Received for publication, February 6, 2003, and in revised form, February 21, 2003
Liver X receptor (LXR) is a nuclear receptor that
plays a crucial role in orchestrating the trafficking of sterols
between tissues. Treatment of mice with a potent and specific LXR
agonist, T0901317, is associated with increased biliary cholesterol
secretion, decreased fractional cholesterol absorption, and increased
fecal neutral sterol excretion. Here we show that expression of two target genes of LXR
, the ATP-binding cassette (ABC) transporters Abcg5 and Abcg8, is required for both the
increase in sterol excretion and the decrease in fractional cholesterol
absorption associated with LXR agonist treatment. Mice expressing no
ABCG5 and ABCG8 (G5G8
/
mice) and their
littermate controls were treated for 7 days with T0901317. In wild type
animals, treatment with the LXR agonist resulted in a 3-fold increase
in biliary cholesterol concentrations, a 25% reduction in fractional
cholesterol absorption, and a 4-fold elevation in fecal neutral sterol
excretion. In contrast, the LXR agonist did not significantly affect
biliary cholesterol levels, fractional cholesterol absorption, or
neutral fecal sterol excretion in the G5G8
/
mice. Thus Abcg5 and Abcg8 are required for LXR
agonist-associated changes in dietary and biliary sterol trafficking.
These results establish a central role for ABCG5 and ABCG8 in promoting
cholesterol excretion in vivo.
 |
INTRODUCTION |
Cholesterol is an important structural component of animal
cell membranes. The cholesterol required to maintain membrane integrity can be synthesized de novo from acetyl-CoA or can be
obtained from cholesterol-containing foods in the diet. The typical
Western diet includes ~400 mg of cholesterol per day, of which
40-50% is absorbed in the proximal small intestine. The major pathway by which cholesterol is eliminated from the body is by excretion into
bile either as free cholesterol or after conversion to bile acids.
A variety of noncholesterol sterols are also present in the diet. The
most plentiful of these are the two plant sterols, sitosterol and
campesterol. The levels of these sterols in tissues are very low,
because plant sterols are poorly absorbed from the intestine and are
preferentially secreted into the bile by hepatocytes (1-3).
One mechanism by which excess cholesterol and other sterols are
eliminated from the body involves the action of two ATP-binding cassette (ABC)1
half-transporters, ABCG5 and ABCG8 (4, 5). Mutations in either of these
genes cause sitosterolemia, a rare autosomal recessive disorder of
sterol trafficking (4, 5). Subjects with sitosterolemia have increased
fractional absorption of dietary noncholesterol sterols and decreased
biliary secretion of plant- and animal-derived sterols (6, 7).
Consequently, these patients accumulate sitosterol, as well as other
plant- and shellfish-derived neutral sterols, in the blood and tissues
(8, 9). Subjects with sitosterolemia also are frequently
hypercholesterolemic and develop tendon xanthomas and premature
coronary artery disease (8, 10).
The pivotal role of ABCG5 and ABCG8 in enterohepatic sterol transport
has been demonstrated directly by manipulating the expression of these
genes in mice (11, 12). Transgenic mice containing ~14 copies of a
human genomic DNA fragment, including both human ABCG5 and
ABCG8 genes have a ~50% reduction in the fractional absorption of dietary cholesterol, dramatically elevated levels of
biliary cholesterol, and a 4.5-fold increase in fecal neutral sterol
excretion (11). Plant sterol levels are more than 50% lower in these
mice than in their wild type littermates. Disruption of the mouse
Abcg5 and Abcg8 genes has the opposite effect on dietary sterol trafficking. The G5G8
/
mice
have 30-fold higher plasma levels of sitosterol than do their wild type
littermates due to increased fractional absorption of dietary plant
sterols and impaired biliary sterol excretion (12).
Abcg5 and Abcg8 are expressed predominantly in
the liver and small intestine (4) and are coordinately up-regulated at
the transcriptional level by dietary cholesterol. The response of Abcg5 and Abcg8 to cholesterol requires the liver
X receptor
(LXR
) (13), a nuclear receptor that regulates the
expression of many key genes in lipid metabolism, including
ABCA1 (14, 15), the gene mutated in Tangier disease
(16-19), murine (but not human) cholesterol 7
-hydroxylase
(Cyp7A1) (20-22), the rate-limiting enzyme in bile acid
synthesis, and sterol regulatory element-binding protein 1c
(SREBP-1c) (23), an important transcription factor in the
regulation of fatty acid biosynthesis (24). By regulating the
expression of these genes, LXR
coordinates the synthesis and
trafficking of cholesterol and fatty acids between tissues. Mice
lacking LXR
accumulate large amounts of cholesterol in the liver
when fed a high cholesterol diet (21), whereas wild type mice treated
with an LXR agonist have decreased fractional absorption of dietary
cholesterol (14) and increased biliary cholesterol excretion (25).
The mechanism by which LXR
prevents the accumulation of dietary
cholesterol has not been fully defined. The decreased fractional absorption of dietary cholesterol associated with LXR agonist treatment
was attributed initially to the action of ABCA1, because levels of
ABCA1 mRNA increased dramatically in the small intestine of animals
given the nonsteroidal synthetic LXR agonist:
N-(2,2,2-trifluoro-ethyl)-N-[4-(2,2,2trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)phenyl]benzenesulfonamide (T0901317) (14). Subsequent characterization of mice expressing no ABCA1 (Abca1
/
mice) revealed no
impairment in biliary cholesterol secretion or fecal neutral sterol
excretion (25, 26). In the current study, we tested the hypothesis that
ABCG5 and ABCG8 mediate the LXR agonist-associated increase in biliary
and fecal excretion of cholesterol and reduction in cholesterol absorption.
 |
EXPERIMENTAL PROCEDURES |
Materials--
The synthetic LXR agonist T0901317 was purchased
from Cayman Chemical Company (Ann Arbor, MI). Sterols were obtained
either from Steraloids Inc. (Newport, RI) or from Sigma-Aldrich (St. Louis, MO).
Animals and Diets--
Mice homozygous for a disrupted
Abcg5 and Abcg8 allele
(G5G8
/
) were generated as described
previously (12). The mice used in these studies were offspring of
G5G8+/
mice of mixed genetic background
(129S6SvEv × C57BL/6J). The mice were housed in plastic cages in
a temperature-controlled room (22 °C) with a daylight cycle from 6 am to 6 pm, and fed ad libitum a cereal-based rodent chow
diet (Diet 7001, Harlan Teklad, Madison, WI) containing 0.02%
cholesterol and 4% fat. All animal procedures were performed with
approval of the Institutional Animal Care and Research Advisory
Committee at the University of Texas Southwestern Medical Center.
T0901317 Treatment--
Diets containing 0.025% of T0901317
(T-diet) were made by mixing powdered chow diet (Diet 7001, Harlan
Teklad) with pure T0901317. The T-diet was stored in aluminum
foil-covered containers at 4 °C for no more than 3 days. Female mice
were housed individually 1 week before initiation of the T-diet and
then fed for 1 week with either the T-diet or the chow diet dispensed
from a feeder jar. The dose and duration of T0901317 treatment were
based on prior studies (14, 27).
Lipid Chemistries--
Sterol levels in plasma and liver were
measured by gas chromatography (GC) as described (28, 29) with some
modifications. Briefly, plasma and tissues were saponified in 3%
potassium hydroxide/ethanol at 66 °C for 3 h after addition of
5
-cholestane as a quantitative recovery standard. Lipids were
extracted using petroleum ether and dried under nitrogen. The residual
lipids were re-dissolved in Tri-Sil reagent (product 48999, Pierce,
Rockford, IL) for analysis by GC. Hepatic triglyceride levels were
measured using Infinity triglycerides reagent (Sigma-Aldrich, St.
Louis, MO). Lipoproteins were size-fractionated using fast
protein liquid chromatography (FPLC), and the total sterol
concentration in each fraction was measured using cholesterol/HP kits
(catalog number 1127771, Roche Diagnostics Corp., Indianapolis, IN).
Biliary Lipid Composition--
Bile was collected from the
gallbladder of anesthetized mice using a 30.5-gauge needle. The
concentrations of cholesterol, phospholipids, and bile acids were
measured as described previously (30).
Fecal Sterol Excretion--
Mice were fed either the control or
T-diet for 4 days prior to being moved to new cages containing fresh
wood shavings. The diets were fed for an additional 3 days during which
time the feces were collected. The feces were dried, weighed, and
ground to a fine powder. An aliquot of 0.5 g of feces was used to
determine fecal neutral and acidic sterol excretion (11, 28).
Fractional Absorption of Dietary Cholesterol--
Mice were fed
either the control or T-diet for 4 days prior to administering an oil
mixture containing deuterated cholesterol and sitostanol by gavage
(12). Mice were then housed individually in new cages containing fresh
wood shavings. The diets were continued, and the feces were collected
for 3 days and processed for sterol absorption as described (12).
Quantitative Real-time PCR--
Total RNA was extracted from
tissues using the RNA Stat-60 kit (Tel-Test Inc., Friendswood, TX), and
real-time PCR was performed to assay the relative amounts of selected
mRNAs as described (31, 32).
Statistical Analysis--
All data are reported as the mean ± S.E. The differences between the mean values were tested for
statistical significance by the two-tailed Student's t test.
 |
RESULTS |
LXR Activation Increases Plasma Levels of Sitosterol and
Campesterol in G5G8
/
Mice--
Plasma levels of
sitosterol and campesterol were 30-fold higher in
G5G8
/
than in G5G8+/+
female mice fed a chow diet. Addition of T0901317 (0.025%) to the diet
for 7 days resulted in a fall of plasma plant sterol levels to barely
detectable levels in wild type mice. Mean plasma sitosterol levels
increased from 20.6 to 39.6 mg/dl in the LXR agonist-treated knockout
animals (Fig. 1); an increase of similar magnitude occurred in the plasma level of campesterol, the other major
dietary plant sterol.

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Fig. 1.
Plasma sterol levels in chow-fed mice with or
without T0901317. 17-week-old female
G5G8+/+ and G5G8 /
mice (n = 5 in each group) were fed a powdered chow
diet (Diet 7001, Harlan Teklad, Madison, WI) with or without 0.025% of
the synthetic LXR agonist T0901317 for 7 days. Mice were sacrificed
during the daylight cycle after a 4-h fast, and venous blood was
collected. Plasma was separated by centrifugation, and the levels of
plasma sterols were determined by GC, as described under
"Experimental Procedures." T, chow diet;
+T, chow diet plus T0901317 (0.025%); *, p < 0.05 between chow-fed and T0901317-fed mice of each genotype; **,
p < 0.01 between chow-fed and T0901317-fed mice of
each genotype.
|
|
Mean plasma levels of cholesterol were lower in chow-fed
G5G8
/
mice than in wild type mice, as
previously described (12) (Fig. 1). The levels of plasma cholesterol
increased by 50% and by 90% in the wild type mice and
G5G8
/
mice with T0901317 treatment. FPLC
analysis was performed to determine the distribution of sterols in the
plasma of these mice. No significant difference was seen in the
distribution of sterols in the knockout and wild type mice. The
increase in plasma sterol levels was due to increases of HDL sterols in
both strains of mice (Fig. 2). Treatment
with T019101317 was associated with widening of the HDL sterol peaks
and a shoulder extending into the larger size fractions, as has been
reported previously (26, 27).

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Fig. 2.
Sterol profiles of FPLC fractions from plasma
of G5G8+/+ and
G5G8 / mice fed a chow diet with or
without T0901317. Plasma isolated from the mice described in the
legend to Fig. 1 was subjected to FPLC analysis. The sterol content of
each fraction was assayed using a cholesterol/HP kit, as described
under "Experimental Procedures." T, chow diet only;
+T, chow diet plus T0901317 (0.025%).
|
|
T0901317 Treatment Is Not Associated with Increased Biliary
Cholesterol Levels in G5G8
/
Mice--
T0901317
treatment increased biliary cholesterol levels of wild type mice by
almost 3-fold (from 7.13 to 20.12 µmol/ml), as was observed
previously (26) (Fig. 3). In contrast to
wild type mice, no significant increase in mean biliary cholesterol
level was seen in the G5G8
/
mice after
treatment with T0901317 (from 0.73 to 0.97 µmol/ml). These data are
consistent with Abcg5 and Abcg8 being the target genes responsible for the increase in biliary cholesterol levels associated with LXR activation.

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Fig. 3.
Biliary lipid levels in
G5G8+/+ and
G5G8 / mice fed a chow diet with or
without T0901317. Gallbladder bile was collected from the mice
described in the legend to Fig. 1. The concentrations of biliary
cholesterol, phospholipids, and bile acids were measured as described
under "Experimental Procedures." T, chow diet;
+T, chow diet plus T0901317 (0.025%); *, p < 0.05 between chow-fed and T0901317-fed mice of each genotype; **,
p < 0.01 between chow-fed and T0901317-fed wild type
mice.
|
|
Biliary phospholipid levels were significantly lower in the knockout
than in the wild type mice. A similar difference in biliary phospholipid levels was observed previously in female, but not male,
G5G8
/
mice (12). Biliary phospholipids and
bile acid levels fell after T0901317 treatment in the
G5G8+/+ mice but not in the
G5G8
/
mice (Fig. 3). Similar reductions in
biliary lipid levels were seen previously in wild type mice treated
with an LXR agonist (26).
Hepatic Cholesterol Levels in the G5G8
/
Mice Do Not
Fall with T0901317 Treatment--
Levels of plant sterols were
significantly higher in chow-fed G5G8
/
mice
than in wild type animals. G5G8
/
mice have
increased fractional absorption of dietary plant sterols and a decrease
in the biliary excretion of sterols, which contribute to the higher
hepatic levels of plant sterols in these mice (12). Treatment of the
G5G8
/
mice with T0901317 resulted in a
modest, but significant reduction in hepatic sitosterol and campesterol
levels (Fig. 4). The hepatic cholesterol
level fell by 30% in the wild type mice after treatment with T0901317,
presumably in part due to the increase in biliary cholesterol secretion
(Fig. 4). In contrast to the wild type mice, no change in hepatic
cholesterol levels was seen in the knockout mice after LXR agonist
treatment, presumably resulting from the lack of increase in biliary
cholesterol secretion in these mice (Fig. 4).

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Fig. 4.
Hepatic lipid levels in
G5G8+/+ and
G5G8 / mice fed a chow diet with or
without T0901317. Livers were obtained from the mice described in
the legend to Fig. 1. An aliquot of liver was weighed, saponified, and
processed for the determination of tissue sterol contents by GC, as
described under "Experimental Procedures." Hepatic triglyceride
levels were measured enzymatically as described under "Experimental
Procedures." T, chow diet only; +T, chow diet
plus T0901317 (0.025%); *, p < 0.05 between chow-fed
and T0901317-fed mice of each genotype; **, p < 0.01 between chow-fed and T0901317-fed mice of each genotype.
|
|
Hepatic triglyceride levels were similar in the chow-fed
G5G8+/+ and G5G8
/
mice. Treatment with T090137 was associated with an increase in hepatic
triglycerides in both groups of mice (Fig. 4), as previously observed
(27). These results are attributed to the activation of
SREBP-1c, which stimulates the expression of multiple genes in the fatty acid biosynthetic pathway and is an LXR target gene (23).
LXR Agonist T0901317 Does Not Reduce Fractional Absorption of
Dietary Cholesterol in G5G8
/
Mice--
The fractional
absorption of dietary cholesterol was reduced from 72% to 52% in the
wild type mice treated with T0901317, which is similar to that observed
by Repa et al. (14). In contrast to wild type mice, the
fractional absorption of cholesterol increased slightly (from 76% to
81%) in T0901317-treated G5G8
/
mice (Fig.
5).

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Fig. 5.
Fractional absorption of dietary cholesterol
in G5G8+/+ and
G5G8 / mice treated with T0901317.
Five-month-old female mice of the indicated genotype (n = 7-8) in each group) were housed individually. After treatment with
either chow diet or chow plus T0901317 (0.025%) diet for 4 days, each
mouse was gavaged with 50 µl of an oil mixture containing deuterated
cholesterol and sitostanol. Feces were collected for 3 days while
continuing the treatment, and the sterols were extracted. The fecal
sterols were subjected to GC-MS as described previously (12).
Deuterated sitostanol was used as a nonabsorbable fecal marker by which
the fractional absorption of dietary cholesterol was calculated. *,
p < 0.01 between chow-fed and T0901317-treated wild
type mice.
|
|
T0901317 Treatment Fails to Increase Fecal Neutral Sterol Excretion
in G5G8
/
Mice--
Decreased fractional cholesterol
absorption and increased biliary cholesterol secretion both may
contribute to the dramatic increase in fecal neutral sterol excretion
that occurs with LXR agonist treatment (14, 26). The level of neutral
sterols excreted into the feces over the 3-day collection period was
~30% lower in the chow-fed G5G8
/
mice
than in the G5G8+/+ mice, and this level failed
to increase with T0901317 treatment (Fig.
6). Thus, ABCG5 and ABCG8 are required
for the stimulation of fecal neutral sterol excretion by the LXR
agonist T0901317. Fecal bile acid excretion was similar in the
G5G8+/+ and G5G8
/
mice and did not change significantly with T0901317 treatment (Fig.
6).

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Fig. 6.
Fecal neutral sterol excretion in
G5G8+/+ and
G5G8 / mice fed a chow diet with or
without T0901317. Feces were collected for the last 3 days of the
experiment described in the legend to Fig. 1. The fecal neutral sterols
and bile acids were measured as described under "Experimental
Procedures." T, chow diet only; +T, chow diet
plus T0901317 (0.025%); *, p < 0.01 between chow-fed
and T0901317-fed wild type mice.
|
|
LXR Agonist (T0901317) Treatment Increases mRNA Levels of
Selected Target Genes in Liver and Small Intestine of
G5G8+/+ and G5G8
/
Mice--
The mRNA
levels of known LXR target genes, including Srebp-1c,
Abca1, Abcg1, Abcg5, and
Abcg8, were determined to confirm that T0901317 had the
expected biological effects in the tissues of the treated mice. The
expression levels of all selected LXR target genes were increased with
T0901317 treatment in both strains of mice with the exceptions of
Abcg5 and Abcg8 in
G5G8
/
mice. The mRNA levels of
Srebp-2, which is not a target gene of LXR, did not increase
significantly with T0901317 treatment in either wild type or
G5G8
/
mice (Fig.
7).

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Fig. 7.
Relative mRNA levels in livers and
intestines of chow-fed mice with or without the addition of the LXR
agonist T0901317. The livers and jejuna were harvested from the
mice described in the legend to Fig. 1 and maintained at 80 °C
after freezing in liquid nitrogen. Total RNA was extracted from the
tissues using the RNA Stat-60 kit (Tel-Test Inc., Friendswood, TX). An
equal amount of RNA from each sample was pooled in each group, and
real-time PCR was performed using gene-specific primers as described
previously (31, 32). Cyclophilin was used as an internal control for
these studies. Values represent the mRNA levels relative to the
mRNA level in the chow-fed wild type mice. T, chow
diet only; +T, chow diet plus T0901317 (0.025%).
|
|
 |
DISCUSSION |
The major finding of this study is that ABCG5 and ABCG8 are
required in mice for the stimulation of biliary and fecal cholesterol excretion by the synthetic LXR agonist, T0901317. Disruption of Abcg5 and Abcg8 abolished the increase in biliary
cholesterol levels, the reduction in fractional cholesterol absorption,
and the increase in fecal neutral sterol excretion associated with LXR
activation (14, 26). These data, taken together with the phenotypic
characterization of mice expressing either no ABCG5 and ABCG8 or higher
levels of both proteins (11, 12), suggest that LXR activation promotes
the excretion of sterols by increasing Abcg5 and
Abcg8 expression.
In wild type mice, treatment with the LXR agonist was associated with
significantly lower plasma levels of both sitosterol and campesterol
(Fig. 1). Similar reductions in plasma plant sterol levels were seen in
transgenic mice containing 14 copies of the human ABCG5 and
ABCG8 transgenes (11). In contrast to wild type mice, plasma
levels of sitosterol and campesterol increased ~2-fold with T0901317
treatment in the G5G8
/
mice (Fig. 1). These
data indicate that increased expression of Abcg5 and
Abcg8 is both necessary and sufficient for the LXR agonist-associated reduction in plasma plant sterol levels observed in
the wild type animals. In the absence of ABCG5 and ABCG8, plant sterols
accumulate in the liver due to an inability to efficiently secrete
sterols into the bile and an increased absorption of dietary plant
sterols (12). The increased hepatic levels of plant sterols in the
knockout animals likely result in an increased incorporation of these
sterols into lipoproteins and secretion into plasma. Further studies
are required to determine if LXR agonist treatment results in a greater
increase in the incorporation of plant sterols into lipoproteins or an
increased secretion of lipoproteins into the circulation in
G5G8
/
mice. The LXR agonist also may promote
the transport of sterols from peripheral tissues into the circulation
of G5G8
/
mice.
Plasma cholesterol levels also increased significantly with T0901317
treatment in G5G8+/+ and
G5G8
/
mice (Fig. 1). The increase in plasma
cholesterol was limited to the HDL fraction (Fig. 2) and was associated
with an increase in the size of HDL particles, as reported previously
(27, 33), which may contribute to LXR agonist-induced expression of
Abca1 in the intestine, liver (Fig. 7), and macrophages
(14). ABCA1 participates in the efflux of excess cholesterol from
peripheral cells to HDL (16-18, 34) and promotes formation of
pre-
-HDL particles by hepatocytes (35) and possibly enterocytes
(36). The fall in hepatic cholesterol levels (Fig. 4) in the
G5G8+/+ mice with LXR activation may also in
part be due to an ABCA1-mediated increase in the efflux of cholesterol
from the liver into the circulation (14, 26) in addition to the
increase in biliary cholesterol secretion.
The most dramatic difference between G5G8+/+ and
G5G8
/
mice in response to T0901317 treatment
was in biliary cholesterol levels. Mean biliary cholesterol levels
increased 3-fold in wild type mice but did not change significantly in
knockout mice. Biliary phospholipid and bile acid levels were lower in
the G5G8
/
mice than in their wild type
littermates, which is comparable to the reductions observed previously
in female mice (12). Both the biliary phospholipid and bile acid levels
fell in wild type mice treated with T0901317 (Fig. 3), as was seen
previously in mice treated with LXR agonists (26). No reduction in the
levels of bile acids or phospholipids in the bile occurred in the
T0901317-treated G5G8
/
mice. No change in
fecal bile acid excretion was seen in either the knockout or the wild
type animals treated with the LXR agonist (Fig. 6). Therefore, the
increased excretion of biliary cholesterol associated with LXR agonist
treatment was not quantitatively coupled to biliary bile acid or
phospholipid excretion.
The results of these studies demonstrate that ABCG5 and ABCG8 mediate
the effects of LXR agonists on the increase in fecal loss of
cholesterol. These studies do not distinguish the relative contributions of the liver and the intestine to the increased fecal
neutral sterol excretion. The stimulation of fecal cholesterol loss by
the LXR agonist may result from an increase in biliary cholesterol
secretion by hepatocytes and/or the decreased fractional absorption of
dietary cholesterol by enterocytes. Tissue-specific disruptions of
Abcg5 and Abcg8 will be required to assess the function of these transporters in the liver and small intestine.
Reverse cholesterol transport involves the efflux of cholesterol from
peripheral tissues to the liver, the secretion of cholesterol into
bile, and the excretion of sterols in feces. The molecular machinery
that affects reverse cholesterol transport has not been fully
characterized. The data in this report are consistent with the notion
that two ABC half-transporters, ABCG5 and ABCG8, mediate the final step
in this pathway.
We thank Robert Guzman, Yinyan Ma, Anja
Kerksiek, and Silvia Winnen for excellent technical assistance. We also
thank Scott Clark, Anh Nguyen, Scott M. Grundy, and Gloria Vega for
measuring lipids in bile, plasma, and tissues. We thank David W. Russell for helpful discussion.
Published, JBC Papers in Press, February 22, 2003, DOI 10.1074/jbc.M301311200
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