help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology, doi:10.1210/en.2008-0637
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Supplemental Data
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Colin, S.
Right arrow Articles by Delerive, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Colin, S.
Right arrow Articles by Delerive, P.
Endocrinology Vol. 149, No. 10 5128-5135
Copyright © 2008 by The Endocrine Society

Intestine-Specific Regulation of PPAR{alpha} Gene Transcription by Liver X Receptors

Sophie Colin1, Elodie Bourguignon1, Anne-Bénédicte Boullay, Jean-Jacques Tousaint, Stéphane Huet, Françoise Caira, Bart Staels, Sophie Lestavel, Jean-Marc A. Lobaccaro and Philippe Delerive

Institut Pasteur de Lille (S.C., B.S., S.L.), Département d’Athérosclérose, Institut National de la Santé et de la Recherche Médicale, Unité 545, F-59019 Lille, and Faculté des Sciences Pharmaceutiques et Biologiques, Université de Lille 2, F-59006 Lille, France; GlaxoSmithKline (E.B., A.-B.B., J.-J.T., S.H., P.D.), Cardiovascular and Urogenital Center of Excellence for Drug Discovery, F-91951 Les Ulis, France; and Centre National de la Recherche Scientifique Unité Mixte de Recherche 6247-GReD (F.C., J.-M.A.L.) and Centre de Recherche en Nutrition Humaine d’Auvergne (F.C., J.-M.A.L.), Clermont Université, F-63177 Aubière, France

Address all correspondence and requests for reprints to: Philippe Delerive, Ph.D., GENFIT, 885 Avenue Eugène Avinée, 59120 Loos, France. E-mail: philippe.delerive{at}genfit.com.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Liver X receptor-{alpha} (LXR{alpha}) and LXRβ are ligand-activated transcription factors belonging to the nuclear receptor superfamily. They have been identified as key players in cholesterol homeostasis and lipid and glucose metabolism as well as immune and inflammatory responses. In the small intestine, LXRs have been shown not only to regulate cholesterol absorption and excretion but also to promote high-density lipoprotein biogenesis via the ATP-binding cassette A1 signaling pathway. Here, using gene expression assays, we identified PPAR{alpha} as an intestine-specific LXR target gene. Chronic administration of LXR synthetic agonists led to a significant increase of PPAR{alpha} mRNA levels in the small intestine but not in the liver. In addition, this specific PPAR{alpha} gene up-regulation occurred in the duodenum, jejunum, and ileum in a dose-dependent manner and translated at the protein level as demonstrated by Western blot analysis. Furthermore, PPAR{alpha} gene induction was completely abolished in LXR-deficient mice. Finally, the physiological relevance of LXR-mediated PPAR{alpha} up-regulation in the small intestine was assessed in PPAR{alpha}-deficient mice. Administration of a synthetic LXR agonist to wild-type mice led to the induction of several PPAR{alpha} target genes including PDK4 and CPT1. Those effects were completely abolished in PPAR{alpha}-deficient mice, demonstrating the biological relevance of this LXR-PPAR{alpha} transcriptional cascade. Taken together, these results demonstrate that PPAR{alpha} is an intestine-specific LXR target gene and suggest the existence of a transcriptional cross talk between those members of the nuclear receptor superfamily.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
LIVER X RECEPTOR-{alpha} (LXR{alpha}) and LXRβ (also known as NR1H3 and NR1H4, respectively) are transcription factors belonging to the nuclear receptor superfamily. LXR{alpha} is highly expressed in the liver and at lower levels in the intestine, adrenal glands, adipose tissue, macrophages, lung, and kidney, whereas LXRβ is ubiquitously expressed (1). LXRs form permissive heterodimers with the retinoid X receptor (RXR) to regulate gene transcription via the binding to cognate DNA response elements consisting of direct repeats of the canonical sequence AGGTCA separated by four nucleotides (DR4). LXRs are activated by cholesterol derivatives such as oxysterols in cell culture (2, 3, 4) as well as in vivo (3). In addition, synthetic agonists including GW3965A and T0901317 displaying higher potency and efficacy for the receptor compared with natural ligands have been described and used as pharmacological tools to dissect out LXR biological functions (5, 6).

In-depth analysis of the LXR-deficient mice revealed their roles as master regulators of whole-body cholesterol homeostasis (see Ref. 1 for review). A number of genes involved in lipid metabolism including CYP7A1, the rate-limiting step in bile acid biosynthesis, were identified as LXR target genes (7). LXRs were also shown to regulate reverse cholesterol transport, the transport of excess of cholesterol on high-density lipoprotein (HDL) particles from peripheral tissues to the liver (8). Indeed, in vivo activation of LXR using a synthetic agonist leads to a significant increase in HDL-cholesterol levels as well as in reverse cholesterol transport (8). Cholesterol excretion is also augmented as a result of both increase in cholesterol catabolism into bile acids and reduction in intestinal cholesterol absorption (9, 10, 11). Those effects are mediated, at least in part, by the regulation of the expression of members of the ATP-binding cassette (ABC) family of membrane transporters, including ABCA1 (9, 12), ABCG5, ABCG8 (13), and ABCG1 (14, 15). ABCA1 and ABCG1 gene regulation by LXR in macrophages leads to cholesterol and phospholipid efflux to lipid-poor HDL particles contributing to the HDL-cholesterol increase in plasma. Moreover, apolipoprotein E, which is a natural cholesterol and phospholipid acceptor, is also regulated by LXR at the transcriptional level (16). Furthermore, intestinal ABCG5/ABCG8 up-regulation results in cholesterol excretion into the lumen thereby increasing sterol output in the feces (10, 13). Interestingly, Hayden and colleagues (17) recently reported an unexpected role for ABCA1 in HDL biosynthesis at the intestinal level. Treatment of intestinal-specific ABCA1-deficient mice with a synthetic LXR agonist did not result in HDL-cholesterol increase, suggesting that LXR-mediated ABCA1 regulation in the gut is required for LXR to raise HDL-cholesterol (18). However, LXRs are also known as master regulators of hepatic lipogenesis (5). A number of genes involved in fatty acid biosynthesis including FAS (19), ACC (20), SCD1 (21), and the transcription factor SREBP1c (5, 22) have been shown to be directly or indirectly regulated by LXRs (23). Surprisingly, LXRs also regulate lipid homeostasis in adrenals (24) and in testes (25), and their activation by the synthetic agonist T0901317 increases steroidogenesis in vivo. Hence, the lipogenic activity of LXR activators, which translate into a strong increase in plasma but also intrahepatic triglycerides upon treatment, as well as their steroidogenic action, prevent their use as therapeutic agent for cardiovascular diseases (5, 26, 27).

LXR agonists have also been shown to improve glucose metabolism in rodent diabetic models (28, 29). Those effects are likely due to the repression of hepatic gluconeogenesis and an increase in glucose utilization (28, 29). Moreover, LXR regulates in adipose tissue the expression of the insulin-dependent glucose transporter (GLUT4), whose induction promotes glucose uptake (29).

In addition to its important role in lipid and carbohydrate metabolism, LXRs have been shown to play a crucial role in the regulation of inflammatory signaling pathways in vitro and in vivo (1). LXR activation leads to the repression of a large set of proinflammatory genes in macrophages after cytokine or bacterial stimulation (30). This phenomenon known as trans-repression occurs in a DNA-binding-independent manner and may involve functional interference with key inflammatory pathways such as nuclear factor (NF)-{kappa}B (30, 31, 32). The exact molecular mechanisms are not well characterized yet. Those studies indicate that LXRs are nuclear receptors at the crossroads of lipid homeostasis and inflammatory response (33).

To better characterize LXR biological functions at the intestinal level, the transcriptional response to GW3965A in both liver and small intestine was investigated in mice after 5 d of treatment. Those experiments led to the identification of the nuclear receptor PPAR{alpha} as a tissue-specific LXR target gene. Furthermore, by using PPAR{alpha}-deficient mice, we show that this transcriptional cascade is biologically relevant at the intestinal level. Those results suggest the existence of a functional cross talk between PPAR{alpha} and LXR receptors at the intestinal level.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Reagents
LXR synthetic agonists GW3965A and T090317 were synthesized by the medicinal chemistry department at GlaxoSmithKline and were determined to be more than 90% pure by HPLC and/or nuclear magnetic resonance analysis. Dosing solutions of GW3965A and T090317 were prepared as suspensions in a vehicle of 0.5% methylcellulose and 0.1% Tween 80.

Animal studies
Experimental protocols were approved by the GlaxoSmithKline Institutional Animal Care and Use Committee. The PPAR{alpha}- and LXR{alpha}β-deficient mice models (in C57BL/6 or mixed C57BL/6:Sv129 genetic background, respectively) have already been described (7, 9, 34). Male wild-type C57BL6 or PPAR{alpha}- or LXR{alpha}β-deficient mice (8 wk old; n = 6 per group) maintained on a standard chow diet were treated for 3 or 5 d (as indicated in figure legends) with synthetic LXR agonists GW3965A (30 mg/kg) or T090317 (50 mg/kg) or vehicle (of 0.5% methylcellulose and 0.1% Tween 80). At the end of the protocol, animals were killed, blood was recovered for serum preparation, and mucosa from small intestine segments and liver samples were quickly collected, frozen in liquid nitrogen, and used for RNA extraction. Total cholesterol (Roche Diagnostics, Indianapolis, IN) and triglycerides (Biomerieux, Craponne, France) were measured by enzymatic colorimetric assays.

RNA analysis
Total RNA was extracted using QIAGEN (Valencia, CA) RNA extraction kits following manufacturer’s instructions. Total RNA was treated with deoxyribonuclease I (Ambion Inc., Austin, TX) at 37 C for 30 min, followed by inactivation at 75 C for 5 min. Real-time quantitative PCR (RT-QPCR) assays were performed using an Applied Biosystems (Foster City, CA) 7900 sequence detector. Total RNA (1 µg) was reverse transcribed with random hexamers using a TaqMan reverse-transcription reagents kit (Applied Biosystems) following the manufacturer’s protocol. Gene expression levels were determined by Sybr green assays as described (35). Cyclophilin transcript was used as an internal control to normalize the variations for RNA amounts. Gene expression levels are expressed relative to Cyclophilin mRNA levels. All the results presented are expressed as mean ± SEM. All the primers used in this study and cycle threshold are available upon request.

Western blot analysis
Small intestine was divided in three segments: duodenum, jejunum, and ileum. The mucosa of the jejunum was gently scraped, and total protein extracts were prepared as described (36). Mucosa protein extracts (50 µg) were fractionated on 10% polyacrylamide gel under reducing conditions (sample buffer containing 10 mM dithiothreitol) and transferred onto nitrocellulose membranes. PPAR{alpha} and β-actin were visualized by probing the membrane with the following antibodies: PPAR{alpha} (sc-9000; Santa Cruz Biotechnology, Santa Cruz, CA) and β-actin (Sigma Chemical Co., St. Louis, MO). After incubation with a secondary peroxidase-conjugated antibody, signals were detected by chemiluminescence (Amersham, Little Chalfont, UK).

Statistical analysis
Results are shown as means ± SEM (figures) or means ± SD (tables). Statistical significance was determined using the Student’s t test. Differences with P < 0.05 were considered to be statistically significant.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
To better understand LXR biological functions at the intestinal level, we measured the expression of a large number of genes involved in lipid metabolism in the small intestine and in the liver as control. C57BL6 mice were gavaged for 5 d with either a synthetic LXR agonist (GW3965A 30 mg/kg) or vehicle. At the end of the protocol, mice were fasted, and gene expression levels were measured. As a control, total cholesterol and triglyceride levels were determined in plasma samples (Table 1Go). GW3965A treatment for 5 d resulted in this model in a significant increase in HDL-cholesterol (+38%, P < 0.05 vs. vehicle) but did not affect significantly plasma triglyceride levels (+10%, P = 0.07 vs. vehicle) (Table 1Go) in line with previous published reports (27). In the intestine, LXR activation led to a robust up-regulation of all its well-characterized target genes such as ABCA1, ABCG5, ABCG8, SCD-1, and SREBP1c (Fig. 1AGo). Surprisingly, PPAR{alpha} gene expression levels were significantly augmented (up to 4-fold) in response to GW3965A treatment in this intestinal section corresponding to the jejunum (Fig. 1AGo). To determine whether a similar gene regulation pattern is obtained in the liver, hepatic gene expression levels were measured by RT-QPCR. Again, all the reference LXR target genes (ABCA1, ABCG5, ABCG8, SCD-1, and SREBP1c) were induced in the GW3965A-treated group (Fig. 1BGo). Interestingly, PPAR{alpha} expression levels were not significantly modified by LXR activation in the liver, suggesting that LXR may regulate PPAR{alpha} gene expression in a tissue-specific manner. Similar results were obtained with another synthetic LXR agonist, T0901317 (data not shown and Fig. 3AGo).


View this table:
[in this window]
[in a new window]

  		TABLE 1. Effects of GW3965A treatment on plasma cholesterol and triglyceride levels in C57BL6 mice

 

Figure 1
View larger version (21K):
[in this window]
[in a new window]

  		FIG. 1. A synthetic LXR agonist (GW3965A) induces PPAR{alpha} gene expression in the small intestine but not in the liver. Male C57BL6 mice (n = 6 per group) maintained on a standard chow diet were administered for 5 d GW3965A (30 mg/kg) or vehicle by oral gavage once a day. At the end of the protocol and after an overnight fast, a section of the small intestine corresponding to the jejunum as well as the liver were removed, and gene expression levels were measured by RT-QPCR. A, Small intestine; B, liver. Means ± SEM are shown. *, P < 0.05, GW3965A vs. vehicle.

 

Figure 3
View larger version (21K):
[in this window]
[in a new window]

  		FIG. 3. T0901317-induced intestinal PPAR{alpha} gene expression is abolished in LXR{alpha}β-deficient mice. Wild-type or LXR{alpha}β-deficient mice (n = 3–4 animals per group) were gavaged with either T0901317 (50 mg/kg) or vehicle once a day for 3 d. At the end of the protocol, mucosa from duodenum, jejunum, and ileum were removed, and gene expression levels were measured by RT-QPCR. Means ± SEM are shown. *, P < 0.05, T0901317 vs. vehicle in the same genotype.

 
To better characterize LXR-mediated PPAR{alpha} gene regulation, we next studied its expression levels throughout the small intestine. GW3965A led to a significant and reproducible PPAR{alpha} gene up-regulation in the duodenum, jejunum, and ileum (Fig. 2AGo). Because PPAR{alpha} expression was similarly regulated in the three main sections of the small intestine, we next focused our attention on the jejunum section, which has been shown to play a crucial role in cholesterol homeostasis (37). Interestingly, this LXR-mediated gene induction was specific to the PPAR{alpha} isotype because both PPAR{delta} and PPAR{gamma} mRNA levels were not modified in response to LXR activation (Fig. 2BGo). In addition, chronic administration of increasing doses of GW3965A to C57BL6 mice led to a dose-dependent increase in both intestinal ABCA1 but also PPAR{alpha} gene expression levels (Fig. 2CGo). Finally, Western blot analysis revealed that LXR activation led to a dramatic increase in PPAR{alpha} protein levels in the jejunum (Fig. 2DGo). Taken together, these data indicate that LXR selectively regulates PPAR{alpha} gene transcription in a tissue-specific and dose-dependent manner.


Figure 2
View larger version (26K):
[in this window]
[in a new window]

  		FIG. 2. GW3965A selectively up-regulates PPAR{alpha} gene expression in the small intestine in a dose-dependent manner. A, PPAR{alpha} gene expression levels were measured by RT-QPCR in various intestinal sections of mice treated or not with GW3965A for 5 d as described in Fig. 1Go. B, PPAR{alpha}, PPAR{delta}, and PPAR{gamma} gene expression levels were compared by RT-QPCR in the samples obtained in the study described in Fig. 1Go. C, C57BL6 mice (n = 6 per group) maintained on a standard chow diet were administered for 5 d GW3965A (3–30 mg/kg) or vehicle by oral gavage once a day. At the end of the protocol and after an overnight fast, a section of the small intestine corresponding to the jejunum was removed, and both ABCA1 and PPAR{alpha} gene expression levels were measured by RT-QPCR. D, PPAR{alpha} and β-actin protein levels were measured by Western blot analysis in jejunum samples derived from the study described in Fig. 1Go. Means ± SEM are shown. *, P < 0.05, GW3965A vs. vehicle.

 
To test a structurally unrelated LXR agonist and to demonstrate that this transcriptional response is truly mediated by LXRs, we next studied the transcriptional response to T0901317 treatment in wild-type and LXR{alpha}β-deficient mice. As expected, ABCA1, SREBP1c, and PPAR{alpha} gene expression levels were significantly augmented in T0901317-treated wild-type mice (Fig. 3Go, A–C), in agreement with our previous results (Figs. 1Go and 2Go). By contrast, PPAR{gamma} expression was not affected by the treatment in line with our previous experiments (Fig. 2BGo). Of note, the magnitude of the observed transcriptional effects was more pronounced with T0901317 compared with what was obtained with GW3965A (compare Fig. 3Go to Fig. 1Go or 2 data). Those results are likely due to the greater efficacy of T0901317 compounds compared with the GW3965A molecule (27, 38). In LXR{alpha}β-deficient mice, intestinal PPAR{alpha} gene expression was not modified under basal expression, in sharp contrast to the ABCA1 gene whose mRNA levels were significantly augmented in the double-knockout animals compared with wild-type mice (Fig. 3BGo), in keeping with a previously published report (39). As expected, T0901317-induced SREBP1c and ABCA1 but also PPAR{alpha} expression was almost completely abolished in LXR{alpha}β-deficient mice, demonstrating that the T0901317-elicited transcriptional regulation is mediated by LXR in the jejunum (Fig. 3Go, A–C). Of note, T0901317 induced a residual 2-fold increase in ABCA1 expression in LXR{alpha}β-deficient mice. As a control, PPAR{gamma} gene expression was not affected by either T0901317 treatment in both genotypes (Fig. 3DGo). Similar results were obtained in the duodenum and ileum (data not shown). Those data clearly indicate that PPAR{alpha} is a novel LXR target gene in the small intestine.

Having shown that PPAR{alpha} is regulated by LXR activation in the small intestine but not in the liver, we next assessed the biological relevance of this transcriptional cascade (Fig. 4Go). To address this question, male C57BL6 PPAR{alpha}+/+ or C57BL6 PPAR{alpha}–/– mice were gavaged for 5 d with either the LXR agonist (GW3965A at 30 mg/kg) or vehicle. At the end of the treatment period, animals were killed, and both intestinal (jejunum) and hepatic gene expression levels were measured by RT-QPCR. Plasma triglyceride and cholesterol levels were also determined to validate the pharmacological LXR response. As expected, GW3965A treatment led to a significant increase in plasma cholesterol in wild-type (+47% vs. vehicle, P < 0.05) but also in PPAR{alpha}-deficient mice (+37% vs. vehicle, P < 0.05) (Table 2Go). Again, plasma triglyceride levels were not affected by the treatment (Table 2Go), irrespective of the genotype. As previously noted (Figs. 1–3GoGoGo), PPAR{alpha} gene expression was up-regulated in the intestinal sections of the GW3965A-treated wild-type animals (3.5-fold vs. vehicle, P < 0.05). By contrast, we failed to detect any significant changes in liver PPAR{alpha} expression upon GW3965A treatment (1.01 ± 0.17 vs. 1.28 ± 0.36, nonsignificant). Interestingly, PPAR{alpha} deficiency did not affect the ligand-mediated induction of well-established LXR target genes in the liver (SREBP1c) or in the intestine (ABCA1) (Fig. 4Go). Similar results were obtained with ABCG5 and ABCG8 (see supplemental figure, published as supplemental data on The Endocrine Society’s Journals Online web site at http://endo.endojournals. org). Of note, we observed in the vehicle-treated groups that SREBP1c mRNA levels were sharply reduced in PPAR{alpha} knockout mice compared with the wild-type littermates, suggesting that PPAR{alpha} contributes somehow to basal SREBP1c expression in the liver. Similar results were recently reported by Hebbachi and co-workers (40). More importantly, GW3965A treatment led to both PDK4 and CPT1 gene up-regulation in the intestine but not in the liver. Those effects were completely abolished in PPAR{alpha}-deficient mice (Fig. 4Go), demonstrating that LXR regulates PDK4 and CPT1 intestinal expression in a PPAR{alpha}-dependent manner. Taken together, those results reveal the existence of a tissue-specific LXR-PPAR{alpha} transcriptional cascade.


Figure 4
View larger version (20K):
[in this window]
[in a new window]

  		FIG. 4. GW3965A induces intestinal but not hepatic PDK4 and CPT1 gene expression in a PPAR{alpha}-dependent manner. Eight-week-old wild-type or PPAR{alpha}-deficient mice were gavaged with either GW3965A (30 mg/kg) or vehicle once a day for 5 d. At the end of the protocol and after an overnight fast, the jejunum and the liver were removed and gene expression levels were measured by RT-QPCR. A, Intestine; B, liver. Means ± SEM are shown. *, P < 0.05, GW3965A vs. vehicle in the same genotype; n = 6 animals per group.

 

View this table:
[in this window]
[in a new window]

  		TABLE 2. Effects of GW3965A treatment on plasma cholesterol and triglyceride levels in wild-type or PPAR{alpha}-deficient mice

 
In this study, we showed for the first time using two different LXR agonists that LXR activation leads to an intestinal-selective up-regulation of PPAR{alpha} gene expression. LXRs are not the first nuclear receptors reported to regulate PPAR{alpha} expression. Interestingly, glucocorticoid receptor agonists (41, 42), farnesoid X receptor agonists such as bile acids (43) and fibrates (44) (synthetic PPAR{alpha} ligands) have been shown to significantly increase PPAR{alpha} gene expression in the liver. For all those receptors, promoter studies led to the identification of DNA binding sites mediating those transcriptional effects. Preliminary bioinformatic analyses revealed the presence of a putative LXR response element within the proximal promoter region of the mouse PPAR{alpha} gene promoter. Chromatin immunoprecipitation experiments as well as transient transfection studies are required not only to delineate the molecular mechanism(s) by which LXR regulates PPAR{alpha} gene transcription but also to understand the intestinal specificity of this response. Those experiments are currently ongoing in our laboratory. Interestingly, APOAIV, PLTP, and LPL genes were also described to be regulated by LXR in a tissue-specific manner (45, 46, 47). Even though a high basal gene expression level may mask some transcriptional regulation, all those studies strongly suggest that LXR may require the involvement of tissue-specific transcription factors, co-activators, or corepressors to mediate a transcriptional response in a promoter context-specific fashion. As a matter of fact, LXR-induced PPAR{alpha} expression in the small intestine was recently reported by Inoue and co-workers (48) in line with our findings. However, those authors failed to map any DNA region involved in LXR-mediated PPAR{alpha} gene regulation using promoter studies.

The use of PPAR{alpha}-deficient mice allowed us to determine the biological relevance of this transcriptional cascade (Fig. 4Go). Indeed, LXR activation resulted in both intestinal CPT1 and PDK4 gene stimulation in wild-type but not in PPAR{alpha} knockout mice, indicating that LXR-mediated CPT1 and PDK4 regulation occurs in a PPAR{alpha}-dependent manner. Those genes are well-characterized PPAR{alpha} target genes in multiple tissues including the small intestine (49) and are linked to fatty acid β-oxidation. The physiological consequences of both PDK4 and CPT1 gene inductions at the intestinal level remain to be determined. Again, this transcriptional cross talk was found to occur only at the intestinal level (Fig. 4Go). Interestingly, different forms of the PPAR/LXR dialogue have already been described in the literature. First, two groups reported independently that PPAR{alpha} and PPAR{gamma} activation led to LXR{alpha} up-regulation in macrophages, resulting in ABCA1 expression and subsequent cholesterol efflux (50, 51). This transcriptional cascade was found to be a key determinant of the atheroprotective activities of PPAR agonists in atherosclerosis models. A similar mechanism was also described in the liver by Tobin and colleagues (52). Second, Yamada and co-workers (53, 54) revealed a bidirectional antagonism between PPAR{alpha} and LXR{alpha} signaling pathways in the liver. They showed that activated PPAR{alpha} could suppress SREBP1c gene transcription by inhibiting LXR/RXR heterodimer formation, whereas LXR activation could block PPAR{alpha}-mediated fatty acid catabolism by also targeting the RXR heterodimer (53, 54). Finally, unsaturated fatty acids, which are known as natural PPAR{alpha} agonists (55), were reported to block SREBP1c gene transcription by antagonizing ligand-dependent activation of LXR (56). Although PPAR{alpha} and LXR signaling pathways seem to antagonize each other within fatty acid metabolism, they can also be complementary regarding cholesterol homeostasis (50, 51). Further studies are required to dissect out this complex interplay between those two signaling pathways in physiological and pathophysiological conditions.

LXR activation is known to reduce cholesterol absorption in vivo via a mechanism involving ABCG5/ABCG8 up-regulations in the small intestine (11, 13). In addition, LXR activation has been shown to modestly reduce NPC1L1 expression in the duodenum (57). NPC1L1 is the central player in intestinal cholesterol absorption (58) and has been shown to be the molecular target of the drug ezetimibe (59). Furthermore, PPAR{alpha} was shown to reduce cholesterol absorption via a NPC1L1-dependent mechanism (60). Because both receptors negatively regulate cholesterol absorption and share similar target genes, it is tempting to speculate that LXR reduces cholesterol absorption at least in part via a PPAR{alpha}-dependent mechanism. LXR activation resulted in HDL-cholesterol increase in wild-type (+47%, P < 0.05) but also in PPAR{alpha}-deficient mice (+37%, P < 0.05) under a chow diet, suggesting that under those experimental conditions, PPAR{alpha} is not playing a significant role in LXR-regulated HDL-cholesterol metabolism. Additional studies involving PPAR{alpha}-deficient mice and the use of cholesterol-supplemented diet should help us to answer this question.

In addition to be central players in lipid homeostasis, LXRs and PPAR{alpha} were shown to play important roles in the control of the inflammatory response (33). Recent studies suggest that PPAR{alpha} may be an interesting target for the treatment of inflammatory bowel diseases (61). Fenofibrate was reported to repress IL-17 and interferon-{gamma} expression and to improve colitis in IL-10-deficient mice (61). Those antiinflammatory properties of PPAR{alpha} agonists at the intestinal level confirm previous results obtained in various mouse model systems (62, 63, 64, 65). Remarkably, both PPAR{alpha} (66) and LXRs (30, 31, 32) negatively regulate the inflammatory response by antagonizing, at least in part, the NF-{kappa}B signaling pathway. In the intestine, NF-{kappa}B plays a crucial role linking innate immunity and inflammation (67, 68). Hence, LXR-mediated PPAR{alpha} expression in the intestine may represent an additional mechanism by which LXR activators may indirectly exert their antiinflammatory properties in the gut. To our knowledge, LXR activators have not been evaluated in inflammatory bowel disease models. This hypothesis should be tested in the future.

In conclusion, this study led to the identification of PPAR{alpha} as a tissue-specific LXR target gene in the intestine and reveals the existence of a transcriptional cascade with likely consequences in lipid homeostasis and in the control of the inflammatory response.


   Acknowledgments
 
We thank Dr. D. J. Mangelsdorf (Howard Hughes Medical Institute, Dallas, TX) for providing the LXR-deficient mice and Julie Dumont and Emmanuel Bouchaert for excellent technical assistance.


   Footnotes
 
This work was supported in part by the Centre National de la Recherche Scientifique, the Université Blaise Pascal, the Fondation Danone, the Fondation pour la Recherche Médicale INE2000-407031/1, Région Nord Pas de Calais/FEDER, Fondation Cœur et Artères, European Vascular Genomics Network, and the Fondation BNP-Paribas (to J.-M.A.L. and F.C.).

Disclosure Statement: A.-B.B., J.-J.T., and S.H. are employees of GlaxoSmithKline. P.D. was previously employed by GlaxoSmithKline. S.C., E.B., F.C., B.S., S.L., and J.-M.L. have nothing to disclose.

First Published Online June 19, 2008

1 S.C. and E.B. contributed equally to this work. Back

Abbreviations: ABC, ATP-binding cassette; HDL, high-density lipoprotein; LXR{alpha}, liver X receptor-{alpha}; NF, nuclear factor; RT-QPCR, real-time quantitative PCR; RXR, retinoid X receptor.

Received May 1, 2008.

Accepted for publication June 10, 2008.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

  1. Zelcer N, Tontonoz P 2006 Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest 116:607–614[CrossRef][Medline]
  2. Chen W, Chen G, Head DL, Mangelsdorf DJ, Russell DW 2007 Enzymatic reduction of oxysterols impairs LXR signaling in cultured cells and the livers of mice. Cell Metab 5:73–79[CrossRef][Medline]
  3. Janowski BA, Grogan MJ, Jones SA, Wisely GB, Kliewer SA, Corey EJ, Mangelsdorf DJ 1999 Structural requirements of ligands for the oxysterol liver X receptors LXR{alpha} and LXRβ. Proc Natl Acad Sci USA 96:266–271[Abstract/Free Full Text]
  4. Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ 1996 An oxysterol signalling pathway mediated by the nuclear receptor LXR{alpha}. Nature 383: 728–731
  5. Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, Lustig KD, Shan B 2000 Role of LXRs in control of lipogenesis. Genes Dev 14:2831–2838[Abstract/Free Full Text]
  6. Collins JL, Fivush AM, Watson MA, Galardi CM, Lewis MC, Moore LB, Parks DJ, Wilson JG, Tippin TK, Binz JG, Plunket KD, Morgan DG, Beaudet EJ, Whitney KD, Kliewer SA, Willson TM 2002 Identification of a nonsteroidal liver X receptor agonist through parallel array synthesis of tertiary amines. J Med Chem 45:1963–1966[CrossRef][Medline]
  7. Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro JM, Hammer RE, Mangelsdorf DJ 1998 Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR{alpha}. Cell 93:693–704[CrossRef][Medline]
  8. Naik SU, Wang X, Da Silva JS, Jaye M, Macphee CH, Reilly MP, Billheimer JT, Rothblat GH, Rader DJ 2006 Pharmacological activation of liver X receptors promotes reverse cholesterol transport in vivo. Circulation 113:90–97[Abstract/Free Full Text]
  9. Repa JJ, Turley SD, Lobaccaro JA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, Mangelsdorf DJ 2000 Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers. Science 289:1524–1529[Abstract/Free Full Text]
  10. Plosch T, Kok T, Bloks VW, Smit MJ, Havinga R, Chimini G, Groen AK, Kuipers F 2002 Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1. J Biol Chem 277:33870–33877[Abstract/Free Full Text]
  11. Kruit JK, Plosch T, Havinga R, Boverhof R, Groot PH, Groen AK, Kuipers F 2005 Increased fecal neutral sterol loss upon liver X receptor activation is independent of biliary sterol secretion in mice. Gastroenterology 128:147–156[CrossRef][Medline]
  12. Costet P, Luo Y, Wang N, Tall AR 2000 Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor. J Biol Chem 275:28240–28245[Abstract/Free Full Text]
  13. Repa JJ, Berge KE, Pomajzl C, Richardson JA, Hobbs H, Mangelsdorf DJ 2002 Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors {alpha} and β. J Biol Chem 277:18793–18800[Abstract/Free Full Text]
  14. Sabol SL, Brewer Jr HB, Santamarina-Fojo S 2005 The human ABCG1 gene: identification of LXR response elements that modulate expression in macrophages and liver. J Lipid Res 46:2151–2167[Abstract/Free Full Text]
  15. Venkateswaran A, Repa JJ, Lobaccaro JM, Bronson A, Mangelsdorf DJ, Edwards PA 2000 Human white/murine ABC8 mRNA levels are highly induced in lipid-loaded macrophages. A transcriptional role for specific oxysterols. J Biol Chem 275:14700–14707[Abstract/Free Full Text]
  16. Laffitte BA, Repa JJ, Joseph SB, Wilpitz DC, Kast HR, Mangelsdorf DJ, Tontonoz P 2001 LXRs control lipid-inducible expression of the apolipoprotein E gene in macrophages and adipocytes. Proc Natl Acad Sci USA 98:507–512[Abstract/Free Full Text]
  17. Brunham LR, Kruit JK, Iqbal J, Fievet C, Timmins JM, Pape TD, Coburn BA, Bissada N, Staels B, Groen AK, Hussain MM, Parks JS, Kuipers F, Hayden MR 2006 Intestinal ABCA1 directly contributes to HDL biogenesis in vivo. J Clin Invest 116:1052–1062[CrossRef][Medline]
  18. Brunham LR, Kruit JK, Pape TD, Parks JS, Kuipers F, Hayden MR 2006 Tissue-specific induction of intestinal ABCA1 expression with a liver X receptor agonist raises plasma HDL cholesterol levels. Circ Res 99:672–674[Abstract/Free Full Text]
  19. Joseph SB, Laffitte BA, Patel PH, Watson MA, Matsukuma KE, Walczak R, Collins JL, Osborne TF, Tontonoz P 2002 Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J Biol Chem 277:11019–11025[Abstract/Free Full Text]
  20. Talukdar S, Hillgartner FB 2006 The mechanism mediating the activation of acetyl-coenzyme A carboxylase-{alpha} gene transcription by the liver X receptor agonist T0-901317. J Lipid Res 47:2451–2461[Abstract/Free Full Text]
  21. Chu K, Miyazaki M, Man WC, Ntambi JM 2006 Stearoyl-coenzyme A desaturase 1 deficiency protects against hypertriglyceridemia and increases plasma high-density lipoprotein cholesterol induced by liver X receptor activation. Mol Cell Biol 26:6786–6798[Abstract/Free Full Text]
  22. Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ 2000 Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXR{alpha} and LXRβ. Genes Dev 14:2819–2830[Abstract/Free Full Text]
  23. Tontonoz P, Mangelsdorf DJ 2003 Liver X receptor signaling pathways in cardiovascular disease. Mol Endocrinol 17:985–993[Abstract/Free Full Text]
  24. Cummins CL, Volle DH, Zhang Y, McDonald JG, Sion B, Lefrancois- Martinez AM, Caira F, Veyssiere G, Mangelsdorf DJ, Lobaccaro JM 2006 Liver X receptors regulate adrenal cholesterol balance. J Clin Invest 116:1902–1912[CrossRef][Medline]
  25. Volle DH, Mouzat K, Duggavathi R, Siddeek B, Dechelotte P, Sion B, Veyssiere G, Benahmed M, Lobaccaro JM 2007 Multiple roles of the nuclear receptors for oxysterols liver X receptor to maintain male fertility. Mol Endocrinol 21:1014–1027[Abstract/Free Full Text]
  26. Grefhorst A, Elzinga BM, Voshol PJ, Plosch T, Kok T, Bloks VW, van der Sluijs FH, Havekes LM, Romijn JA, Verkade HJ, Kuipers F 2002 Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles. J Biol Chem 277:34182–34190[Abstract/Free Full Text]
  27. Miao B, Zondlo S, Gibbs S, Cromley D, Hosagrahara VP, Kirchgessner TG, Billheimer J, Mukherjee R 2004 Raising HDL cholesterol without inducing hepatic steatosis and hypertriglyceridemia by a selective LXR modulator. J Lipid Res 45:1410–1417[Abstract/Free Full Text]
  28. Cao G, Liang Y, Broderick CL, Oldham BA, Beyer TP, Schmidt RJ, Zhang Y, Stayrook KR, Suen C, Otto KA, Miller AR, Dai J, Foxworthy P, Gao H, Ryan TP, Jiang XC, Burris TP, Eacho PI, Etgen GJ 2003 Antidiabetic action of a liver X receptor agonist mediated by inhibition of hepatic gluconeogenesis. J Biol Chem 278:1131–1136[Abstract/Free Full Text]
  29. Laffitte BA, Chao LC, Li J, Walczak R, Hummasti S, Joseph SB, Castrillo A, Wilpitz DC, Mangelsdorf DJ, Collins JL, Saez E, Tontonoz P 2003 Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue. Proc Natl Acad Sci USA 100:5419–5424[Abstract/Free Full Text]
  30. Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ, Tontonoz P 2003 Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med 9:213–219[CrossRef][Medline]
  31. Castrillo A, Joseph SB, Marathe C, Mangelsdorf DJ, Tontonoz P 2003 Liver X receptor-dependent repression of matrix metalloproteinase-9 expression in macrophages. J Biol Chem 278:10443–10449[Abstract/Free Full Text]
  32. Ogawa S, Lozach J, Benner C, Pascual G, Tangirala RK, Westin S, Hoffmann A, Subramaniam S, David M, Rosenfeld MG, Glass CK 2005 Molecular determinants of crosstalk between nuclear receptors and toll-like receptors. Cell 122:707–721[CrossRef][Medline]
  33. Glass CK, Ogawa S 2006 Combinatorial roles of nuclear receptors in inflammation and immunity. Nat Rev Immunol 6:44–55[CrossRef][Medline]
  34. Peters JM, Hennuyer N, Staels B, Fruchart JC, Fievet C, Gonzalez FJ, Auwerx J 1997 Alterations in lipoprotein metabolism in peroxisome proliferator-activated receptor {alpha}-deficient mice. J Biol Chem 272:27307–27312[Abstract/Free Full Text]
  35. Delerive P, Galardi CM, Bisi JE, Nicodeme E, Goodwin B 2004 Identification of liver receptor homolog-1 as a novel regulator of apolipoprotein AI gene transcription. Mol Endocrinol 18:2378–2387[Abstract/Free Full Text]
  36. Volle DH, Repa JJ, Mazur A, Cummins CL, Val P, Henry-Berger J, Caira F, Veyssiere G, Mangelsdorf DJ, Lobaccaro JM 2004 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 18:888–898[Abstract/Free Full Text]
  37. Lammert F, Wang DQ 2005 New insights into the genetic regulation of intestinal cholesterol absorption. Gastroenterology 129:718–734[CrossRef][Medline]
  38. Albers M, Blume B, Schlueter T, Wright MB, Kober I, Kremoser C, Deuschle U, Koegl M 2006 A novel principle for partial agonism of liver X receptor ligands. Competitive recruitment of activators and repressors. J Biol Chem 281:4920–4930[Abstract/Free Full Text]
  39. Wagner BL, Valledor AF, Shao G, Daige CL, Bischoff ED, Petrowski M, Jepsen K, Baek SH, Heyman RA, Rosenfeld MG, Schulman IG, Glass CK 2003 Promoter-specific roles for liver X receptor/corepressor complexes in the regulation of ABCA1 and SREBP1 gene expression. Mol Cell Biol 23:5780–5789[Abstract/Free Full Text]
  40. Hebbachi AM, Knight BL, Wiggins D, Patel DD, Gibbons GF 2008 Peroxisome proliferator-activated receptor {alpha} deficiency abolishes the response of lipogenic gene expression to re-feeding: restoration of the normal response by activation of liver X receptor {alpha}. J Biol Chem 283:4866–4876[Abstract/Free Full Text]
  41. Lemberger T, Staels B, Saladin R, Desvergne B, Auwerx J, Wahli W 1994 Regulation of the peroxisome proliferator-activated receptor {alpha} gene by glucocorticoids. J Biol Chem 269:24527–24530[Abstract/Free Full Text]
  42. Bernal-Mizrachi C, Weng S, Feng C, Finck BN, Knutsen RH, Leone TC, Coleman T, Mecham RP, Kelly DP, Semenkovich CF 2003 Dexamethasone induction of hypertension and diabetes is PPAR-{alpha} dependent in LDL receptor-null mice. Nat Med 9:1069–1075[CrossRef][Medline]
  43. Pineda Torra I, Claudel T, Duval C, Kosykh V, Fruchart JC, Staels B 2003 Bile acids induce the expression of the human peroxisome proliferator-activated receptor {alpha} gene via activation of the farnesoid X receptor. Mol Endocrinol 17:259–272[Abstract/Free Full Text]
  44. Pineda Torra I, Jamshidi Y, Flavell DM, Fruchart JC, Staels B 2002 Characterization of the human PPAR{alpha} promoter: identification of a functional nuclear receptor response element. Mol Endocrinol 16:1013–1028[Abstract/Free Full Text]
  45. Cao G, Beyer TP, Yang XP, Schmidt RJ, Zhang Y, Bensch WR, Kauffman RF, Gao H, Ryan TP, Liang Y, Eacho PI, Jiang XC 2002 Phospholipid transfer protein is regulated by liver X receptors in vivo. J Biol Chem 277:39561–39565[Abstract/Free Full Text]
  46. Liang Y, Jiang XC, Liu R, Liang G, Beyer TP, Gao H, Ryan TP, Dan Li S, Eacho PI, Cao G 2004 Liver X receptors (LXRs) regulate apolipoprotein AIV-implications of the antiatherosclerotic effect of LXR agonists. Mol Endocrinol 18:2000–2010[Abstract/Free Full Text]
  47. Zhang Y, Repa JJ, Gauthier K, Mangelsdorf DJ 2001 Regulation of lipoprotein lipase by the oxysterol receptors, LXR{alpha} and LXRβ. J Biol Chem 276:43018–43024[Abstract/Free Full Text]
  48. Inoue J, Satoh S, Kita M, Nakahara M, Hachimura S, Miyata M, Nishimaki-Mogami T, Sato R 2008 PPAR{alpha} gene expression is up-regulated by LXR and PXR activators in the small intestine. Biochem Biophys Res Commun 371:675–678[CrossRef][Medline]
  49. Bunger M, van den Bosch HM, van der Meijde J, Kersten S, Hooiveld GJ, Muller M 2007 Genome-wide analysis of PPAR{alpha} activation in murine small intestine. Physiol Genomics 30:192–204[Abstract/Free Full Text]
  50. Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L, Edwards PA, Curtiss LK, Evans RM, Tontonoz P 2001 A PPAR{gamma}-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell 7:161–171[CrossRef][Medline]
  51. Chinetti G, Lestavel S, Bocher V, Remaley AT, Neve B, Torra IP, Teissier E, Minnich A, Jaye M, Duverger N, Brewer HB, Fruchart JC, Clavey V, Staels B 2001 PPAR-{alpha} and PPAR-{gamma} activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med 7:53–58[CrossRef][Medline]
  52. Tobin KA, Ulven SM, Schuster GU, Steineger HH, Andresen SM, Gustafsson JA, Nebb HI 2002 Liver X receptors as insulin-mediating factors in fatty acid and cholesterol biosynthesis. J Biol Chem 277:10691–10697[Abstract/Free Full Text]
  53. Ide T, Shimano H, Yoshikawa T, Yahagi N, Amemiya-Kudo M, Matsuzaka T, Nakakuki M, Yatoh S, Iizuka Y, Tomita S, Ohashi K, Takahashi A, Sone H, Gotoda T, Osuga J, Ishibashi S, Yamada N 2003 Cross-talk between peroxisome proliferator-activated receptor (PPAR) {alpha} and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. II. LXRs suppress lipid degradation gene promoters through inhibition of PPAR signaling. Mol Endocrinol 17:1255–1267[Abstract/Free Full Text]
  54. Yoshikawa T, Ide T, Shimano H, Yahagi N, Amemiya-Kudo M, Matsuzaka T, Yatoh S, Kitamine T, Okazaki H, Tamura Y, Sekiya M, Takahashi A, Hasty AH, Sato R, Sone H, Osuga J, Ishibashi S, Yamada N 2003 Cross-talk between peroxisome proliferator-activated receptor (PPAR) {alpha} and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. I. PPARs suppress sterol regulatory element binding protein-1c promoter through inhibition of LXR signaling. Mol Endocrinol 17:1240–1254[Abstract/Free Full Text]
  55. Kliewer SA, Forman BM, Blumberg B, Ong ES, Borgmeyer U, Mangelsdorf DJ, Umesono K, Evans RM 1994 Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA 91:7355–7359[Abstract/Free Full Text]
  56. Ou J, Tu H, Shan B, Luk A, DeBose-Boyd RA, Bashmakov Y, Goldstein JL, Brown MS 2001 Unsaturated fatty acids inhibit transcription of the sterol regulatory element-binding protein-1c (SREBP-1c) gene by antagonizing ligand-dependent activation of the LXR. Proc Natl Acad Sci USA 98:6027–6032[Abstract/Free Full Text]
  57. Duval C, Touche V, Tailleux A, Fruchart JC, Fievet C, Clavey V, Staels B, Lestavel S 2006 Niemann-Pick C1 like 1 gene expression is down-regulated by LXR activators in the intestine. Biochem Biophys Res Commun 340:1259–1263[CrossRef][Medline]
  58. Altmann SW, Davis HR, Jr., Zhu LJ, Yao X, Hoos LM, Tetzloff G, Iyer SP, Maguire M, Golovko A, Zeng M, Wang L, Murgolo N, Graziano MP 2004 Niemann-Pick C1 like 1 protein is critical for intestinal cholesterol absorption. Science 303:1201–1204[Abstract/Free Full Text]
  59. Garcia-Calvo M, Lisnock J, Bull HG, Hawes BE, Burnett DA, Braun MP, Crona JH, Davis Jr HR, Dean DC, Detmers PA, Graziano MP, Hughes M, Macintyre DE, Ogawa A, O'Neill KA, Iyer SP, Shevell DE, Smith MM, Tang YS, Makarewicz AM, Ujjainwalla F, Altmann SW, Chapman KT, Thornberry NA 2005 The target of ezetimibe is Niemann-Pick C1-like 1 (NPC1L1). Proc Natl Acad Sci USA 102:8132–8137[Abstract/Free Full Text]
  60. Valasek MA, Clarke SL, Repa JJ 2007 Fenofibrate reduces intestinal cholesterol absorption via PPAR{alpha}-dependent modulation of NPC1L1 expression in mouse. J Lipid Res 48:2725–2735[Abstract/Free Full Text]
  61. Lee JW, Bajwa PJ, Carson MJ, Jeske DR, Cong Y, Elson CO, Lytle C, Straus DS 2007 Fenofibrate represses interleukin-17 and interferon-{gamma} expression and improves colitis in interleukin-10-deficient mice. Gastroenterology 133:108–123[Medline]
  62. Lo Verme J, Fu J, Astarita G, La Rana G, Russo R, Calignano A, Piomelli D 2005 The nuclear receptor peroxisome proliferator-activated receptor-{alpha} mediates the anti-inflammatory actions of palmitoylethanolamide. Mol Pharmacol 67:15–19[Abstract/Free Full Text]
  63. Delerive P, De Bosscher K, Besnard S, Vanden Berghe W, Peters JM, Gonzalez FJ, Fruchart JC, Tedgui A, Haegeman G, Staels B 1999 Peroxisome proliferator-activated receptor {alpha} negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-{kappa}B and AP-1. J Biol Chem 274:32048–32054[Abstract/Free Full Text]
  64. Cuzzocrea S, Di Paola R, Mazzon E, Genovese T, Muia C, Caputi AP 2004 WY 14643, a potent exogenous PPAR-{alpha} ligand, reduces intestinal injury associated with splanchnic artery occlusion shock. Shock 22:340–346[CrossRef][Medline]
  65. Cuzzocrea S, Di Paola R, Mazzon E, Genovese T, Muia C, Centorrino T, Caputi AP 2004 Role of endogenous and exogenous ligands for the peroxisome proliferators activated receptors {alpha} (PPAR-{alpha}) in the development of inflammatory bowel disease in mice. Lab Invest 84:1643–1654[CrossRef][Medline]
  66. Delerive P, Fruchart JC, Staels B 2001 Peroxisome proliferator-activated receptors in inflammation control. J Endocrinol 169:453–459[Abstract]
  67. Nenci A, Becker C, Wullaert A, Gareus R, van Loo G, Danese S, Huth M, Nikolaev A, Neufert C, Madison B, Gumucio D, Neurath MF, Pasparakis M 2007 Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature 446:557–561[CrossRef][Medline]
  68. Shibata W, Maeda S, Hikiba Y, Yanai A, Ohmae T, Sakamoto K, Nakagawa H, Ogura K, Omata M 2007 Cutting edge: the I{kappa}B kinase (IKK) inhibitor, NEMO-binding domain peptide, blocks inflammatory injury in murine colitis. J Immunol 179:2681–2685[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 EndocrinologyHome page
C. D. Green, D. B. Jump, and L. K. Olson
Elevated Insulin Secretion from Liver X Receptor-Activated Pancreatic {beta}-Cells Involves Increased de Novo Lipid Synthesis and Triacylglyceride Turnover
Endocrinology, June 1, 2009; 150(6): 2637 - 2645.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
C. J. Nelson, J. P. Otis, and H. V. Carey
A role for nuclear receptors in mammalian hibernation
J. Physiol., May 1, 2009; 587(9): 1863 - 1870.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Supplemental Data
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Colin, S.
Right arrow Articles by Delerive, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Colin, S.
Right arrow Articles by Delerive, P.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals