Nuclear Pregnane X Receptor Cross-talk with FoxA2 to Mediate Drug-induced Regulation of Lipid Metabolism in Fasting Mouse Liver

Abstract

Upon drug activation, the nuclear pregnane X receptor (PXR) regulates not only hepatic drug but also energy metabolism. Using Pxr–/– mice, we have now investigated the PXR-mediated repression of lipid metabolism in the fasting livers. Treatment with PXR activator pregnenolone 16α-carbonitrile (PCN) down-regulated the mRNA levels of carnitine palmitoyltransferase 1A (in β-oxidation) and mitochondrial 3-hydroxy-3-methylglutarate-CoA synthase 2 (in ketogenesis) in wild-type (Pxr+/+) mice only. In contrast, the stearoyl-CoA desaturase 1 (in lipogenesis) mRNA was up-regulated in the PCN-treated Pxr+/+ mice. Reflecting these up- and down-regulations and consistent with decreased energy metabolism, the levels of hepatic triglycerides and of serum 3-hydroxybutylate were increased and decreased, respectively, in the PCN-treated Pxr+/+ mice. Using gel shift, glutathione S-transferase pull-down and cell-based reporter assays, we then examined whether PXR could cross-talk with the insulin response forkhead factor FoxA2 to repress the transcription of the Cpt1a and Hmgcs2 genes, because FoxA2 activates these genes in fasting liver. PXR directly bound to FoxA2 and repressed its activation of the Cpt1a and Hmgcs2 promoters. Moreover, ChIP assays showed that PCN treatment attenuated the binding of FoxA2 to these promoters in fasting Pxr+/+ but not Pxr–/– mice. These results are consistent with the conclusion that PCN-activated PXR represses FoxA2-mediated transcription of Ctp1a and Hmgcs2 genes in fasting liver. Upon drug activation, the nuclear pregnane X receptor (PXR) regulates not only hepatic drug but also energy metabolism. Using Pxr–/– mice, we have now investigated the PXR-mediated repression of lipid metabolism in the fasting livers. Treatment with PXR activator pregnenolone 16α-carbonitrile (PCN) down-regulated the mRNA levels of carnitine palmitoyltransferase 1A (in β-oxidation) and mitochondrial 3-hydroxy-3-methylglutarate-CoA synthase 2 (in ketogenesis) in wild-type (Pxr+/+) mice only. In contrast, the stearoyl-CoA desaturase 1 (in lipogenesis) mRNA was up-regulated in the PCN-treated Pxr+/+ mice. Reflecting these up- and down-regulations and consistent with decreased energy metabolism, the levels of hepatic triglycerides and of serum 3-hydroxybutylate were increased and decreased, respectively, in the PCN-treated Pxr+/+ mice. Using gel shift, glutathione S-transferase pull-down and cell-based reporter assays, we then examined whether PXR could cross-talk with the insulin response forkhead factor FoxA2 to repress the transcription of the Cpt1a and Hmgcs2 genes, because FoxA2 activates these genes in fasting liver. PXR directly bound to FoxA2 and repressed its activation of the Cpt1a and Hmgcs2 promoters. Moreover, ChIP assays showed that PCN treatment attenuated the binding of FoxA2 to these promoters in fasting Pxr+/+ but not Pxr–/– mice. These results are consistent with the conclusion that PCN-activated PXR represses FoxA2-mediated transcription of Ctp1a and Hmgcs2 genes in fasting liver. The nuclear receptors CAR 2The abbreviations used are: CAR, constitutive active/androstane receptor; PXR, pregnane X receptor; RXR, retinoid X receptor; FoxA2, forkhead box A2; CPT1A, carnitine palmitoyltransferase 1; HMGCS2, mitochondrial 3-hydroxy-3-methylglutarate-CoA synthase 2; PCN, pregnenolone 16α-carbonitrile; SCD1, stearoyl-CoA desaturase 1; PEPCK1, phosphoenolpyruvate carboxykinase 1; G6Pase, glucose 6-phosphatase; GST, glutathione S-transferase; DBD, DNA binding domain; LBD, ligand binding domain; AF2, activation function 2; SREBP, sterol regulatory element-binding protein; ACC1, acetyl CoA carboxylase 1; FAS, fatty acid synthase; DGAT2, diglycerol acyltransferase 2; MTTP, microsomal triacylglyceride transfer protein; ChIP, chromatin immunoprecipitation; m, mouse; h, human; CMV, cytomegalovirus; WT, wild type. 2The abbreviations used are: CAR, constitutive active/androstane receptor; PXR, pregnane X receptor; RXR, retinoid X receptor; FoxA2, forkhead box A2; CPT1A, carnitine palmitoyltransferase 1; HMGCS2, mitochondrial 3-hydroxy-3-methylglutarate-CoA synthase 2; PCN, pregnenolone 16α-carbonitrile; SCD1, stearoyl-CoA desaturase 1; PEPCK1, phosphoenolpyruvate carboxykinase 1; G6Pase, glucose 6-phosphatase; GST, glutathione S-transferase; DBD, DNA binding domain; LBD, ligand binding domain; AF2, activation function 2; SREBP, sterol regulatory element-binding protein; ACC1, acetyl CoA carboxylase 1; FAS, fatty acid synthase; DGAT2, diglycerol acyltransferase 2; MTTP, microsomal triacylglyceride transfer protein; ChIP, chromatin immunoprecipitation; m, mouse; h, human; CMV, cytomegalovirus; WT, wild type. (NR1I3) and PXR (NR1I2) were first characterized as xenobiotic-sensing transcription factors (1Honkakoski P. Zelko I. Sueyoshi T. Negishi M. Mol. Cell. Biol. 1998; 18: 5652-5658Crossref PubMed Scopus (640) Google Scholar, 2Sueyoshi T. Kawamoto T. Zelko I. Honkakoski P. Negishi M. J. Biol. Chem. 1999; 274: 6043-6046Abstract Full Text Full Text PDF PubMed Scopus (614) Google Scholar, 3Kliewer S.A. Moore J.T. Wade L. Staudinger J.L. Watson M.A. Jones S.A. McKee D.D. Oliver B.B. Willson T.M. Zetterstrom R.H. Perlmann T. Lehmann J.M. Cell. 1998; 92: 73-82Abstract Full Text Full Text PDF PubMed Scopus (1300) Google Scholar) coordinately inducing the expression of hepatic genes that encode various enzymes and proteins involved in drug metabolism and excretion (4Honkakoski P. Sueyoshi T. Negishi M. Ann. Med. 2003; 35: 172-182Crossref PubMed Scopus (149) Google Scholar, 5Willson T.M. Kliewer S.A. Nat. Rev. Drug Discov. 2002; 1: 259-266Crossref PubMed Scopus (394) Google Scholar, 6Yamamoto Y. 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It is also known that PXR can regulate the expression of the Pepck1 and Cpt1a genes (17Kodama S. Koike C. Negishi M. Yamamoto Y. Mol. Cell. Biol. 2004; 24: 7931-7940Crossref PubMed Scopus (254) Google Scholar, 18Rosenfeld J.M. Vargas Jr., R. Xie W. Evans R.M. Mol. Endocrinol. 2003; 17: 1268-1282Crossref PubMed Scopus (194) Google Scholar). Thus, in addition to drug metabolism, these nuclear receptors modulate hepatic energy metabolism, gluconeogenesis, and fatty acid oxidation (6Yamamoto Y. Kawamoto T. Negishi M. Arch. Biochem. Biophys. 2003; 409: 207-211Crossref PubMed Scopus (66) Google Scholar). The molecular mechanism through which CAR and PXR mediate the drug-induced repression of energy metabolism is currently of high research interest. The liver is the major organ that metabolizes lipids to produce energy sources. Through β-oxidation and ketogenesis the liver supplies the major energy sources ketone bodies (acetoacetate and 3-hydroxybutylate) to the extra-hepatic tissues and organs when blood glucose levels are low after fasting and prolonged exercise (19Bartlett K. Eaton S. Eur. J. Biochem. 2004; 271: 462-469Crossref PubMed Scopus (286) Google Scholar, 20Laffel L. Diabetes Metab. Res. Rev. 1999; 15: 412-426Crossref PubMed Google Scholar, 21Fukao T. Lopaschuk G.D. Mitchell G.A. Prostaglandins Leukot. Essent. Fatty Acids. 2004; 70: 243-251Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar, 22Eaton S. Bartlett K. Pourfarzam M. Biochem. J. 1996; 320: 345-357Crossref PubMed Scopus (340) Google Scholar). The genes such as Cpt1a and mitochondrial 3-hydroxy-3-methylglutarate-CoA synthase 2 (Hmgcs2) are activated to increase the supply of ketone-bodies (23Hegardt F.G. Biochem. J. 1999; 338: 569-582Crossref PubMed Scopus (270) Google Scholar, 24Louet J.F. Le May C. Pegorier J.P. Decaux J.F. Girard J. Biochem. Soc. Trans. 2001; 29: 310-316Crossref PubMed Google Scholar). Recently, FoxA2, a winged-helix/forkhead transcription factor, is found to be the key regulatory factor that activates these genes in fasting mouse liver (25Wolfrum C. Asilmaz E. Luca E. Friedman J.M. Stoffel M. Nature. 2004; 432: 1027-1032Crossref PubMed Scopus (311) Google Scholar). Insulin decreases lipid metabolism by inactivating the transcription factor FoxA2 to control energy metabolism (26Wolfrum C. Besser D. Luca E. Stoffel M. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 11624-11629Crossref PubMed Scopus (164) Google Scholar, 27Wang H. Wollheim C.B. Trends Mol. Med. 2005; 11: 262-265Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar). Treatment with drugs such as phenobarbital can modulate lipid metabolism in an insulin-independent manner by changing the expression of many genes under control of insulin signaling cascade (28Kiyosawa N. Tanaka K. Hirao J. Ito K. Niino N. Sakuma K. Kanbori M. Yamoto T. Manabe S. Matsunuma N. Arch. Toxicol. 2004; 78: 435-442Crossref PubMed Scopus (30) Google Scholar), suggesting that there may be cross-talk between the xenobiotic-sensing transcription and insulin-regulated transcription factors. Recently, the molecular mechanism by which both CAR and PXR decrease gluconeogenesis was elucidated. Both receptors directly bind to FoxO1, preventing its interaction with the insulin response sequence and repressing the FoxO1-mediated activation of IRS-bearing genes such as Pepck1 (17Kodama S. Koike C. Negishi M. Yamamoto Y. Mol. Cell. Biol. 2004; 24: 7931-7940Crossref PubMed Scopus (254) Google Scholar). However, the molecular mechanism by which CAR and PXR represses lipid metabolism remains unexplored. We have investigated the molecular mechanism of PXR-mediated regulation of hepatic lipid metabolism in fasting mouse. Pxr–/– mice were used to demonstrate that the activation of PXR down-regulated the key enzymes in β-oxidation and ketogenesis, CPT1A, and HMGCS2, respectively, while up-regulating stearoyl-CoA desaturase 1 (SCD1), the key enzyme in lipogenesis. By cloning and characterizing the promoters of the mouse Cpt1a and Hmgcs2 genes, we deciphered the repression mechanism by PXR of FoxA2-mediated transcription of these genes. Here we present experimental considerations to propose the regulatory mechanism by which the drug activation of PXR can result in decreased energy metabolism by up-regulating lipogenesis and by down-regulating β-oxidation and ketogenesis in fasting mouse liver. Materials—Me2SO and pregnenolone 16α-carbonitrile (PCN) were purchased from Sigma-Aldrich. The plasmids pGL3-basic, pBIND, and pACT were obtained from Promega (Madison, WI). Restriction endonucleases and DNA-modifying enzymes were purchased from New England and were by H. Y. R.H. Mol. Cell. Biol. 2003; PubMed Scopus Google Scholar, L. A. E. R.H. Mol. Cell. Biol. PubMed Google Scholar). In and mouse and The plasmids were (1Honkakoski P. Zelko I. Sueyoshi T. Negishi M. Mol. Cell. Biol. 1998; 18: 5652-5658Crossref PubMed Scopus (640) Google Scholar), Sueyoshi T. Negishi M. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar), and Sueyoshi T. Negishi M. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). FoxA2 DNA was with as the and and pACT to and were by cloning of The were also a Y. R.H. Mol. Cell. Biol. 2003; PubMed Scopus Google and plasmids and were Cpt1a to and Hmgcs2 to from mouse used these cloning were and Cpt1a and and The DNA are and respectively, the in the as by and and were in with 2 and in an of The were with to the after were with drug in the serum an was the reporter and from The were in and the results are as the was the to the plasmids DNA binding and were with reporter and was as S-transferase and were in and with DBD, LBD, and were with the was with the and then a pull-down was as K. Sueyoshi T. K. Moore R. Negishi M. Mol. Pharmacol. 2003; PubMed Scopus Google Scholar). proteins were by after RXR, and FoxA2 proteins were by in expression and the the a FoxA2 binding of the to R.M. A. PubMed Scopus Google Scholar), the FoxA2 binding Cpt1a the to the to the to the binding Hmgcs2 the to and the to were with and DNA England The that were in by assays were as (1Honkakoski P. Zelko I. Sueyoshi T. Negishi M. Mol. Cell. Biol. 1998; 18: 5652-5658Crossref PubMed Scopus (640) Google Scholar). were in a with a to were with the PXR wild-type (Pxr+/+) mice obtained from L. Staudinger were and mice were with PCN only mice mice were with and were by the of liver were the with with was with the with the and and S. S. Negishi M. Drug Metab. 2002; PubMed Scopus Google Scholar). In the from were and The control was used as assays were to the S. K. K. Proc. Natl. Acad. Sci. U. S. A. 2004; PubMed Scopus Google Scholar) with The liver were to K. M. U. Cell. Full Text PDF PubMed Scopus Google Scholar). were with and with the was and the was with the were in 1 and and the nuclear was to DNA to a of was by and the was with ChIP 1 1 and The chromatin was by with of of and of with serum The was 2 and the was to bind to of were and with the ChIP DNA in the was by h, and with 2 The DNA were used with as and Cpt1a and Hmgcs2 and were from the of mice, and a The serum levels of fatty acid and 3-hydroxybutylate were fatty acid and from glucose and were and from and the levels of insulin and were these from liver lipids were from from of liver to and J. Biochem. PubMed Scopus Google Scholar). the was and The was in in and was was by the drug in Pxr+/+ mice Pxr–/– mice and the between Pxr+/+ mice and Pxr–/– mice. of the and we have the expression of Cpt1a and which are known to be by FoxA2, in mouse liver. with (23Hegardt F.G. Biochem. J. 1999; 338: 569-582Crossref PubMed Scopus (270) Google Scholar, 24Louet J.F. Le May C. Pegorier J.P. Decaux J.F. Girard J. Biochem. Soc. Trans. 2001; 29: 310-316Crossref PubMed Google Scholar), expression of Cpt1a and Hmgcs2 were and by fasting in mouse through regulation of the was by PCN to PXR in the of Cpt1a and Hmgcs2 genes in mouse we the of the genes between Pxr+/+ and Pxr–/– after PCN treatment in fasting in Pxr+/+ mice, PCN treatment repressed Cpt1a and Hmgcs2 mRNA expression In contrast, the treatment increased mRNA in fasting Pxr+/+ mice The of the Cpt1a and Hmgcs2 genes and the of the were not in the PCN-treated Pxr–/– mice, these were treatment with PCN mRNA only in mice, the control of the function of PXR and its activation by PCN in the used these genes are we serum insulin and and that PCN treatment not levels Thus, these results that PXR directly down-regulated Cpt1a and Hmgcs2 genes and up-regulated the We also examined the of PCN treatment that regulates the Cpt1a and Hmgcs2 genes and found that PCN not the levels of mRNA in the Pxr+/+ and Pxr–/– mice not genes involved in lipid metabolism and were of these genes and which are down-regulated in PCN-treated Pxr+/+ mice and up-regulated in Pxr–/– mice, respectively, expression in the treatment regulates of and in fasting mouse liver. Pxr+/+ Pxr–/– mice were by with PCN The mice were after the and mRNA levels in these mice liver were by mRNA was by with as Pxr+/+ PCN Pxr+/+ Pxr+/+ Pxr–/– levels of insulin and in wild-type and Pxr+/+ Pxr+/+ Pxr+/+ PCN-treated PCN-treated Pxr+/+ Pxr+/+ Pxr+/+ PCN-treated PCN-treated Pxr+/+ Pxr+/+ Pxr+/+ PCN-treated PCN-treated in a mRNA of key genes involved in lipid acid the Pxr+/+ and the Pxr+/+ in a the serum levels of insulin were found to be in the Pxr–/– mice with in the Pxr+/+ mice of insulin have the of the Cpt1a and Hmgcs2 genes attenuated and of the in the Pxr–/– mice the of PXR is directly insulin levels because is the present that the mouse with to be of of Pxr–/– mice. of the of molecular mechanism the Cpt1a and Hmgcs2 regulation in 1 and the interaction between and FoxA2 was in a reporter Cpt1a and Hmgcs2 the we mouse Cpt1a promoters to a reporter and the reporter with the expression plasmids FoxA2 and FoxA2 activated the Cpt1a with control and repressed with repression in the of PCN and In the of FoxA2 not the of Cpt1a Thus, the results that to be activated to repress the FoxA2 we FoxA2 binding in the of the genes. The results of the reporter FoxA2 binding between and in Cpt1a the FoxA2 binding binding and shown in that have with FoxA2 binding were by and reporter assays FoxA2 with both and but not in gel and from the reporter of FoxA2 activation Hmgcs2 activated also FoxA2 activation of The Hmgcs2 reporter to was and with and FoxA2 activated the Hmgcs2 and in the of Using as shown we FoxA2 binding in and the to In the of FoxA2 PXR repressed the constitutive of Hmgcs2 reporter It is not known whether constitutive was by the FoxA2 the transcription the results that Cpt1a and Hmgcs2 promoters have FoxA2 binding and activated represses in reporter Cpt1a reporter and Hmgcs2 of to the molecular mechanism the repression of FoxA2 by we interaction of with FoxA2 in The reporter was increased by PCN when was with However, PCN was when only of these was with the activation was not the PXR these results could with FoxA2 only when the receptor was activated by pull-down was to which are the interaction between and We proteins FoxA2 and its which have a activation the DNA binding These proteins were from and a pull-down was with in with the FoxA2 with the DNA binding showed high with and to in PXR the interaction with FoxA2, pull-down assays were a of of The ligand binding of showed with but the DNA binding the high with suggesting that is not the interaction between FoxA2 and the the the binding of the with FoxA2, assays the Cpt1a reporter were The of but not the repressed the reporter these results that directly with the FoxA2 DNA binding in of FoxA2 to the results that to the DNA binding of FoxA2 and a of FoxA2 DNA binding by Thus, we examined FoxA2 DNA binding a gel in the in FoxA2 with an FoxA2 binding major was The in the of the In contrast, by with the was the and could FoxA2 DNA is in liver in we ChIP mouse liver from Pxr+/+ and Pxr–/– mice with the repression of Cpt1a and Hmgcs2 by PXR was to of FoxA2 to the ChIP could the FoxA2 the the genes by PCN Cpt1a and Hmgcs2 in and were from from mouse liver shown in both DNA of the Cpt1a and Hmgcs2 genes were decreased only in Pxr+/+ mice with PCN but not in Pxr–/– mice. of the from ChIP assays that PCN treatment decreased the FoxA2 the Cpt1a and Hmgcs2 promoters by and with the these of FoxA2 DNA binding Cpt1a and Hmgcs2 promoters by the interaction between activated PXR and FoxA2 in and regulation we found in the be in blood hepatic lipid by PCN we blood and hepatic and of PCN-treated Pxr+/+ and Pxr–/– mice in fasting glucose and ketone levels were decreased in Pxr+/+ mice with PCN Moreover, the treatment increased hepatic only in mice serum and fatty acid were not with the hepatic a of lipid was in PCN-treated mice liver Pxr+/+ Pxr+/+ Pxr+/+ Pxr+/+ in a hepatic in Pxr–/– mice were of Pxr+/+ mice lipid of the from these mice showed from in shown in Pxr–/– mice lipid in In were also increased with mice livers. PCN treatment in blood in hepatic in lipid in Pxr–/– mice livers. these results that PXR in lipid in fasting mouse and the expression we found in 1 and may these in mice. We have that activation of PXR the and the Ctp1a and genes in the liver of fasting mice. the of hepatic triglycerides is increased and that of serum 3-hydroxybutylate Thus, activated PXR represses hepatic energy metabolism by and β-oxidation and ketogenesis in the fasting mice regulation by PXR is to that by which also the of and decreases that of and (23Hegardt F.G. Biochem. J. 1999; 338: 569-582Crossref PubMed Scopus (270) Google Scholar, 24Louet J.F. Le May C. Pegorier J.P. Decaux J.F. Girard J. Biochem. Soc. Trans. 2001; 29: 310-316Crossref PubMed Google Scholar, J.M. J. Biol. Chem. Full Text PDF PubMed Google Scholar, C. J. Pharmacol. PubMed Google Scholar). PXR represses the FoxA2-mediated transcription of the Cpt1a and Hmgcs2 genes by directly binding to FoxA2, which from insulin that represses transcription by the (25Wolfrum C. Asilmaz E. Luca E. Friedman J.M. Stoffel M. Nature. 2004; 432: 1027-1032Crossref PubMed Scopus (311) Google Scholar). Thus, PXR can repress hepatic energy metabolism in an insulin-independent the to and liver The Cpt1a the in the and the Hmgcs2 the sequence in the of these the FoxA2-mediated transcription of these promoters. Through its LBD, PXR directly to the of FoxA2 and the FoxA2 binding to its response of the repressing the transcription of the Cpt1a and Hmgcs2 PXR and CAR are known to repress insulin response transcription factor, FoxO1, that the major in the regulation of hepatic gluconeogenesis (17Kodama S. Koike C. Negishi M. Yamamoto Y. Mol. Cell. Biol. 2004; 24: 7931-7940Crossref PubMed Scopus (254) Google Scholar). the repression of FoxA2 PXR directly to and the FoxO1-mediated transcription of the Pepck1 In the Pepck1 and genes are up-regulated in the mice activated PXR J. Y. Y. Gong H. H. D. S. Evans R.M. Xie W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Thus, the nuclear receptors of a molecular mechanism to repress gluconeogenesis, and ketogenesis through binding to of the forkhead transcription factor and The enzymes and in fatty acid were not by the hepatic of triglycerides not to be to an increase of fatty acid in the liver. In addition to SCD1, the enzymes and involved in and were examined and found not to be by Thus, is the major enzyme the hepatic of triglycerides and lipid in the present The was up-regulated in the mouse the activated PXR J. Y. Y. Gong H. H. D. S. Evans R.M. Xie W. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). known to the key in the mice have a of in the liver wild-type mice and in the of triglycerides S. Jr., Proc. Natl. Acad. Sci. U. S. A. 2003; 100: PubMed Scopus Google Scholar, M. J.M. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). The molecular mechanism of PXR-mediated activation of the remains the present Insulin treatment also the in which insulin activates the regulatory transcription J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). not PXR cross-talk with the regulatory to the be an The of Cpt1a by PXR may also have to the increase of hepatic triglycerides in the PCN-treated mice. It shown that mice with the acid hepatic triglycerides A. J. J.F. R. J. 2005; PubMed Scopus Google Scholar). Moreover, the mouse an of serum triglycerides J. L. Mol. Metab. 2005; PubMed Scopus Google Scholar). By up-regulating and down-regulating and CPT1A, respectively, drug activation of PXR can the liver to The serum glucose in the fasting Pxr+/+ mouse was by PCN that the activated PXR the drug-induced decrease of serum PXR can directly FoxO1-mediated repressing gluconeogenesis (17Kodama S. Koike C. Negishi M. Yamamoto Y. Mol. Cell. Biol. 2004; 24: 7931-7940Crossref PubMed Scopus (254) Google Scholar). the that PXR the Cpt1a and drugs such as PCN that PXR may also repress gluconeogenesis by down-regulating the genes such as Cpt1a and β-oxidation energy and such as and its the supply of these gluconeogenesis to the decreases of both glucose and ketone the PCN-treated mice a to the in Prostaglandins Leukot. Essent. Fatty Acids. 2004; 70: Full Text Full Text PDF PubMed Scopus Google Scholar, P. D. Annu. Rev. 2002; PubMed Scopus Google Scholar) and with an to the from our present was the that the Pxr–/– mice as by the of triglycerides and lipid in the liver. the and Cpt1a were up- and respectively, in the liver of these mice. The Hmgcs2 was also and the serum of 3-hydroxybutylate was decreased in Pxr–/– mice. The in the Pxr–/– mouse to be to in the PCN-treated Pxr+/+ both the activation and of PXR regulate these genes in the of These were with the high levels of serum insulin in the Pxr–/– mice. remains to be there is the that the PXR not activated by is of insulin to its serum preventing the liver from and to control The mechanism of PXR regulates serum insulin levels is the present In PXR is of lipogenesis in the liver and of hepatic β-oxidation and ketogenesis by the genes encoding the key enzymes that these hepatic The PXR, in regulates these genes through cross-talk with the insulin response transcription factor FoxA2, the of PXR also regulates the of genes that are by the PXR, which the molecular mechanism is not in the PXR regulates serum insulin the of the PXR in the of in the Pxr+/+ mice, our is to the ligand that regulates function of