepatocytes, and rat liver (16-21).
However, in the liver, nuclear levels of SREBP-1c but not of SREBP-2
are suppressed by PUFAs (18-21). Feeding rodents diets supplemented
with polyunsaturated fatty acids or treating primary hepatocytes with
PUFA will suppress mRNASREBP-1c and lead to a decline
in both the precursor and nuclear forms of SREBP-1c (18-20). Clarke
and co-workers (20) have reported that the principal mechanism for the
pre-translational control involves PUFA-enhanced mRNASREBP-1c turnover. Overexpression of nSREBP-1c in
primary hepatocytes or in vivo eliminates the PUFA effects
on several lipogenic genes, indicating that SREBP-1c is a key target
for PUFA suppression of de novo lipogenesis (19, 21).
During postnatal development of rats and mice, hepatic lipogenesis is
low prior to weaning at 21 days postpartum (22-29). The activities of
key enzymes, as well as their mRNAs, are very low during the
suckling phase. Where examined, low lipogenic gene expression is due to
low transcription rates (24). Based on studies with adult animals (2),
low lipogenic gene transcription in newborns has been attributed to the
ingestion of a high fat milk diet (26).
Because PUFA controls nuclear SREBP-1c levels through a
pre-translational regulatory mechanism (18-20), we were interested in
determining whether low hepatic lipogenic gene expression in preweaned
animals correlates with low mRNASREBP-1c. Contrary to expectations, our studies indicated that both
mRNASREBP-1 and pSREBP-1c are well expressed in rat
liver prior to weaning. Only nSREBP-1c levels are low in neonatal
liver, reflecting abrogated maturation of pSREBP-1 to
nSREBP-1.
Animals--
Female Sprague-Dawley rats with litters were
obtained from Charles River Laboratories (Kalamazoo, MI) and maintained
on a Tek-Lad chow diet, ad libitum. Male rats at 15, 18, and
21 days postpartum were used for this analysis and compared with adult male rats ( Cell Extracts and Western Blotting--
Extracts of rat liver
were prepared by homogenizing tissue in Buffer A (0.25 M
sucrose, 10 mM Tris-Cl, pH 7.5, and 3 mM
MgCl2 plus the protease inhibitors phenylmethylsulfonyl
fluoride (1 mM), pefabloc (0.1 mM), pepstatin
(5 µg/ml), leupeptin (5 µg/ml), and aprotinin (2 µg/ml)). The
homogenate was centrifuged (300 × g for 5 min at
2 °C.). The supernatant was then centrifuged (100,000 × g for 1 h at 4 °C) to obtain microsomes. The pellet from the first centrifugation was resuspended in Buffer A, adjusted to
1% Nonidet P-40, and homogenized. The homogenate was centrifuged (300 × g for 5 min at 2 °C.). The supernatant was retained for analysis. The nuclear pellet was resuspended in Buffer B (50 mM Hepes, pH 7.4, 0.1 M KCl, 3 mM
MgCl2, 1 mM EDTA, and 10% glycerol plus the
protease inhibitors phenylmethylsulfonyl fluoride (0.1 mM),
pefabloc (0.1 mM), pepstatin (5 µg/ml), leupeptin (5 µg/ml), and aprotinin (2 µg/ml)), adjusted to 0.4 M
ammonium sulfate, and centrifuged at 100,000 × g for
60 min. The supernatant was used for analysis of nuclear proteins.
Proteins (50-100 µg) were separated electrophoretically by
SDS-polyacrylamide gel electrophoresis (NuPAGE 4-10% polyacrylamide Bis-Tris, Invitrogen) and transferred to nitrocellulose
membranes. Membranes were incubated with antibodies for SREBP-1
(IgG-2A4) or SREBP-2 (IgG-7D4) obtained from the supernatants of the
hybridoma cell lines CRL 2121 and CRL2198, respectively (American Type
Culture Collection, Manassas, VA), and CYP4A (Affinity Bioreagents,
Inc., Warrendale, PA) or HNF-4 Plasmids--
cDNAs for SREBP-1c, fatty acid synthase, S14,
and cytochrome P450 4A (CYP4A) were described previously (19).
cDNAs for HMG-CoA reductase and mtHMG-CoA reductase were prepared
by RT-PCR and subcloned into a pSp72 vector. Sequence analysis was
verified at the Michigan State University Genomic Core facility. The
primers used to generate HMG-CoA reductase are as follows: sense,
5'-GTGGCCTCCATTGAGATCCGGAGGATCCAA-3'; and antisense,
5'-GGATCGCCATCCCACGCGCTATATTCTCCC-3'. The primers used to generate
mtHMG-CoA synthase are as follows: sense,
5'-GATGTGGGCATCCTTGCCCTGGAGGTCTAC-3'; and antisense,
5'-AGTTGGCAGCGTTGAAGAGGGAGG CAGTGC-3'.
RNA Analysis--
Livers were extracted with Triazol
as described and used for Northern analysis (19). RNA was separated
electrophoretically in denaturating agarose gels, transferred to
nitrocellulose, and probed with [32P]cDNAs. Levels of
hybridization were quantified using a PhosphorImager 820 (Amersham
Biosciences). RT-PCR analysis (Superscript One-Step RT-PCR with
platinum Taq, Invitrogen) of the SREBP-1 subtype used the
SREBP-1a specific primer (5'-ATGGACGAGCTGGCCTTCGGTGAGGCG-3'), and the
SREBP-1c-specific primer (5'-GATTGCACATTTGAAGACATGCTT-3') was used for
sense strand synthesis (30). The internal primer (5'-GGGTCCTCCCAGGAAGGCTTCCAGAGA-3') was used for antisense
strand synthesis and is common to both the SREBP-1a and SREBP-1c
transcripts. Total liver RNA from 15-, 18-, 21-, and 30-day-old rats
was used as template. Amplified DNAs were separated electrophoretically and visualized by ethidium bromide staining.
Post-translational Processing of SREBP-1c Regulates
Nuclear SREBP-1c Levels during Postnatal Development--
In this
report, we tested the hypothesis that low levels of hepatic lipogenesis
prior to weaning correlate with low mRNASREBP-1c, which
leads to a decline in pSREBP-1 and nSREBP-1. Levels of mRNA encoding SREBP-1 and the lipogenesis-associated protein S14 were measured in 15- and 42-day-old rats and 42-day old rats, respectively, fed a high carbohydrate-fat free diet for 5 days (Fig.
1). S14 was used because SREBP-1c induces
S14 gene transcription (19, 31). The high carbohydrate fat-free diet
was used to illustrate the effect of a fat-free diet on hepatic SREBP-1
and S14 mRNA levels. Hepatic mRNAS14 is essentially
absent at 15 days postpartum (Fig. 1). At this age, S14 gene
transcription is not detectable (24). In contrast to
mRNAS14, hepatic mRNASREBP-1 in 15 day old rats is ~1.5-fold higher than that seen in 42-day-old chow-fed rats and is comparable with the level seen in rats fed a high carbohydrate fat-free diet for 5 days. RT-PCR analysis using SREBP-1a- and SREBP-1c-specific primers indicated that SREBP-1c represents >90%
of the SREBP-1 expressed in rat liver at 15 days postpartum (not
shown). The ratio of SREBP-1c to SREBP-1a was not different at 15 days
postpartum and in adults. Thus, SREBP-1c is the predominant SREBP-1
transcript expressed in neonatal and adult liver.
Insulin-mediated induction of S14 and SREBP-1 gene transcription
accounts for the elevated levels of S14 and SREBP-1c mRNAs in
livers of adult animals fed high carbohydrate fat-free diets (12-14,
31, 32). However, high SREBP-1c mRNA levels prior to weaning cannot
be ascribed to elevated insulin, because blood insulin levels are
typically low, and the liver displays elevated ketogenesis (26, 28,
29). Thus, factors controlling hepatic SREBP-1c mRNA levels in the
suckling animal differ from that seen in the adult rat.
Because low lipogenic gene expression cannot be explained by
pre-translational suppression of mRNASREBP-1c, we
examined hepatic precursor and nuclear SREBP-1 and SREBP-2 levels in
15- and 30-day-old rats (Fig. 2).
Precursor levels of SREBP-1 and SREBP-2 were ~1.5- and 2-fold higher
in livers of 15-day old rats when compared with adults. As a control,
the microsomal monooxygenase CYP4A was ~2-fold higher in livers
derived from 30-day-old animals than in those from 15-day-old animals.
Although nSREBP-2 was present in nuclear extracts obtained from both
15- and 30-day-old animals, nSREBP-1 was not detected in hepatic nuclei
isolated from 15-day-old rats. However, nSREBP-1 was present in nuclear
extracts from 30-day-old animals. HNF-4
These studies indicate that SREBP-2 matures to the nuclear form, but
SREBP-1 maturation is abrogated, leading to little or no nSREBP-1
accumulation in hepatic nuclei of 15-day-old rats. The absence of
nSREBP-1c in nuclei correlates with low hepatic de novo
lipogenesis in the neonate. Thus, the principal mechanism accounting
for low lipogenic gene expression in hepatic nuclei prior to weaning is
due, at least in part, to low nSREBP-1 but not low
mRNASREBP-1 or pSREBP-1. The mechanism controlling
hepatic nSREBP-1 levels in neonatal and adult liver is clearly different.
Developmental Regulation of SREBP-1c Maturation Correlates with the
Induction of Hepatic Lipogenic Gene Expression--
Lipogenic gene
expression, i.e. S14 and FAS, increases dramatically when
rats are weaned (22-25). To determine whether SREBP-1 maturation
followed this same time line, we examined SREBP-1 protein levels in
hepatic microsomes and nuclei of animals at 15, 18, 22, and 30 days
postpartum. Although these animals are normally weaned at 21 days of
age, they begin to ingest solid food between 18 and 21 days postpartum.
Microsomal pSREBP-1 remained unchanged over the 15-, 18-, 22-, and
30-day-old period (Fig. 3), a finding that correlates with the modest changes in mRNASREBP-1c
in 15-day-old and adult animals (Fig. 1). Hepatic nuclear nSREBP-1 was
not detected at 15 days postpartum (Figs. 2 and 3) but was detected at
18 days postpartum. By 22 days of age, nSREBP-1 levels are comparable with adult levels. The maturation of SREBP-1c parallels the dietary switch from a high fat milk diet to a control chow diet.
To determine whether the change in nSREBP-1 correlated with the onset
of lipogenic gene expression, we measured the expression of three
SREBP-1 target genes (S14, FAS, and
GPAT) as well as the SREBP-2 regulated gene HMG-CoA
reductase (Fig. 4A). The
mRNAs encoding S14 and FAS increased progressively from very low
levels at 15 days of age to high levels at 30 days of age. These
changes correlated with increased nSREBP-1 levels (Fig. 3). In
contrast, glycerophosphate acyl transferase (GPAT) mRNA levels were
above adult levels at 15-22 days postpartum. Unlike de novo
lipogenesis, GPAT is required for the synthesis of phospholipids as
well as triglycerides. The growing liver likely requires GPAT
expression throughout all phases of development. Expression of the
SREBP-2-regulated transcript, HMG-CoA reductase, was also above adult
values during the 15-22 day old period, a finding consistent with
abundant nSREBP-2 (Fig. 2) and elevated cholesterol synthesis in
neonatal liver (28).
The mRNA encoding mtHMG-CoA synthase, a
PPAR Conclusion--
Our studies provide the first in vivo
evidence for differential regulation of hepatic SREBP-1 and SREBP-2
proteolytic processing. SREBP-2 is expressed as both pSREBP-2 and
nSREBP-2 in livers derived from 15-day-old preweaned animals.
Moreover, its target gene, HMG-CoA reductase, is well
expressed in the liver prior to weaning. In contrast, hepatic lipogenic
gene expression (FAS and S14) is very low prior to weaning. Low
lipogenic gene expression correlates with low nSREBP-1 levels. The
mechanism limiting nSREBP-1 in preweaned animals involves abrogated
conversion of pSREBP-1 to nSREBP-1 (Figs. 2 and 3) and not
pre-translational suppression of mRNASREBP-1 as seen in
the adult (18-20). The physiological consequence of selective
processing of SREBP-1 and SREBP-2 is a shift of hepatic metabolism
toward cholesterol synthesis, i.e. HMG-CoA reductase, and
away from de novo lipogenesis, i.e. S14 and FAS
(Figs. 2-4).
Because SCAP and S1P are required for both SREBP-1 and SREBP-2
processing (4, 6, 7), it is unlikely that the selective blockade of
SREBP-1 maturation is due to deficient SCAP or S1P. Alternatively, two
other mechanisms might contribute to selective SREBP-1 and SREBP-2
proteolytic processing. Worgall et al. (17) reported that
unsaturated fatty acid inhibition of SREBP processing was linked to
sphingolipid metabolism and ceramide generation. This mechanism
inhibited both SREBP-1 and SREBP-2 proteolytic processing without
effects on SREBP-1 or SREBP-2 mRNAs.
An alternative mechanism involves the insulin regulated
ER-associated proteins INSIG-1 and INSIG-2. INSIG-1 mRNA was
originally isolated by Taub and co-workers (36) and found to be induced by insulin in Rueber H35 hepatoma cells. Yang et al. (37)
and Yabe et al. (38) reported that INSIG-1 and INSIG-2 bind
SCAP in the ER and block SREBP export to the Golgi for proteolytic processing. Janowski (10) recently reported that LXR agonists attenuate
INSIG-1 gene expression (10). The LXR-regulated transcripts, ABCG5 and
CYP7A1, are well expressed in neonatal liver implicating elevated
hepatic oxysterols and active LXR (Fig. 4B). This
observation, coupled with the fact that neonatal rats have low blood
insulin levels and elevated hepatic ketogenesis (Refs. 28 and 29, and
Fig. 4B), suggests that INSIG-1 or INSIG-2 might be low in the neonatal liver.
Clearly, more studies will be required to establish the roles
sphingolipid metabolism, INSIG-1, and INSIG-2 play in the control of
hepatic SREBP-1 and SREBP-2 proteolytic processing. We anticipate that
definition of the molecular basis of differential processing of SREBP-1
and SREBP-2 in neonatal rat liver will provide important clues to
selective control hepatic cholesterol and fatty acid synthesis.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS AND DISCUSSION
REFERENCES
gene
transcription might also contribute to this regulatory scheme (15).
Much of insulin action on lipogenic gene transcription has been
ascribed to the insulin-mediated induction of SREBP-1c (12-14).
Studies with primary rat hepatocytes suggest that SREBP-1 may be
constitutively processed to the nuclear form (12).
MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS AND DISCUSSION
REFERENCES
30 days postpartum).
(Santa Cruz Biotechnology). The
anti-mouse secondary antibody was obtained from Bio-Rad). The detection
system employed the SuperSignal West Pico chemiluminescence kit (Pierce).
RESULTS AND DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS AND DISCUSSION
REFERENCES
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Fig. 1.
Expression of S14 and SREBP-1 mRNA in rat
liver. RNA was extracted from five suckling rats (15 days
postpartum), two chow-fed rats, and three rats fed a high carbohydrate
(HiCHO) fat-free diet for 7 days. The chow and high
carbohydrate fat-free fed animals were 42 days postpartum. RNAs were
separated electrophoretically, transferred to nitrocellulose, and
probed with [32P]cDNAs for S14 and SREBP-1c. Levels
of expression were quantified by PhosphorImager analysis. The results
are representative of at least two separate studies.
levels were ~2-fold higher
in 30- versus 15-day-old rats.
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Fig. 2.
Expression of SREBP-1 and SREBP-2 in hepatic
microsomes and nuclear extracts from 15- and 30-day-old rats.
Microsomal and nuclear extracts were prepared from two adult (30 days
postpartum) and three preweaned (15 days postpartum) male rats as
described under "Materials and Methods." Proteins from microsomal
(panel A) and nuclear (panel B) extracts were
separated electrophoretically, transferred to nitrocellulose, and
reacted with antibodies for SREBP-1, SREBP-2, HNF-4, and CYP4A. The
results are representative of two separate studies.
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Fig. 3.
Time course of hepatic SREBP-1 appearance in
microsomal and nuclear fractions during postnatal development.
Microsomal and nuclear extracts (one animal per time point) were
prepared from animals 15, 18, 22, and 30 days postpartum. Proteins from
microsomal (pSREBP-1c, 125 kDa) and nuclear (nSREBP-1c, 65 kDa)
extracts were separated electrophoretically, transferred to
nitrocellulose, and reacted with an SREBP-1 antibody. These results are
representative of four separate sets of animals at each time
point.
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Fig. 4.
Time course of hepatic lipogenic gene
expression. RNAs were extracted from livers of male rats 15, 18, 22, and 30 days postpartum and separated electrophoretically. After
transfer to nitrocellulose, blots were probed with
32P-cDNAs. A, S14; fatty acid synthase
(FAS); glycerophosphate acyl transferase (GPAT);
and HMG-CoA reductase (RED). B, mitochondrial
HMG-CoA synthase (mtSYN); cytochrome P450 4A
(CYP4A); cytochrome P450 7A (CYP7A); and
ATP-binding cassette-G5 (ABCG5); 15 (black bar),
18 (white bar), 22 (gray bar), and 30 days
postpartum (shaded bar). Results are expressed as
relative mRNA abundance, i.e. relative to adult levels
at 30 days postpartum animal. Three animals are used at each time
point. Mean ± standard deviation.
-regulated gene, is high prior to weaning (Fig. 4B).
High levels of mtHMG-CoA synthase are consistent with elevated
ketogenesis associated with suckling rats (26, 28). In contrast,
another PPAR
-regulated gene, CYP4A, is low prior to
weaning. This apparent paradox is explained by the fact that low blood
levels of insulin prior to weaning promote ketogenesis (26, 28, 29).
Long-chain PUFAs are PPAR
ligands and induce CYP4A gene
transcription (33, 34). Milk fats are enriched in short to medium chain
saturated fatty acids. Based on structural studies, these fatty acids
are likely not good ligands for PPAR
(23). The LXR-regulated
transcripts (35), CYP7A (bile acid synthesis), and ABCG5 (cholesterol
efflux) are well expressed throughout the 15-30-day postpartum period. Thus, the expression of genes encoding proteins involved in cholesterol synthesis (HMG-CoA-reductase), bile acid synthesis
(CYP7A), and cholesterol efflux (ABCG5) are well
expressed in liver prior to weaning.
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ACKNOWLEDGEMENTS |
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We thank Drs. Karl Olson and Julia Busik for critical reading of the manuscript. We gratefully acknowledge Drs. Coleman, Hobbs, and Russell for the generous gifts of cDNAs used in these studies. We thank Tim Osborne for helpful discussions.
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FOOTNOTES |
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* This research was supported by National Institutes of Health Grant DK43220, United States Department of Agriculture Grant 98-35200-6064, and the Michigan Agriculture Experiment Station.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Physiology,
3165 Biomedical and Physical Science Bldg., Michigan State University,
East Lansing, MI 48824. Tel.: 517-355-6475 (ext. 1246); Fax:
517-355-5125; E-mail: Jump@msu.edu.
Published, JBC Papers in Press, December 17, 2002, DOI 10.1074/jbc.M212846200
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ABBREVIATIONS |
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The abbreviations used are:
PUFA, polyunsaturated fatty acids;
SREBP, sterol regulatory binding protein;
pSREBP, precursor SREBP;
nSREBP, nuclear form of SREBP;
ER, endoplasmic
reticulum;
SCAP, SREBP-cleavage activating protein;
LXR, liver X
receptor;
S1P, site-1 protease;
RT, reverse transcription;
GPAT, glycerophosphate acyl transferase;
PPAR, peroxisome proliferator
activated receptor;
FAS, fatty acid synthase;
ABCG5, ATP-binding
cassette-G5, CYP7A, cytochrome P450 7A (7-hydroxylase);
CYP4A, cytochrome P450 4A;
HMG-CoA, hydroxymethylglutaryl coenzyme A;
mtHMG-CoA, mitochondrial HMG-CoA;
HNF, hepatocyte nuclear factor.
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