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From the
Received for publication, October 4, 2002, and in revised form, October 30, 2002
The oxysterol receptors LXR (liver X
receptor)- Type II diabetes mellitus is a prevalent metabolic disease in
developed countries, with insufficient therapies for treatment and
prevention (1, 2). Studies in recent years have suggested that nuclear
receptors are intimately linked to the pathophysiology of diabetes. The
antidiabetic thiazolidinediones have been identified as ligands of
proxisome proliferator-activated receptor Originally identified as orphan members of the nuclear receptor
superfamily, liver X receptors exist as two isoforms, LXR As a result of the close relationship between lipid and carbohydrate
metabolism, we examined the potential role LXRs may play in glucose
homeostasis by using a specific LXR agonist, T0901317, (11) in rodent
models of diabetes. Our findings indicated that T0901317
dose-dependently lowered plasma glucose level in both db/db
and Zucker diabetic fatty (ZDF) rat models. In the fa/fa insulin-resistant rat model, T0901317 significantly improved insulin sensitivity. Examination of the liver gluconeogenesis pathway revealed
dramatic repression of key genes involved in this pathway. As a result,
hepatic glucose output was dramatically suppressed. PEPCK mRNA
suppression appeared to originate primarily from transcriptional repression as indicated by the nuclear run-on experiments. Further studies in cultured hepatocytes indicated that hepatic activation of
LXRs was sufficient to mediate the suppression of the hepatic gluconeogenesis pathway. Moreover, in an in vitro adipocyte
differentiation assay, we showed that LXR agonists only minimally
induced adipocyte differentiation compared with the robust effect by
classic PPAR In Vivo Glucose-lowering Studies--
Five-week-old male db/db
mice were purchased from Harlan (Madison, WI) and acclimated for 2 weeks prior to the start of the study. Mice were provided Purina 5008 food ad libitum, and the compounds were dosed once daily via
oral gavage for 7 days. Blood samples were taken 1 h after dosing
via the tail vein, and plasma glucose and triglyceride levels were
measured on a Hitachi 912 clinical chemistry analyzer. Animals were
sacrificed in the morning, 1 h after the eighth dose, and tissues
were collected and frozen in liquid nitrogen for processing. A similar
protocol was used for ZDF rats that were purchased from Charles
River/Genetic Models, Inc. (Zionsville, IN). The rats were 8 weeks old
at the start of the study.
Oral Glucose Tolerance Study in fa/fa Rats--
Obese
insulin-resistant female Zucker (fa/fa) rats (Charles River/Genetic
Models, Inc.), 10 weeks of age, were orally gavaged for 9 days with
either vehicle or T0901317 (3 mg/kg/d). A pair-fed group was also
included, to ascertain the effects of a mild reduction in food
consumption noted in the T0901317 group. Eight hours after the last
dose, animals were fasted overnight and on the following morning
subjected to an oral glucose tolerance test. Briefly, blood was
obtained from the animals in the conscious state, via the tail vein, at
time 0 and times 15, 30, 60, and 120 min after an oral glucose
challenge (2.5 g of glucose/kg body weight). Plasma glucose and insulin
levels were analyzed on all samples, and the results are expressed as
the product of glucose AUC and insulin AUC.
Glucose Output with ZDF Rat Liver Slices--
Precision-cut
liver slices were generated from control, T0901317-treated (10 and 30 mg/kg/d for 7 days), and pair-fed to male ZDF rats following 7 days of treatment and an overnight fast. After preincubation and
wash phases, the slices were incubated for 2 h at 29 °C in
Krebs-Henseleit bicarbonate buffer containing 40 mM
mannitol in either the presence or absence of 10 mM
lactate. Incubation media glucose levels were assessed at the 2-h time point. Lactate-stimulated glucose output for each condition was derived
by subtracting the basal rate of glucose output per gram of liver
tissue from the substrate-stimulated rate of glucose output per gram of
liver tissue. This rate of glucose output largely reflects the
gluconeogenic rate because no group displayed a net increase in
glycogen formation during the incubation period (data not shown).
Nuclear Run-on Experiment--
A nuclear run-on experiment was
performed essentially as described (15). Briefly, db/db mice
were treated by T0901317 as described above. Liver samples were
collected after animals were sacrificed. Nuclei were isolated, and
in vivo elongation reaction was performed. The radiolabeled
RNA was then subjected to slot blot to probes.
mRNA Measurement--
Total RNAs were prepared from frozen
tissue samples or cells with TRIzol reagent (Invitrogen) or Qiagen RNA
prep kit. Mouse PEPCK and G6P mRNA were measured by RNase
protection assay and quantified with a Molecular Dynamics
Phosphorimager Model 51. Rat mRNA was subjected to reverse
transcription reactions using the Omniscript reverse transcriptase kit
(Qiagen) according to the manufacturer's directions. The resulting
cDNA was amplified using TaqMan 2× PCR master mix (Applied
Biosystems). The PCR products were detected in real time using an
ABI-7900HT sequence detection system (Applied Biosystems). The rat
PEPCK bDNA was performed as described (16).
In Vitro Adipocyte Differentiation--
3T3-L1 preadipocytes
were grown in Dulbecco's modified Eagle's medium (DMEM)
containing 10% fetal bovine serum. Two-day postconfluent 3T3-L1 cells
(designated day 0) were induced to differentiate by exposure for 4 days
to DMEM with 10% fetal bovine serum containing either DII (1 µM dexamethasone, 1 µM insulin, and 0.5 mM isobutylmethylxanthine) or single compound (10 µM each of T0901317 or 22(R)-hydroxycholesterol or
rosiglitazone). From day 4 to day 8, cells were exposed to DMEM with
10% fetal bovine serum. Oil Red O staining was performed as described
(17). C3H10T1/2 mouse preadipocyte cells were grown up in DMEM and 10%
calf serum. Cells at passage six were plated at 1.0 × 104 cells per well in 96-well clear bottom plates. The next
day, compounds were diluted in media containing 0.03 mg/ml insulin. Media was aspirated off cells and replaced with 100 µl of
media containing insulin and different concentrations of compound in quadruplicate. The cells were treated for 6 days, followed by washing
once with 200 µl/well phosphate-buffered saline, and lysed in 50 µl/well 0.1% IGEPAL in phosphate-buffered saline for 10 min at room
temperature. 100 µl/well of Sigma infinity triglyceride reagent
(Sigma Diagnostics no. 343) was added, and absorbencies were read at
490 nm using a Molecular Devices THERMOmax microplate reader.
In 7-week-old male diabetic db/db mice, the specific LXR agonist,
T0901317, dose-dependently lowered plasma glucose (Fig. 1a). The maximum efficacy in
plasma glucose-lowering achieved with T0901317 was comparable with
rosiglitazone (Invitrogen; Avandia®) treatment. Food
consumption and body weight gain were similar to control in all dose
groups with the exception of the 100 mg/kg T0901317 treatment, which
trended downward (Table I).
Subsequently we tested T0901317 in the male ZDF model. Eight-week-old
ZDF rats were treated orally with various doses of T0901317 for 7 days. Consistent with the data from the db/db model, plasma glucose levels
were significantly reduced at 3 and 10 mg/kg doses. At a greater dose
of T0901317 (30 mg/kg) a more striking reduction in plasma glucose was
noted but was associated with a significant decrease in food
consumption and weight loss, possibly as a result of toxicity of the
high dose of compound used (Table II).
Both plasma and liver triglycerides in db/db and ZDF rat studies
increased dramatically (Tables I and II), which is consistent with
earlier reports in C57B6 mice (11). There was no significant change in
plasma insulin levels in these studies (Tables I and II). Treatment of
normal C57BL6 mice resulted in no significant change in plasma glucose
levels (Fig. 1c). An oral glucose tolerance test in female
obese insulin-resistant Zucker (fa/fa) rats, subsequent to 9 days of
treatment with T0901317 (3 mg/kg/d), revealed a significant improvement
in glucose tolerance in the treated animals relative to both vehicle
control and pair-fed control groups. Although the insulin response to
the glucose challenge was not significantly altered, the insulin
sensitivity index, calculated as the product of the glucose AUC and the
insulin AUC during the oral glucose tolerance test, was significantly
improved in the treated group (Fig. 1d). Thus T0901317,
presumably functioning as an LXR agonist, effectively lowers glucose in
diabetic rodents and improves insulin sensitivity in insulin-resistant
rodents but does not cause hypoglycemia in normal mice.
In assessing potential mechanisms underlying the antidiabetic actions,
we found significant reductions in mRNA levels of two key
gluconeogenic enzymes, PEPCK and glucose 6-phosphatase (G6P), in liver
samples from T0901317-treated db/db mice. PEPCK mRNA levels in
T0901317-treated liver samples were reduced
dose-dependently and correlated well with the
glucose-lowering effects (Fig.
2a). Similar alterations were
also observed in liver samples from C57BL6 mice but to a lesser extent
(Fig. 2c). G6P mRNA levels were reduced more than 50%
in a dose-dependent fashion in liver samples from T0901317-treated db/db mice (Fig. 2b). We then measured
lactate-stimulated glucose output from precision-cut liver slices
derived from ZDF rats treated with either vehicle, T0901317 (10 mg/kg),
or T0901317 (30 mg/kg). Compared with either control or a pair-fed
group (matched to T0901317 30 mg/kg), T0901317 at 10 mg/kg inhibited
lactate-stimulated glucose output by ~80%, whereas the 30 mg/kg
treatment resulted in virtually complete inhibition of glucose output
(Fig. 2d). Very similar trends were observed for lactate
utilization as the vehicle control; pair-fed groups displayed the
greatest rates, followed distantly by T0901317 at 10 mg/kg and T0901317
at 30 mg/kg, which utilized essentially no lactate. These results
indicate that the LXR agonist, T0901317, improves glucose homeostasis
in diabetic rodents, at least in part, through down-regulation of key
enzymes in the hepatic gluconeogenesis pathway.
Antidiabetic Action of a Liver X Receptor Agonist
Mediated By Inhibition of Hepatic Gluconeogenesis*
§,,,,,,,,,,,,,,, and
Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46285 and the ¶ Department of
Anatomy and Cell Biology, State University of New York Downstate
Medical Center, Brooklyn, New York 11203
ABSTRACT
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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
and LXR
are nuclear receptors that play a key role in
regulation of cholesterol and fatty acid metabolism. We found
that LXRs also play a significant role in glucose metabolism. Treatment
of diabetic rodents with the LXR agonist, T0901317, resulted in
dramatic reduction of plasma glucose. In insulin-resistant Zucker
(fa/fa) rats, T0901317 significantly improved insulin sensitivity.
Activation of LXR did not induce robust adipogenesis but rather
inhibited the expression of several genes involved in hepatic
gluconeogenesis, including phosphoenolpyruvate carboxykinase (PEPCK).
Hepatic glucose output was dramatically reduced as a result of this
regulation. Nuclear run-on studies indicated that transcriptional
repression was primarily responsible for the inhibition of PEPCK by the
LXR agonist. In addition, we show that the regulation of the
liver gluconeogenic pathway by LXR agonists was a direct effect on
hepatocytes. These data not only suggest that LXRs are novel
targets for diabetes but also reveal an unanticipated role for these
receptors, further linking lipid and glucose metabolism.
INTRODUCTION
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INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
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(PPAR)1 (3, 4). Retinoid X
receptor (RXR) ligands have also been shown to lower plasma glucose
levels in rodent diabetic models (3-5).
and
LXR. The two isoforms display distinct patterns of expression with
LXR being primarily expressed in liver, intestine, and kidney, whereas LXR is expressed ubiquitously (6). Oxysterols were identified as the putative physiological ligands for the LXRs (7), and
additional studies have demonstrated that these receptors act as
sensors for these cholesterol metabolites and are essential components
of a physiological feedback loop regulating cholesterol metabolism and
transport (8). Consistent with their role in regulation of these
metabolic pathways, several LXR-regulated genes involved in lipid
metabolism and cholesterol transport have been identified including
ABCA1, ABCG1, ABCG5, ABCG8, ApoE, CETP, Cyp7a, LPL, SREBP1c, and FAS
(8-14).
agonists.
MATERIALS AND METHODS
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MATERIALS AND METHODS
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RESULTS
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DISCUSSION
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View larger version (32K):
[in a new window]
Fig. 1.
LXR agonist T0901317 lowers plasma glucose in
male db/db mice and male Zucker diabetic fatty rats and improves
insulin sensitivity in female Zucker (fa/fa) rats. Five animals in
each group were orally dosed with T0901317 for 7 days, and plasma
glucose levels were measured. Female Zucker (fa/fa) rats were dosed for
9 days and subjected to an oral glucose tolerance test. Insulin
sensitivity index is glucose AUC × insulin AUC. *,
p < 0.05.
Metabolic parameters of db/db mice treated with either BRL
(30 mg/kg) or various doses of T0901317
Metabolic parameters of ZDF rats treated with either vehicle or various
doses of T0901317
View larger version (41K):
[in a new window]
Fig. 2.
LXR agonist T0901317 down-regulates the
hepatic gluconeogenesis pathway in vivo. Animals
were treated as described under "Materials and Methods." Tissues
were collected, and total RNAs were prepared and pooled for analysis.
Mouse PEPCK and G6P mRNA were measured by RNase protection assay
using the Ambion RPAIII kit. Signal was quantified with a Molecular
Dynamics Phosphorimager Model 51. 28 S RNA was used as control
(a-c). Lactate-stimulated glucose production from
precision-cut liver slices derived from vehicle control, pair-fed
control, and T0901317-treated ZDF rats. *, p < 0.05 (d). Nuclear run-on studies were performed on db/db mice as
described under "Materials and Methods." Glyceraldehyde-3-phosphate
dehydrogenase (GAPDH) was used as a control for normalization
(e).
To investigate the mechanism of PEPCK mRNA reduction upon LXR
activation, we performed nuclear run-on experiments with liver samples
from db/db mice treated with either T0901317 or vehicle (Fig.
2e). The results suggested that reduction of PEPCK mRNA upon T0901317 treatment in db/db mice was largely from transcriptional repression. To determine whether the aforementioned alterations were
the result of T0901317 acting directly on hepatocytes, we treated rat
hepatoma Fao cells with either 0.2 nM insulin or 100 nM T0901317 or a combination of both for 24 h. The
mRNA levels of PEPCK, G6P, pyruvate carboxylase, and fructose
1,6-bisphosphatase decreased dramatically upon either insulin or
T0901317 treatment. The combination of both agents did not result in an
additive effect (Fig. 3a). To
confirm our observations, we treated rat hepatoma H4IIE cells with
either T0901317 or another structurally distinct synthetic LXR agonist,
GW3965, (18) and measured PEPCK mRNA. Both compounds showed
dose-dependent reductions of PEPCK mRNA levels. The
calculated IC50 values for PEPCK inhibition of these two
compounds are 26 nM and 108 nM, respectively
(Fig. 3b), which agrees closely with their respective
described LXR potencies (11, 18). These results suggest that the
in vivo regulation of hepatic gluconeogenic genes was a
direct action of the LXR agonist on the liver.
|
As a result of recent studies indicating that LXR is a target gene
of PPAR (19, 20), we further explored the mechanisms of LXR action
by comparing the effects of LXR agonists and a PPAR agonist,
rosiglitazone, on adipocyte differentiation in vitro. Although rosiglitazone induced dramatic adipocyte differentiation, both
the natural LXR ligand, 22(R)-hydroxycholesterol, and T0901317 failed
to induce robust adipocyte differentiation as assessed by Oil Red O
staining (Fig. 4a). Similar
results were obtained in C3H10T1/2 cells where adipocyte
differentiation was quantitated (Fig. 4b). Examination of
aP2 mRNA in 3T3L1 cells did not reveal any regulation by the LXR
agonist, T0901317 (data not shown). These results show that although
LXR is a direct target gene of PPAR, LXR agonists do not merely
mimic PPAR action in adipocytes, suggesting a unique mechanism for
LXR-mediated antidiabetic action. Our results however, do not rule out
the potential involvement of LXR-mediated contributions in peripheral
tissues.
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Our studies reveal for the first time that an LXR agonist, T0901317, exerts antidiabetic effects through suppression of the hepatic gluconeogenic process. Because inhibition of hepatic glucose production has been identified as an effective approach for lowering hyperglycemia (2), LXRs potentially represent novel targets for treating diabetes.
LXR and RXR function as permissive heterodimers (21), and our results suggest that the glucose-lowering effect of rexinoids may be mediated, at least partially, through decreased hepatic gluconeogenesis via activation of the LXR/RXR heterodimer. Recent studies indicated that LXR/RXR heterodimers regulate a spectrum of important gene products involved in lipid metabolism. One of the target genes, SREBP1c, has been identified as the master transcription factor controlling the entire fatty acid biosynthetic pathway (22, 23). In our studies, we observed dose-dependent plasma and liver triglyceride increases in both db/db mice and ZDF rats (Tables I and II), which is consistent with previous reports in C57BL6 mice. It is interesting to note that despite the increase in triglyceride levels, hyperglycemia was reduced dose-dependently. This observation is strikingly similar to the previous report on the effects of RXR agonists (24).
Although LXRs have been regarded as potential targets for mediating cardiovascular benefits, the induction of hypertriglyceridemia and liver steatosis has severely hampered its development. A selective modulator that does not lead to accumulation of liver triglycerides will be essential if therapeutic potentials of LXRs for both cardiovascular and diabetic diseases can be realized.
In contrast to previous reports that have identified positively
regulated target genes for LXR, we have identified several gene
products that are down-regulated by LXR activation. Traditional LXR
target genes possess an LXR-responsive element (LXRE) in their promoter
or intron; however, it is unclear whether LXR represses genes through a
negative LXRE or through indirect regulation similar to farnesoid X
receptor repression of cholesterol 7-hydroxylase expression (25,
26).
Our novel findings suggest that LXR activation alters liver metabolism
in a manner reminiscent of insulin, increased lipogenesis and decreased
gluconeogenesis. Despite the similarities, T0901317 does not appear to
work through the classic insulin signaling cascade because we found
that LXR activation does not alter AKT phosphorylation or PGC-1
expression (data not shown). In contrast, insulin has been shown to
regulate LXR in hepatocytes, and thus it is plausible that the
effects of insulin on lipogenesis and gluconeogenesis may be regulated,
at least in part, through changes in LXR expression.
In summary, we have discovered an additional metabolic pathway
regulated by LXRs. Activation of this pathway by an LXR agonist leads
to a significant reduction in hyperglycemia and an improvement in
insulin sensitivity in preclinical models. These studies strongly implicate LXRs as alternative targets for intervention in diabetes mellitus.
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ACKNOWLEDGEMENTS |
|---|
We thank Drs. Simeon Taylor and Dod Michael for helpful discussions and Dr. Laura Michael for help in real-time PCR experiments. We are indebted to Drs. Timothy Grese, George Cullinan, Steve Kulong Yu, Jean Defauw, and Jeff Schkeryantz for making the compound available for the study. We would also like to thank Richard Tielking, Jack Cochran, Phyllis Cross, and Pat Forler for invaluable technical assistance.
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FOOTNOTES |
|---|
* 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. Tel.: 317-433-3535; Fax: 317-276-1417; E-mail: guoqing_cao@lilly.com.
Published, JBC Papers in Press, October 31, 2002, DOI 10.1074/jbc.M210208200
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ABBREVIATIONS |
|---|
The abbreviations used are:
PPAR, proxisome
proliferative-activated receptor;
PEPCK, phosphoenolpyruvate
carboxykinase;
G6P, glucose-6-phosphatase;
ABC, ATP binding cassette
transporter;
CETP, cholesterol ester transport protein;
ApoE, Apolipoprotein E;
SREBP, sterol responsive element-binding protein;
LXR, liver X receptor;
RXR, retinoid X receptor;
LPL, lipoprotein
lipase;
FAS, fatty acid synthase;
Cyp7a, cholesterol 7-hydroxylase;
ZDF, Zucker diabetic fatty rat.
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ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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H. Dang, Y. Liu, W. Pang, C. Li, N. Wang, J. Y.-J. Shyy, and Y. Zhu Suppression of 2,3-Oxidosqualene Cyclase by High Fat Diet Contributes to Liver X Receptor-{alpha}-mediated Improvement of Hepatic Lipid Profile J. Biol. Chem., March 6, 2009; 284(10): 6218 - 6226. [Abstract] [Full Text] [PDF]
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 S. Nakamichi, Y. Senga, H. Inoue, A. Emi, Y. Matsuki, E. Watanabe, R. Hiramatsu, W. Ogawa, and M. Kasuga Role of the E3 ubiquitin ligase gene related to anergy in lymphocytes in glucose and lipid metabolism in the liver J. Mol. Endocrinol., February 1, 2009; 42(2): 161 - 169. [Abstract] [Full Text] [PDF]
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 A. Cignarella, C. Bolego, V. Pelosi, C. Meda, A. Krust, C. Pinna, R. M. Gaion, E. Vegeto, and A. Maggi Distinct Roles of Estrogen Receptor-{alpha} and {beta} in the Modulation of Vascular Inducible Nitric-Oxide Synthase in Diabetes J. Pharmacol. Exp. Ther., January 1, 2009; 328(1): 174 - 182. [Abstract] [Full Text] [PDF]
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 Z. Ravid, M. Bendayan, E. Delvin, A. T. Sane, M. Elchebly, J. Lafond, M. Lambert, G. Mailhot, and E. Levy Modulation of intestinal cholesterol absorption by high glucose levels: impact on cholesterol transporters, regulatory enzymes, and transcription factors Am J Physiol Gastrointest Liver Physiol, November 1, 2008; 295(5): G873 - G885. [Abstract] [Full Text] [PDF]
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 S. Colin, E. Bourguignon, A.-B. Boullay, J.-J. Tousaint, S. Huet, F. Caira, B. Staels, S. Lestavel, J.-M. A. Lobaccaro, and P. Delerive Intestine-Specific Regulation of PPAR{alpha} Gene Transcription by Liver X Receptors Endocrinology, October 1, 2008; 149(10): 5128 - 5135. [Abstract] [Full Text] [PDF]
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M. H. Oosterveer, T. H. van Dijk, A. Grefhorst, V. W. Bloks, R. Havinga, F. Kuipers, and D.-J. Reijngoud Lxr{alpha} Deficiency Hampers the Hepatic Adaptive Response to Fasting in Mice J. Biol. Chem., September 12, 2008; 283(37): 25437 - 25445. [Abstract] [Full Text] [PDF]
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 S. Lee, J. Lee, S.-K. Lee, and J. W. Lee Activating Signal Cointegrator-2 Is an Essential Adaptor to Recruit Histone H3 Lysine 4 Methyltransferases MLL3 and MLL4 to the Liver X Receptors Mol. Endocrinol., June 1, 2008; 22(6): 1312 - 1319. [Abstract] [Full Text] [PDF]
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 K. R. Stayrook, P. M. Rogers, R. S. Savkur, Y. Wang, C. Su, G. Varga, X. Bu, T. Wei, S. Nagpal, X. S. Liu, et al. Regulation of Human 3{alpha}-Hydroxysteroid Dehydrogenase (AKR1C4) Expression by the Liver X Receptor {alpha} Mol. Pharmacol., February 1, 2008; 73(2): 607 - 612. [Abstract] [Full Text] [PDF]
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S. R. Commerford, L. Vargas, S. E. Dorfman, N. Mitro, E. C. Rocheford, P. A. Mak, X. Li, P. Kennedy, T. L. Mullarkey, and E. Saez Dissection of the Insulin-Sensitizing Effect of Liver X Receptor Ligands Mol. Endocrinol., December 1, 2007; 21(12): 3002 - 3012. [Abstract] [Full Text] [PDF]
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B. Herzog, M. Hallberg, A. Seth, A. Woods, R. White, and M. G. Parker The Nuclear Receptor Cofactor, Receptor-Interacting Protein 140, Is Required for the Regulation of Hepatic Lipid and Glucose Metabolism by Liver X Receptor Mol. Endocrinol., November 1, 2007; 21(11): 2687 - 2697. [Abstract] [Full Text] [PDF]
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P. Kotokorpi, E. Ellis, P. Parini, L.-M. Nilsson, S. Strom, K. R. Steffensen, J.-A. Gustafsson, and A. Mode Physiological Differences between Human and Rat Primary Hepatocytes in Response to Liver X Receptor Activation by 3-[3-[N-(2-Chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl)amino]propyloxy]phenylacetic Acid Hydrochloride (GW3965) Mol. Pharmacol., October 1, 2007; 72(4): 947 - 955. [Abstract] [Full Text] [PDF]
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 M. Nilsson, K. Dahlman-Wright, C. Karelmo, J.-A. Gustafsson, and K. R. Steffensen Elk1 and SRF transcription factors convey basal transcription and mediate glucose response via their binding sites in the human LXRB gene promoter Nucleic Acids Res., July 10, 2007; (2007) gkm492v1. [Abstract] [Full Text] [PDF]
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 C. G. Woods, J. P. Vanden Heuvel, and I. Rusyn Genomic Profiling in Nuclear Receptor-Mediated Toxicity Toxicol Pathol, June 1, 2007; 35(4): 474 - 494. [Abstract] [Full Text] [PDF]
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 S. S. Choe, A H. Choi, J.-W. Lee, K. H. Kim, J.-J. Chung, J. Park, K.-M. Lee, K.-G. Park, I.-K. Lee, and J. B. Kim Chronic Activation of Liver X Receptor Induces {beta}-Cell Apoptosis Through Hyperactivation of Lipogenesis: Liver X Receptor-Mediated Lipotoxicity in Pancreatic {beta}-Cells Diabetes, June 1, 2007; 56(6): 1534 - 1543. [Abstract] [Full Text] [PDF]
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T. Yamamoto, H. Shimano, N. Inoue, Y. Nakagawa, T. Matsuzaka, A. Takahashi, N. Yahagi, H. Sone, H. Suzuki, H. Toyoshima, et al. Protein Kinase A Suppresses Sterol Regulatory Element-binding Protein-1C Expression via Phosphorylation of Liver X Receptor in the Liver J. Biol. Chem., April 20, 2007; 282(16): 11687 - 11695. [Abstract] [Full Text] [PDF]
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W. Wente, M. B. Brenner, H. Zitzer, J. Gromada, and A. M. Efanov Activation of Liver X Receptors and Retinoid X Receptors Induces Growth Arrest and Apoptosis in Insulin-Secreting Cells Endocrinology, April 1, 2007; 148(4): 1843 - 1849. [Abstract] [Full Text] [PDF]
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Y. Liu, C. Yan, Y. Wang, Y. Nakagawa, N. Nerio, A. Anghel, K. Lutfy, and T. C. Friedman Liver X Receptor Agonist T0901317 Inhibition of Glucocorticoid Receptor Expression in Hepatocytes May Contribute to the Amelioration of Diabetic Syndrome in db/db Mice Endocrinology, November 1, 2006; 147(11): 5061 - 5068. [Abstract] [Full Text] [PDF]
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H. Zitzer, W. Wente, M. B. Brenner, S. Sewing, K. Buschard, J. Gromada, and A. M. Efanov Sterol Regulatory Element-Binding Protein 1 Mediates Liver X Receptor-{beta}-Induced Increases in Insulin Secretion and Insulin Messenger Ribonucleic Acid Levels Endocrinology, August 1, 2006; 147(8): 3898 - 3905. [Abstract] [Full Text] [PDF]
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 Y. Zhang, X. Zhang, L. Chen, J. Wu, D. Su, W. J. Lu, M.-T. Hwang, G. Yang, S. Li, M. Wei, et al. Liver X receptor agonist TO-901317 upregulates SCD1 expression in renal proximal straight tubule Am J Physiol Renal Physiol, May 1, 2006; 290(5): F1065 - F1073. [Abstract] [Full Text] [PDF]
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M. Loffler, M. Bilban, M. Reimers, W. Waldhausl, and T. M. Stulnig Blood Glucose-Lowering Nuclear Receptor Agonists Only Partially Normalize Hepatic Gene Expression in db/db Mice J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 797 - 804. [Abstract] [Full Text] [PDF]
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 A. Grefhorst, T. H. van Dijk, A. Hammer, F. H. van der Sluijs, R. Havinga, L. M. Havekes, J. A. Romijn, P. H. Groot, D.-J. Reijngoud, and F. Kuipers Differential effects of pharmacological liver X receptor activation on hepatic and peripheral insulin sensitivity in lean and ob/ob mice Am J Physiol Endocrinol Metab, November 1, 2005; 289(5): E829 - E838. [Abstract] [Full Text] [PDF]
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I. Gerin, V. W. Dolinsky, J. G. Shackman, R. T. Kennedy, S.-H. Chiang, C. F. Burant, K. R. Steffensen, J.-A. Gustafsson, and O. A. MacDougald LXR{beta} Is Required for Adipocyte Growth, Glucose Homeostasis, and {beta} Cell Function J. Biol. Chem., June 17, 2005; 280(24): 23024 - 23031. [Abstract] [Full Text] [PDF]
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K. R. Stayrook, K. S. Bramlett, R. S. Savkur, J. Ficorilli, T. Cook, M. E. Christe, L. F. Michael, and T. P. Burris Regulation of Carbohydrate Metabolism by the Farnesoid X Receptor Endocrinology, March 1, 2005; 146(3): 984 - 991. [Abstract] [Full Text] [PDF]
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K. R Steffensen, S. Y. Neo, T. M Stulnig, V. B Vega, S. S Rahman, G. U Schuster, J.-A. Gustafsson, and E. T Liu Genome-wide expression profiling; a panel of mouse tissues discloses novel biological functions of liver X receptors in adrenals J. Mol. Endocrinol., December 1, 2004; 33(3): 609 - 622. [Abstract] [Full Text] [PDF]
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A. M. Efanov, S. Sewing, K. Bokvist, and J. Gromada Liver X Receptor Activation Stimulates Insulin Secretion via Modulation of Glucose and Lipid Metabolism in Pancreatic Beta-Cells Diabetes, December 1, 2004; 53(suppl_3): S75 - S78. [Abstract] [Full Text] [PDF]
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Y. Liang, X.-C. Jiang, R. Liu, G. Liang, T. P. Beyer, H. Gao, T. P. Ryan, S. Dan Li, P. I. Eacho, and G. Cao Liver X Receptors (LXRs) Regulate Apolipoprotein AIV-Implications of the Antiatherosclerotic Effect of LXR Agonists Mol. Endocrinol., August 1, 2004; 18(8): 2000 - 2010. [Abstract] [Full Text] [PDF]
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T. P. Beyer, R. J. Schmidt, P. Foxworthy, Y. Zhang, J. Dai, W. R. Bensch, R. F. Kauffman, H. Gao, T. P. Ryan, X.-C. Jiang, et al. Coadministration of a Liver X Receptor Agonist and a Peroxisome Proliferator Activator Receptor-{alpha} Agonist in Mice: Effects of Nuclear Receptor Interplay on High-Density Lipoprotein and Triglyceride Metabolism in Vivo J. Pharmacol. Exp. Ther., June 1, 2004; 309(3): 861 - 868. [Abstract] [Full Text] [PDF]
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Q. Shen, G. W. Cline, G. I. Shulman, M. D. Leibowitz, and P. J. A. Davies Effects of Rexinoids on Glucose Transport and Insulin-mediated Signaling in Skeletal Muscles of Diabetic (db/db) Mice J. Biol. Chem., May 7, 2004; 279(19): 19721 - 19731. [Abstract] [Full Text] [PDF]
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 J. B. Seo, H. M. Moon, W. S. Kim, Y. S. Lee, H. W. Jeong, E. J. Yoo, J. Ham, H. Kang, M.-G. Park, K. R. Steffensen, et al. Activated Liver X Receptors Stimulate Adipocyte Differentiation through Induction of Peroxisome Proliferator-Activated Receptor {gamma} Expression Mol. Cell. Biol., April 15, 2004; 24(8): 3430 - 3444. [Abstract] [Full Text] [PDF]
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S. Hummasti, B. A. Laffitte, M. A. Watson, C. Galardi, L. C. Chao, L. Ramamurthy, J. T. Moore, and P. Tontonoz Liver X receptors are regulators of adipocyte gene expression but not differentiation: identification of apoD as a direct target J. Lipid Res., April 1, 2004; 45(4): 616 - 625. [Abstract] [Full Text] [PDF]
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D. H. Volle, J. J. Repa, A. Mazur, C. L. Cummins, P. Val, J. Henry-Berger, F. Caira, G. Veyssiere, D. J. Mangelsdorf, and J.-M. A. Lobaccaro Regulation of the Aldo-Keto Reductase Gene akr1b7 by the Nuclear Oxysterol Receptor LXR{alpha} (Liver X Receptor-{alpha}) in the Mouse Intestine: Putative Role of LXRs in Lipid Detoxification Processes Mol. Endocrinol., April 1, 2004; 18(4): 888 - 898. [Abstract] [Full Text] [PDF]
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D. S. Ng, C. Xie, G. F. Maguire, X. Zhu, F. Ugwu, E. Lam, and P. W. Connelly Hypertriglyceridemia in Lecithin-cholesterol Acyltransferase-deficient Mice Is Associated with Hepatic Overproduction of Triglycerides, Increased Lipogenesis, and Improved Glucose Tolerance J. Biol. Chem., February 27, 2004; 279(9): 7636 - 7642. [Abstract] [Full Text] [PDF]
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K. R. Steffensen and J.-A. Gustafsson Putative Metabolic Effects of the Liver X Receptor (LXR) Diabetes, February 1, 2004; 53(90001): S36 - 42. [Abstract] [Full Text]
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X.-C. Jiang, T. P. Beyer, Z. Li, J. Liu, W. Quan, R. J. Schmidt, Y. Zhang, W. R. Bensch, P. I. Eacho, and G. Cao Enlargement of High Density Lipoprotein in Mice via Liver X Receptor Activation Requires Apolipoprotein E and Is Abolished by Cholesteryl Ester Transfer Protein Expression J. Biol. Chem., December 5, 2003; 278(49): 49072 - 49078. [Abstract] [Full Text] [PDF]
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K. T. Dalen, S. M. Ulven, K. Bamberg, J.-A. Gustafsson, and H. I. Nebb Expression of the Insulin-responsive Glucose Transporter GLUT4 in Adipocytes Is Dependent on Liver X Receptor {alpha} J. Biol. Chem., November 28, 2003; 278(48): 48283 - 48291. [Abstract] [Full Text] [PDF]
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K. S. Bramlett, K. A. Houck, K. M. Borchert, M. S. Dowless, P. Kulanthaivel, Y. Zhang, T. P. Beyer, R. Schmidt, J. S. Thomas, L. F. Michael, et al. A Natural Product Ligand of the Oxysterol Receptor, Liver X Receptor J. Pharmacol. Exp. Ther., October 1, 2003; 307(1): 291 - 296. [Abstract] [Full Text] [PDF]
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A. Barthel and D. Schmoll Novel concepts in insulin regulation of hepatic gluconeogenesis Am J Physiol Endocrinol Metab, October 1, 2003; 285(4): E685 - E692. [Abstract] [Full Text] [PDF]
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 E. G. Lund, J. G. Menke, and C. P. Sparrow Liver X Receptor Agonists as Potential Therapeutic Agents for Dyslipidemia and Atherosclerosis Arterioscler. Thromb. Vasc. Biol., July 1, 2003; 23(7): 1169 - 1177. [Abstract] [Full Text] [PDF]
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H. Lan, M. E. Rabaglia, J. P. Stoehr, S. T. Nadler, K. L. Schueler, F. Zou, B. S. Yandell, and A. D. Attie Gene Expression Profiles of Nondiabetic and Diabetic Obese Mice Suggest a Role of Hepatic Lipogenic Capacity in Diabetes Susceptibility Diabetes, March 1, 2003; 52(3): 688 - 700. [Abstract] [Full Text] [PDF]
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