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• W2134645520 abstract "Human plasma, unlike mouse plasma, contains the cholesteryl ester transfer protein (CETP) that may influence the reverse cholesterol transport. Liver X receptor (LXR), an oxysterol-activated nuclear receptor induces CETP transcription via a direct repeat 4 element in the CETP gene promoter. The aim of the study was to assess in vivo the impact of LXR activation on CETP expression and its consequences on plasma lipid metabolism and hepatic and bile lipid content. Wild-type and humanized mice expressing CETP were treated for five days with T0901317 LXR agonist. This treatment produced marked rises in both hepatic CETP mRNA and plasma CETP activity levels. Interestingly, the LXR agonist-mediated, 2-fold rise in both total and HDL cholesterol levels in treated wild-type mice was not observed in CETPTg mice, and the accumulation of cholesterol in the liver of CETPTg mice was reversed by LXR agonist treatment. Moreover, LXR activation induced a 2-fold increase in hepatic LDL-receptor expression in wild-type and CETPTg mice, and it produced a significantly greater rise in biliary cholesterol concentration in CETPTg mice as compared with wild-type mice.In conclusion, induction of CETP constitutes a major determinant of the effect of LXR agonists on cholesterol transport and excretion. Human plasma, unlike mouse plasma, contains the cholesteryl ester transfer protein (CETP) that may influence the reverse cholesterol transport. Liver X receptor (LXR), an oxysterol-activated nuclear receptor induces CETP transcription via a direct repeat 4 element in the CETP gene promoter. The aim of the study was to assess in vivo the impact of LXR activation on CETP expression and its consequences on plasma lipid metabolism and hepatic and bile lipid content. Wild-type and humanized mice expressing CETP were treated for five days with T0901317 LXR agonist. This treatment produced marked rises in both hepatic CETP mRNA and plasma CETP activity levels. Interestingly, the LXR agonist-mediated, 2-fold rise in both total and HDL cholesterol levels in treated wild-type mice was not observed in CETPTg mice, and the accumulation of cholesterol in the liver of CETPTg mice was reversed by LXR agonist treatment. Moreover, LXR activation induced a 2-fold increase in hepatic LDL-receptor expression in wild-type and CETPTg mice, and it produced a significantly greater rise in biliary cholesterol concentration in CETPTg mice as compared with wild-type mice. In conclusion, induction of CETP constitutes a major determinant of the effect of LXR agonists on cholesterol transport and excretion. Recently, the use of synthetic liver X receptor (LXR) agonists appeared as a potential new pharmacological approach to stimulating reverse cholesterol transport (RCT) in vivo (1Bocher V. Millatt L.J. Fruchart J.C. Staels B. Liver X receptors and the control of cholesterol homeostasis: potential therapeutic targets for the treatment of atherosclerosis.Curr. Opin. Lipidol. 2003; 14: 137-143Crossref PubMed Scopus (21) Google Scholar, 2Joseph S.B. Tontonoz P. LXRs: new therapeutic targets in atherosclerosis?.Curr. Opin. Pharmacol. 2003; 14: 192-197Crossref Scopus (90) Google Scholar). LXRs α and β are nuclear receptors that are activated by oxysterols (3Janowski B.A. Willy P.J. Devi T.R. Falck J.R. Mangelsdorf D.J. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha.Nature. 1996; 383: 728-731Crossref PubMed Scopus (1475) Google Scholar, 4Peet D.J. Turley S.D. Ma W. Janowski B.A. Lobaccaro J.M. Hammer R.E. Mangelsdorf D.J. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha.Cell. 1998; 93: 693-704Abstract Full Text Full Text PDF PubMed Scopus (1251) Google Scholar). They are involved in the regulation of cholesterol homeostasis, lipogenesis, glucose metabolism, and inflammation (4Peet D.J. Turley S.D. Ma W. Janowski B.A. Lobaccaro J.M. Hammer R.E. Mangelsdorf D.J. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha.Cell. 1998; 93: 693-704Abstract Full Text Full Text PDF PubMed Scopus (1251) Google Scholar, 5Schultz J.R. Tu H. Luk A. Repa J.J. Medina J.C. Li L. Schwendner S. Wang S. Thoolen M. Mangelsdorf D.J. Lustig K.D. Shan B. Role of LXRs in control of lipogenesis.Genes Dev. 2000; 14: 2831-2838Crossref PubMed Scopus (1403) Google Scholar, 6Liang G. Yang J. Horton J.D. Hammer R.E. Goldstein J.L. Brown M.S. Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c.J. Biol. Chem. 2002; 277: 9520-9528Abstract Full Text Full Text PDF PubMed Scopus (527) Google Scholar, 7Grefhorst A. Elzinga B.M. Voshol P.J. Plosch T. Kok T. Bloks V.W. van der Sluijs F.H. Havekes L.M. Romijn J.A. Verkade H.J. Kuipers F. 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. 2002; 277: 34182-34190Abstract Full Text Full Text PDF PubMed Scopus (408) Google Scholar, 8Laffitte B.A. Chao L.C. Li J. Walczak R. Hummasti S. Joseph S.B. Castrillo A. Wilpitz D.C. Mangelsdorf D.J. Collins J.L. Saez E. Tontonoz P. Activation of liver X receptor improves glucose tolerance through coordinate regulation of glucose metabolism in liver and adipose tissue.Proc. Natl. Acad. Sci. USA. 2003; 100: 5419-5424Crossref PubMed Scopus (420) Google Scholar, 9Joseph S.B. Castrillo A. Laffitte B.A. Mangelsdorf D.J. Tontonoz P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors.Nat. Med. 2003; 9: 213-219Crossref PubMed Scopus (1014) Google Scholar). Moreover, LXR agonist administration inhibits the development of atherosclerosis in LDL receptor (LDLR)-deficient and apolipoprotein E (apoE)-deficient mouse models, an effect that probably results from the modulation of the expression of both metabolic and inflammatory genes (10Joseph S.B. McKilligin E. Pei L. Watson M.A. Collins A.R. Laffitte B.A. Chen M. Noh G. Goodman J. Hagger G.N. Tran J. Tippin T.K. Wang X. Lusis A.J. Hsueh W.A. Law R.E. Collins J.L. Willson T.M. Tontonoz P. Synthetic LXR ligand inhibits the development of atherosclerosis in mice.Proc. Natl. Acad. Sci. USA. 2002; 99: 7604-7609Crossref PubMed Scopus (785) Google Scholar, 11Tangirala R.K. Bischoff E.D. Joseph S.B. Wagner B.L. Walczak R. Laffitte B.A. Daige C.L. Thomas D. Heyman R.A. Mangelsdorf D.J. Wang X. Lusis A.J. Tontonoz P. Schulman I.G. Identification of macrophage liver X receptors as inhibitors of atherosclerosis.Proc. Natl. Acad. Sci. USA. 2002; 99: 11896-11901Crossref PubMed Scopus (375) Google Scholar). With regard to cholesterol metabolism, LXRs regulate RCT by inducing the expression of genes that are involved in cellular efflux, plasma transport, and biliary excretion of cholesterol. In animal models, the activation of LXR by synthetic agonists was shown to increase plasma HDL concentration, probably as the result of the induction of phospholipid transfer protein (PLTP), and ATP binding cassette (ABC) transporters A1 and G1 (12Cao G. Beyer T.P. Yang X.P. Schmidt R.J. Zhang Y. Bensch W.R. Kauffman R.F. Gao H. Ryan T.P. Liang Y. Eacho P.I. Jiang X.C. Phospholipid transfer protein is regulated by liver X receptors in vivo.J. Biol. Chem. 2002; 277: 39561-39565Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 13Costet P. Luo Y. Wang N. Tall A.R. Sterol-dependent transactivation of the ABC1 promoter by the liver X receptor/retinoid X receptor.J. Biol. Chem. 2000; 275: 28240-28245Abstract Full Text Full Text PDF PubMed Scopus (853) Google Scholar, 14Kennedy M.A. Venkateswaran A. Tarr P.T. Xenarios I. Kudoh J. Shimizu N. Edwards P.A. Characterization of the human ABCG1 gene: liver X receptor activates an internal promoter that produces a novel transcript encoding an alternative form of the protein.J. Biol. Chem. 2001; 276: 39438-39447Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar). LXR activation is also associated with a decrease in cholesterol content of the liver, an increase in biliary cholesterol secretion, and an increase in fecal neutral sterol excretion (5Schultz J.R. Tu H. Luk A. Repa J.J. Medina J.C. Li L. Schwendner S. Wang S. Thoolen M. Mangelsdorf D.J. Lustig K.D. Shan B. Role of LXRs in control of lipogenesis.Genes Dev. 2000; 14: 2831-2838Crossref PubMed Scopus (1403) Google Scholar, 15Yu L. York J. von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Stimulation of cholesterol excretion by the liver X receptor agonist requires ATP-binding cassette transporters G5 and G8.J. Biol. Chem. 2003; 278: 15565-15570Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, 16Plosch T. Kok T. Bloks V.W. Smit M.J. Havinga R. Chimini G. Groen A.K. Kuipers F. Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1.J. Biol. Chem. 2002; 277: 33870-33877Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar). Expression of the transporters ABCG5/G8 is known to be required for the latter phenomena to occur (15Yu L. York J. von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Stimulation of cholesterol excretion by the liver X receptor agonist requires ATP-binding cassette transporters G5 and G8.J. Biol. Chem. 2003; 278: 15565-15570Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar). It is worth noting that most of the previous studies with LXR agonists were conducted in the mouse, an animal model having no plasma cholesteryl ester transfer protein (CETP) activity (17Hogarth C.A. Roy A. Ebert D.L. Genomic evidence for the absence of a functional cholesteryl ester transfer protein gene in mice and rats.Comp. Biochem. Physiol. B Biochem. Mol. Biol. 2003; 135: 219-229Crossref PubMed Scopus (55) Google Scholar). CETP is a plasma glycoprotein that promotes the exchange of neutral lipids, i.e., cholesteryl esters (CEs) and triglycerides, between different lipoprotein classes (18Barter P.J. Brewer Jr., H.B. Chapman M.J. Hennekens C.H. Rader D.J. Tall A.R. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis.Arterioscler. Thromb. Vasc. Biol. 2003; 23: 160-167Crossref PubMed Scopus (717) Google Scholar). Through its action, CETP is likely to influence both the atherogenicity of the lipoprotein profile and the centripetal flux of cholesterol from peripheral tissues toward the liver, a process also called reverse cholesterol transport. In particular, the rise in plasma CETP level in CETP transgenic mice is associated with the redistribution of CEs from the antiatherogenic HDLs to the proatherogenic VLDLs and LDLs (19Agellon L.B. Walsh A. Hayek T. Moulin P. Jiang X.C. Shelanski S.A. Breslow J.L. Tall A.R. Reduced high density lipoprotein cholesterol in human cholesteryl ester transfer protein transgenic mice.J. Biol. Chem. 1991; 266: 10796-10801Abstract Full Text PDF PubMed Google Scholar, 20Jiang X.C. Agellon L.B. Walsh A. Breslow J.L. Tall A.R. Dietary cholesterol increases transcription of the human cholesteryl ester transfer protein gene in transgenic mice. Dependence on natural flanking sequences.J. Clin. Invest. 1992; 90: 1290-1295Crossref PubMed Google Scholar, 21Marotti K.R. Castle C.K. Boyle T.P. Lin A.H. Murray R.W. Melchior G.W. Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein.Nature. 1993; 364: 73-75Crossref PubMed Scopus (414) Google Scholar, 22Takahashi H. Takahashi A. Maki M. Sasai H. Kamada M. Effect of CETP on the plasma lipoprotein profile in four strains of transgenic mouse.Biochem. Biophys. Res. Commun. 2001; 283: 118-123Crossref PubMed Scopus (13) Google Scholar, 23Jiang X.C. Masucci-Magoulas L. Mar J. Lin M. Walsh A. Breslow J.L. Tall A.R. Down-regulation of mRNA for the low density lipoprotein receptor in transgenic mice containing the gene for human cholesteryl ester transfer protein. Mechanism to explain accumulation of lipoprotein B particles.J. Biol. Chem. 1993; 268: 27406-27412Abstract Full Text PDF PubMed Google Scholar). The lack of active CETP in the mouse may be a major limitation to the study of cholesterol homeostasis after LXR agonist administration, because CETP, one key factor in RCT, is a well-known LXR target (24Luo Y. Tall A.R. Sterol upregulation of human CETP expression in vitro and in transgenic mice by an LXR element.J. Clin. Invest. 2000; 105: 513-520Crossref PubMed Scopus (308) Google Scholar, 25Luo Y. Liang C.P. Tall A.R. The orphan nuclear receptor LRH-1 potentiates the sterol-mediated induction of the human CETP gene by liver X receptor.J. Biol. Chem. 2001; 276: 24767-24773Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). Although CETP was proposed to exert a beneficial action in RCT by offering an alternative pathway for cholesterol to be brought back to the liver through the apoB-containing lipoprotein pathway, its potential beneficial action is counterbalanced by the concomitant downregulation of the LDLR in the liver that results from increased hepatic cholesterol content in CETPTg mice (23Jiang X.C. Masucci-Magoulas L. Mar J. Lin M. Walsh A. Breslow J.L. Tall A.R. Down-regulation of mRNA for the low density lipoprotein receptor in transgenic mice containing the gene for human cholesteryl ester transfer protein. Mechanism to explain accumulation of lipoprotein B particles.J. Biol. Chem. 1993; 268: 27406-27412Abstract Full Text PDF PubMed Google Scholar). This increased hepatic cholesterol content is likely to be modified upon LXR agonist administration, because many genes controlling cholesterol homeostasis, in addition to CETP, were shown to be stimulated by pharmacological LXR agonists. The aim of the present study was to determine the impact of the synthetic T0901317 LXR agonist on the lipoprotein profile, hepatic lipid metabolism, and biliary cholesterol secretion in the absence or in the presence of CETP, an LXR target gene that plays a major role in HDL metabolism. To this end, C57Bl6 wild-type and CETPTg mice expressing human CETP under the control of its natural flanking regions containing an LXR-responsive element (20Jiang X.C. Agellon L.B. Walsh A. Breslow J.L. Tall A.R. Dietary cholesterol increases transcription of the human cholesteryl ester transfer protein gene in transgenic mice. Dependence on natural flanking sequences.J. Clin. Invest. 1992; 90: 1290-1295Crossref PubMed Google Scholar) were treated for 5 days with a synthetic LXR agonist at a dose of 10 mg/kg/day, shown to be efficient in increasing HDL cholesterol. After treatment with the agonist, lipid content of plasma, liver, and bile was determined, and resulting data were analyzed in the context of concomitant changes in the expression of several genes, i.e., CETP, ABCG5, LDLR, and sterol-responsive element binding proteins (SREBPs), that are known to be involved in cholesterol metabolism. The present study using the synthetic LXR agonist demonstrated that expression of CETP in the mouse modulates the biological response to LXR activation. The T0901317 LXR agonist produced a marked rise in hepatic CETP mRNA and plasma CETP activity levels. The LXR agonist-mediated, 2-fold rise in plasma HDL cholesterol levels in treated wild-type mice was not observed in mice expressing human CETP. The CETP-mediated accumulation of cholesterol in the liver of CETPTg mice was fully reversed by administration of the LXR agonist, which produced a significantly greater rise in biliary cholesterol secretion in CETPTg mice, as compared with wild-type mice. Wild-type mice (4–6 month-old) and age-matched C57Bl6 mice expressing the human CETP under the control of its natural flanking regions (CETPTg) (20Jiang X.C. Agellon L.B. Walsh A. Breslow J.L. Tall A.R. Dietary cholesterol increases transcription of the human cholesteryl ester transfer protein gene in transgenic mice. Dependence on natural flanking sequences.J. Clin. Invest. 1992; 90: 1290-1295Crossref PubMed Google Scholar) were used in the present study. Both male and female mice were used for the experiments. The mice had free access to water and food, and they were placed on a standard chow diet. All experimental procedures were in accordance with the local guidelines for animal experimentation. The synthetic LXR agonist T0901317 was solubilized in DMSO (100 mg/ml). The stock solution was further diluted 1:100 (v/v) with water containing 1% carboxy-methyl-cellulose. Animals received 10 mg/kg/day of the agonist by gavage for 5 days. Control groups were treated with the vehicle solution only. At day 6, mice were anesthetized by intraperitoneal injection of pentobarbital. Blood samples were collected by intracardiac puncture in heparin-containing tubes that were centrifuged at 5,000 rpm for 10 min and stored at −80°C. Bile was collected by puncture of the gallbladder and stored at −80°C. Livers were excised, weighed, and divided into three parts that were immediately snap frozen in liquid nitrogen and stored at −80°C before mRNA isolation and biochemical analysis. All assays were performed on a Victor2 1420 Multilabel Counter (Perkin Elmer Life Sciences, Boston, MA). Total cholesterol was measured by the enzymatic method, using Cholesterol 100 reagent (ABX Diagnostics, Montpellier, France), and unesterified cholesterol concentration was determined by the CHOD-PAP method (Sigma, St. Louis, MO). Esterified cholesterol concentration was calculated as the difference between total and free cholesterol. Phospholipids and triglycerides were determined by enzymatic methods, as described previously (26Gautier T. Masson D. Jong M.C. Duverneuil L. Le Guern N. Deckert V. Pais de Barros J.P. Dumont L. Bataille A. Zak Z. Jiang X.C. Tall A.R. Havekes L.M. Lagrost L. Apolipoprotein CI deficiency markedly augments plasma lipoprotein changes mediated by human cholesteryl ester transfer protein (CETP) in CETP transgenic/ApoCI-knocked out mice.J. Biol. Chem. 2002; 277: 31354-31363Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). HDL and non-HDL cholesterol fractions were determined by fast-protein liquid chromatography (FPLC) analysis. Hepatic lipids were extracted according to the method of Bligh and Dyer (27Bligh E.G. Dyer W.J. A rapid method of total lipid purification and extraction.Can. J. Med. Sci. 1959; 37: 911-917Google Scholar), and cholesterol and phospholipid levels were determined by enzymatic methods, as described above. Triglycerides were determined by the method of Danno et al. (28Danno H. Jincho Y. Budiyanto S. Furukawa Y. Kimura S. A simple enzymatic quantitative analysis of triglycerides in tissues.J. Nutr. Sci. Vitaminol. (Tokyo). 1992; 38: 517-521Crossref PubMed Scopus (69) Google Scholar). Biliary acids in the bile were determined by capillary gas-liquid chromatography as described previously (29Batta A.K. Salen G. Rapole K.R. Batta M. Earnest D. Alberts D. Capillary gas chromatographic analysis of serum bile acids as the n-butyl ester-trimethylsilyl ether derivatives.J. Chromatogr. B Biomed. Sci. Appl. 1998; 706: 337-341Crossref PubMed Scopus (14) Google Scholar), except for the detection step, which was performed by mass spectrometry determination (MSD). N-butylester trimethylsilane (TMS) ether derivatives of biliary acids and TMS ether derivatives of sterols were detected by selected ion monitoring at m/z = 253 for cholic acid, 255 for desoxycholic acid and chenodesoxycholic acid, and 257 for lithocholic acid. A 6890 Gas Chromatograph coupled with a 7673 MSD (Agilent Technologies, Palo Alto, CA) was used. The column was a 30 m × 0.25 mm HP-5MS (Agilent Technologies), with helium as the carrier gas. The conditions were as follows: injector temperature 250°C, oven temperature programmed after injection at a rate of 10°C/min from 150 to 260°C then at a rate of 2°C/min to 280°C. The MSD operating conditions for electron impact ionization mass spectrometry were: source temperature, 230°C, and ionizing voltage, 70 eV. Biliary cholesterol was quantitated by an enzymatic method using bilirubin oxidase to remove interference by bilirubin, as previously described (30Luhman C.M. Galloway S.T. Beitz D.C. Simple enzymatic assay for determining cholesterol concentrations in bile.Clin. Chem. 1990; 36: 331-333Crossref PubMed Scopus (6) Google Scholar). Individual plasma samples (200 μl) were injected on a Superose 6 HR 10/30 column (Amersham-Pharmacia Biosciences, Freiburg, Germany) connected to an FPLC (Amersham-Pharmacia Biosciences). Lipoproteins were eluted at a constant 0.3 ml/min flow rate with Tris-buffered saline (Tris 10 mmol/l, NaCl 150 mmol/l, pH 7.4) containing 0.074% EDTA and 0.02% sodium azide. Total cholesterol concentrations were assayed in individual 0.3 ml fractions (26Gautier T. Masson D. Jong M.C. Duverneuil L. Le Guern N. Deckert V. Pais de Barros J.P. Dumont L. Bataille A. Zak Z. Jiang X.C. Tall A.R. Havekes L.M. Lagrost L. Apolipoprotein CI deficiency markedly augments plasma lipoprotein changes mediated by human cholesteryl ester transfer protein (CETP) in CETP transgenic/ApoCI-knocked out mice.J. Biol. Chem. 2002; 277: 31354-31363Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). VLDLs and LDLs were contained in fractions 1–25; HDLs were contained in fractions 26–45. CE transfer activity was measured with a commercially available fluorescence assay using synthetic liposomes enriched with nitrobenz-oxadiazol (NBD)-labeled CEs as donors and VLDLs as acceptors (Roar Biomedical, New York, NY). The fluorescent CE is present in a self-quenched state in the core of the donor. The CETP-mediated transfer is determined by the increase in fluorescence intensity as the fluorescent CE is removed from the self-quenched donor and transferred to the acceptor particle. Briefly, plasma samples (5 μl), fluorescent-CE-labeled liposomes (4 μl), and unlabeled VLDL acceptors (4 μl) were incubated at 37°C in a final volume of 200 μl Tris-buffered saline in 96-well microplates. Changes in fluorescence were monitored for a 3 h period using a Victor2 TM fluorescent counter (Perkin Elmer Life Sciences) with 465 nm excitation and 535 nm emission wavelengths. Total RNA was isolated with Trizol (Eurogentec). The following specific primer pairs were used: mouse SREBP1c sense: 5′-GTTACTCGAGCCTGCCTTCAGG-3′, mouse SREBP1c antisense: 5′-CAAGCTTTGGACCTGGGTGTG-3′; mouse LDLR sense: 5′-CAGGCAGCAGGAACGAGTTC-3′, mouse LDLR antisense: 5′-GGAGTCAGGAATGCATCGGC-3′; mouse angiopoietin-like protein 3 (Angptl3) sense: 5′-AGGGCTTTGGAGGAGCAGCTAACC-3′; mouse Angptl3 antisense: 5′-GCAGTCGGCAGGAAGGTCATCTTG-3′; 28S sense: 5′-AAACTCTGGTGGAGGTCCGT-3′, 28S antisense: 5′-CTTACCAAAAGTGGCCCACTA-3′; CETP sense: 5′-CAGATCAGCCACTTGTCCAT-3′, CETP antisense: 5′-CAGCTGTGTGTTGATCTGGA-3′. Other primers [fatty acid synthase (FAS), ABCG5, ABCA1, SREBP2] have been described previously (6Liang G. Yang J. Horton J.D. Hammer R.E. Goldstein J.L. Brown M.S. Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element-binding protein-1c.J. Biol. Chem. 2002; 277: 9520-9528Abstract Full Text Full Text PDF PubMed Scopus (527) Google Scholar, 31Le Lay S. Lefrere I. Trautwein C. Dugail I. Krief S. Insulin and sterol-regulatory element-binding protein-1c (SREBP-1C) regulation of gene expression in 3T3–L1 adipocytes. Identification of CCAAT/enhancer-binding protein beta as an SREBP-1C target.J. Biol. Chem. 2002; 277: 35625-35634Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar). CETP, FAS, ABCG5, SREBP2, and 18S RNA levels were quantified by reverse transcription followed by real-time PCR using an ABI PRISM 7700 Sequence Detection System instrument (Applied Biosystems, Courtaboeuf, France). Reactions were carried out with 200 nM of both sense and antisense primers using the Quantitect SYBR Green amplification kit (Quiagen S.A., Courtaboeuf, France) following the instructions provided by the manufacturer. CETP, FAS, ABCG5, and SREBP2 mRNA levels were normalized to the 18S internal control and expressed as fold induction over the untreated wild-type group. SREBP1c, LDLR, Angptl3, and 28S RNA levels were quantified by reverse transcription followed by real-time PCR using a MX4000 apparatus (Stratagene, La Jolla, CA). Reactions were carried out with 100 nM of each primer using the Brilliant SybR Green QPCR Master Mix as recommended by the manufacturer. SREBP1c, LDLR, and Angptl3 mRNA levels were normalized to the 28S internal control and expressed as fold induction over the untreated control group. Mann-Whitney U test was used to determine the significance between the data means. To assess the effect of LXR agonist treatment on CETP expression in CETPTg mice, both hepatic CETP mRNA and plasma CETP activity levels were compared in animals that were treated or not with T0901317. CETPTg mice receiving only the solvent vehicle displayed moderate CE transfer activity that was in the same range as that of a pool of normolipidemic human plasmas (∼17 pmol NBD-CE transferred per μl plasma per h in both cases). As shown by real-time quantitative PCR, the 5 day treatment with LXR agonist induced an 8-fold increase in the level of hepatic CETP mRNA (Fig. 1)that was associated with a significant but less-pronounced 3-fold rise in plasma CETP activity, as compared with CETPTg mice receiving the vehicle only (Fig. 2). As expected, neither CETP mRNA nor CETP activity was detected in wild-type mice, whether they were treated or not with the agonist (data not shown).Fig. 2Plasma cholesteryl ester (CE) transfer activity in CETPTg mice receiving or not the LXR agonist. Over 5 days, CETPTg mice received either the T0901317 LXR agonist (10 mg/kg/day) or solvent vehicle only (n = 6 per group). Plasma CE transfer activity was determined in each group as described in Materials and Methods. Values are means ± SEM. Asterisks indicate significance of the difference from untreated CETPTg mice (P < 0.001; Mann-Whitney test).View Large Image Figure ViewerDownload Hi-res image Download (PPT) CETPTg mice receiving only the solvent vehicle displayed moderate but significant differences in plasma lipid levels, as compared with wild-type mice, with higher non-HDL cholesterol and higher HDL triglyceride concentrations (significant 2-fold increases in both parameters in CETPTg mice vs wild-type mice; P < 0.05). As previously reported (5Schultz J.R. Tu H. Luk A. Repa J.J. Medina J.C. Li L. Schwendner S. Wang S. Thoolen M. Mangelsdorf D.J. Lustig K.D. Shan B. Role of LXRs in control of lipogenesis.Genes Dev. 2000; 14: 2831-2838Crossref PubMed Scopus (1403) Google Scholar, 12Cao G. Beyer T.P. Yang X.P. Schmidt R.J. Zhang Y. Bensch W.R. Kauffman R.F. Gao H. Ryan T.P. Liang Y. Eacho P.I. Jiang X.C. Phospholipid transfer protein is regulated by liver X receptors in vivo.J. Biol. Chem. 2002; 277: 39561-39565Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 15Yu L. York J. von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Stimulation of cholesterol excretion by the liver X receptor agonist requires ATP-binding cassette transporters G5 and G8.J. Biol. Chem. 2003; 278: 15565-15570Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar, 16Plosch T. Kok T. Bloks V.W. Smit M.J. Havinga R. Chimini G. Groen A.K. Kuipers F. Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1.J. Biol. Chem. 2002; 277: 33870-33877Abstract Full Text Full Text PDF PubMed Scopus (176) Google Scholar), treatment with the LXR agonist T0901317 induced profound changes in plasma lipid parameters in wild-type mice (Table 1). After treatment, wild-type mice displayed significantly elevated plasma levels of phospholipids (+60%; P < 0.05), esterified cholesterol (+75%; P < 0.05), and free cholesterol (+160%; P < 0.05) but no significant variations in plasma triglyceride levels (Table 1). Gel permeation chromatography analysis revealed that plasma lipid changes were largely explained by an increase in the HDL fraction, in particular with the emergence of large-sized HDL1 (Fig. 3). In contrast to wild-type mice, CETPTg mice did not undergo significant changes in plasma lipid parameters after T0901317 treatment (Table 1). Only a nonsignificant tendency toward a shift of total cholesterol from the HDL- to the LDL-containing fractions was observed by FPLC analysis (Fig. 3). In agreement with previous studies (12Cao G. Beyer T.P. Yang X.P. Schmidt R.J. Zhang Y. Bensch W.R. Kauffman R.F. Gao H. Ryan T.P. Liang Y. Eacho P.I. Jiang X.C. Phospholipid transfer protein is regulated by liver X receptors in vivo.J. Biol. Chem. 2002; 277: 39561-39565Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 32Zak Z. Lagrost L. Gautier T. Masson D. Deckert V. Duverneuil L. De Barros J.P. Le Guern N. Dumont L. Schneider M. Risson V. Moulin P. Autran D. Brooker G. Sassard J. Bataillard A. Expression of simian CETP in normolipidemic Fisher rats has a profound effect on large sized apoE-containing HDL.J. Lipid Res. 2002; 43: 2164-2171Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar), no HDL1-like particles were detected in CETPTg mice, and the present results show that this phenotype was not modified by treatment with the LXR agonist (Fig. 3).TABLE 1Effect of T0901317 LXR agonist treatment on plasma lipid levels in C57Bl6 wild-type and CETPTg miceC57Bl6 Control (n = 8)CETPTg Control (n = 8)C57Bl6 T0901317 (n = 6)CETPTg T0901317 (n = 6)mmol/lTotal cholesterol1.79 ± 0.252.22 ± 0.50aP < 0.05 versus C57Bl6-control.3.37 ± 0.69aP < 0.05 versus C57Bl6-control.2.08 ± 0.46bP < 0.05 versus C5" @default.
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