TY - JOUR A1 - Henkel, Janin A1 - Neuschaefer-Rube, Frank A1 - Pathe-Neuschaefer-Rube, Andrea A1 - Püschel, Gerhard Paul T1 - Aggravation by prostaglandin e-2 of interleukin-6-dependent insulin resistance in hepatocytes N2 - Hepatic insulin resistance is a major contributor to fasting hyperglycemia in patients with metabolic syndrome and type 2 diabetes. Circumstantial evidence suggests that cyclooxygenase products in addition to cytokines might contribute to insulin resistance. However, direct evidence for a role of prostaglandins in the development of hepatic insulin resistance is lacking. Therefore, the impact of prostaglandin E-2 (PGE(2)) alone and in combination with interleukin-6 (IL-6) on insulin signaling was studied in primary hepatocyte cultures. Rat hepatocytes were incubated with IL-6 and/or PGE(2) and subsequently with insulin. Glycogen synthesis was monitored by radiochemical analysis; the activation state of proteins of the insulin receptor signal chain was analyzed by western blot with phosphospecific antibodies. In hepatocytes, insulin-stimulated glycogen synthesis and insulin-dependent phosphorylation of Akt-kinase were attenuated synergistically by prior incubation with IL-6 and/or PGE(2) while insulin receptor autophosphorylation was barely affected. IL-6 but not PGE(2) induced suppressors of cytokine signaling (SOCS3). PGE(2) but not IL-6 activated extracellular signal-regulated kinase 1/2 (ERK1/2) persistently. Inhibition of ERK1/2 activation by PD98059 abolished the PGE(2)-dependent but not the IL-6-dependent attenuation of insulin signaling. In HepG2 cells expressing a recombinant EP3-receptor, PGE(2) pre-incubation activated ERK1/2, caused a serine phosphorylation of insulin receptor substrate 1 (IRS1), and reduced the insulin-dependent Akt-phosphorylation. Conclusion: PGE(2) might contribute to hepatic insulin resistance via an EP3-receptor-dependent ERK1/2 activation resulting in a serine phosphorylation of insulin receptor substrate, thereby preventing an insulin-dependent activation of Akt and glycogen synthesis. Since different molecular mechanisms appear to be employed, PGE(2) may synergize with IL-6, which interrupted the insulin receptor signal chain, principally by an induction of SOCS, namely SOCS3. Y1 - 2009 UR - http://onlinelibrary.wiley.com/journal/10.1002/%28ISSN%291527-3350 U6 - https://doi.org/10.1002/Hep.23064 SN - 0270-9139 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 - 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 -