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• W1504024013 abstract "Phenobarbital (PB) is a prototype inducer of genes encoding drug metabolizing enzymesincluding the cytochromes P450 (CYPs). Additionally, phenobarbital was found torepress genes that encode enzymes involved in gluconeogenesis such asphosphoenolpyruvate carboxykinase (PEPCK). Constitutive androstane receptor (CAR)is known to play a fundamental role in the phenobarbital-mediated regulation ofcytochromes P450 and in gluconegenesis in the liver. Phenobarbital was recently shownin our laboratory to activate a known inhibitor of hepatic glucose production, the energysensor AMP-activated kinase (AMPK). In the present thesis, we investigated the role ofAMPK in the phenobarbital-mediated inhibition of gluconeogenesis. Our experimentsreveal that both CAR and AMPK are necessary to mediate the PB inhibitory effect onPEPCK mRNA expression. Furthermore, our study indicates that AMPK and CARphysically interact in this process. We speculate that once activated by PB, the CARAMPKcomplex may prevent coactivators such as PGC-1α to interact with partners at thePEPCK promoter. However, overexpression of exogenous CAR dose-dependentlyincreased PEPCK mRNA expression and its promoter activity in a human hepatoma cellline. The co-transfection of CAR with PGC-1α, a master regulator of PEPCK, clearlyincreases PEPCK promoter activity. Moreover, we show that the cotransfection of CARand protein kinase A (PKA), a well established inducer of gluconeogenic pathways, dosedependently activates PEPCK.Our results also indicate that similarily to PEPCK, CAR mRNA expression is inducedduring fasting and in the absence of glucose. CAR also induces genes that encode forglucose transport during fasting. On the other hand, insulin represses CAR mRNAexpression suggesting that CAR plays a significant role in the fasting-feeding transition.Finally, we demonstrate that CAR regulates the expression of genes encoding for ofacetyl-CoA carboxylase (ACC), an enzyme known to be involved in the control oflipogenesis and beta oxidation of fatty acids. Altogether, these studies indicate that CAR is involved in the regulation of glucose and lipid metabolism and the regulation of itsactivity may be crucial to understand the molecular mechanisms that link drugmetabolism to energy metabolism." @default.
• W1504024013 created "2016-06-24" @default.
• W1504024013 creator A5043305813 @default.
• W1504024013 date "2010-01-01" @default.
• W1504024013 modified "2023-09-27" @default.
• W1504024013 title "Crossroads between drug and energy metabolism : role of constitutive androstane receptor and AMP-activated kinase" @default.
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