TY - JOUR A1 - Neuschaefer-Rube, Frank A1 - Lieske, Stefanie A1 - Kuna, Manuela A1 - Henkel, Janin A1 - Perry, Rachel J. A1 - Erion, Derek M. A1 - Pesta, Dominik A1 - Willmes, Diana M. A1 - Brachs, Sebastian A1 - von Loeffelholz, Christian A1 - Tolkachov, Alexander A1 - Schupp, Michael A1 - Pathe-Neuschaefer-Rube, Andrea A1 - Pfeiffer, Andreas F. H. A1 - Shulman, Gerald I. A1 - Püschel, Gerhard Paul A1 - Birkenfeld, Andreas L. T1 - The mammalian INDY homolog is induced by CREB in a rat model of type 2 diabetes JF - Diabetes : a journal of the American Diabetes Association Y1 - 2014 SN - 0012-1797 SN - 1939-327X VL - 63 IS - 3 SP - 1048 EP - 1057 PB - American Diabetes Association CY - Alexandria ER - TY - JOUR A1 - Wieneke, Nadine A1 - Neuschaefer-Rube, Frank A1 - Bode, L. M. A1 - Kuna, Manuela A1 - Andres, Jesus A1 - Carnevali Junior, Luiz Carlos A1 - Hirsch-Ernst, Karen I. A1 - Püschel, Gerhard Paul T1 - Synergistic acceleration of thyroid hormone degradation by phenobarbital and the PPAR alpha agonist WY14643 in rat hepatocytes N2 - Energy balance is maintained by controlling both energy intake and energy expenditure. Thyroid hormones play a crucial role in regulating energy expenditure. Their levels are adjusted by a tight feed back-control led regulation of thyroid hormone production/incretion and by their hepatic metabolism. Thyroid hormone degradation has previously been shown to be enhanced by treatment with phenobarbital or other antiepileptic drugs due to a CAR-dependent induction of phase 11 enzymes of xenobiotic metabolism. We have recently shown, that PPAR alpha agonists synergize with phenobarbital to induce another prototypical CAR target gene, CYP2B1. Therefore, it was tested whether a PPAR alpha agonist could enhance the phenobarbital-dependent acceleration of thyroid hormone elimination. In primary cultures of rat hepatocytes the apparent half-life of T3 was reduced after induction with a combination of phenobarbital and the PPARa agonist WY14643 to a larger extent than after induction with either Compound alone. The synergistic reduction of the half-life could be attributed to a synergistic induction of CAR and the CAR target genes that code for enzymes and transporters involved in the hepatic elimination of T3, such as OATP1A1, OATP1A3, UGT1A3 and UCT1A10. The PPAR alpha-dependent CAR induction and the subsequent induction of T3-eliminating enzymes might be of physiological significance for the fasting- incluced reduction in energy expenditure by fatty acids as natural PPARa ligands. The synergism of the PPAR alpha agonist WY14643 and phenobarbital in inducing thyroid hormone breakdown might serve as a paradigm for the synergistic disruption of endocrine control by other combinations of xenobiotics. Y1 - 2009 UR - http://www.sciencedirect.com/science/journal/0041008X U6 - https://doi.org/10.1016/j.taap.2009.07.014 SN - 0041-008X ER - TY - JOUR A1 - Wieneke, Nadine A1 - Hirsch-Ernst, Karen I. A1 - Kuna, Manuela A1 - Kersten, Sander A1 - Püschel, Gerhard Paul T1 - PPARalpha-dependent induction of the energy homeostasis-regulating nuclear N2 - A tight hormonal control of energy homeostasis is of pivotal relevance for animals. Recent evidence suggests an involvement of the nuclear receptor NR1i3 (CAR). Fasting induces CAR by largely unknown mechanisms and CAR-deficient mice are defective in fasting adaptation. In rat hepatocytes CAR was induced by WY14643, a PPARalpha-agonist. A DR1 motif in the CAR promoter was necessary and sufficient for this control. The PPARalpha-dependent increase in CAR potentiated the phenobarbital-induced transcription of the prototypical CAR-dependent gene CYP2B1. Since free fatty acids are natural ligands for PPARalpha, a fasting-induced increase in free fatty acids might induce CAR. In accordance with this hypothesis, CAR induction by fasting was abrogated in PPARalpha-deficient mice. Y1 - 2007 UR - http://www.sciencedirect.com/science/article/pii/S0014579307011556 SN - 0014-5793 ER - TY - JOUR A1 - Neuschäfer-Rube, Frank A1 - Hermosilla, Ricardo A1 - Kuna, Manuela A1 - Pathe-Neuschäfer-Rube, Andrea A1 - Schulein, R. A1 - Püschel, Gerhard Paul T1 - A Ser/Thr cluster within the C-terminal domain of the rat prostaglandin receptor EP3 alpha is essential for agonist-induced phosphorylation, desensitization and internalization N2 - 1 Two isoforms of the rat prostaglandin E-2 receptor, rEP3 alpha-R and rEP3 beta-R, differ only in their C- terminal domain. To analyze the function of the rEP3-R C-terminal domain in agonist induced desensitization, a cluster of Ser/Thr residues in the C-terminal domain of the rEP3 alpha-R was mutated to Ala and both isoforms and the receptor mutant (rEP3 alpha-ST341-349A-R) were stably expressed in HEK293 cells. 2 All rEP3-R receptors showed a similar ligand- binding profile. They were functionally coupled to Gi and reduced forskolin-induced cAMP-formation. 3 Repeated exposure of cells expressing the rEP3 alpha-R isoform to PGE(2) reduced the agonist induced inhibition of forskolin-stimulated cAMP-formation by 50% and led to internalization of the receptor to intracellular endocytotic vesicles. By contrast, Gi- response as well as plasma membrane localization of the rEP3 beta-R and the rEP3 alpha-ST341-349A-R were not affected by prior agonist-stimulation. 4 Agonist-stimulation of HEK293-rEP3 alpha-R cells induced a time- and dose-dependent phosphorylation of the receptor most likely by G protein-coupled receptor kinases and not by protein kinase A or protein kinase C. By contrast, upon agonist-stimulation the rEP3 beta-R was not phosphorylated and the rEP3 alpha-ST341-349A-R was phosphorylated only weakly. 5 These results led to the hypothesis that agonist-induced desensitization of the rEP3 alpha-R isoform is mediated most likely by a GRK-dependent phosphorylation of Ser/Thr residues 341 - 349. Phosphorylation then initiates uncoupling of the receptor from Gi protein and receptor internalization Y1 - 2005 SN - 0007-1188 ER - TY - JOUR A1 - Neuschäfer-Rube, Frank A1 - Hermosilla, Ricardo A1 - Kuna, Manuela A1 - Pathe-Neuschaefer-Rube, Andrea A1 - Püschel, Gerhard Paul T1 - Agonist-induced desensitization of rat prostaglandin EP3 receptor isoforms Y1 - 2004 SN - 0028-1298 ER - TY - JOUR A1 - Steinberg, Pablo A1 - Zschaler, Ingrid A1 - Thom, Elke A1 - Kuna, Manuela A1 - Wüst, Günter A1 - Schäfer-Schwebel, Angelika A1 - Müller, Rolf A1 - Kramer, Peter-Jürgen A1 - Weiße, Günter T1 - The polycyclic musk 7-acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthaline lacks liver tumor initiating and promoting activity in rats exposed to human-relevant doses Y1 - 2001 UR - http://www.springerlink.com/content/100462 U6 - https://doi.org/10.1007/s002040100274 SN - 0340-5761 ER -