Aryl hydrocarbon receptor-dependent liver development and hepatotoxicity are mediated by different cell types

Abstract

The aryl hydrocarbon receptor (AHR) plays a role in three areas of biology that include the adaptive metabolism of xenobiotics, the toxic responses associated with exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin), and vascular remodeling of the developing embryo. To test the hypothesis that receptor signaling in different cell types is responsible for these aspects of AHR biology, we generated a conditional Ahr allele where exon 2 is flanked by loxP sites. Through the use of Cre-lox technology, we then investigated the role of AHR signaling in hepatocytes or endothelial cells in mediating prototypical endpoints of adaptive, toxic, or developmental signaling. Using this model, we provide evidence that AHR signaling in endothelial͞hematopoietic cells is necessary for developmental closure of the ductus venosus, whereas AHR signaling in hepatocytes is necessary to generate adaptive and toxic responses of the liver in response to dioxin exposure. Taken together, these data illustrate the importance of cell-specific receptor signaling for the generation of distinct AHR-dependent physiological outcomes.Cre recombinase ͉ ductus venosus ͉ endothelial cell ͉ hepatocyte ͉ dioxin T he aryl hydrocarbon receptor (AHR) is a basic helix-loophelix͞Per-Arnt-Sim protein that plays an essential role in three areas of biology. In response to polycyclic aromatic hydrocarbons, the AHR up-regulates a battery of xenobiotic metabolizing enzymes that include the cytochromes P450, CYP1A1, CYP1A2, and CYP1B1 as well as the phase II enzymes GST-A1 and UGT1-06 (1, 2). In response to halogenateddibenzo-p-dioxins, AHR activation results in the induction of xenobiotic metabolism plus a variety of toxic responses that include hepatocellular damage, thymic involution, epithelial hyperplasia, teratogenesis, and cancer (3-6). Finally, in response to an unknown developmental cue, the AHR influences normal vascular development, most notably the closure of a fetal vascular structure known as the ductus venosus (DV) (3, 7-9).The mouse liver is a powerful model for investigations related to AHR biology. The mouse system allows the production of recombinant loci by gene targeting, whereas the liver provides a representation of each of the three aspects of AHR signal transduction. Using this model, we have provided evidence to suggest that the intracellular details of AHR signal transduction are similar for the adaptive, toxic, and developmental pathways. Through the use of recombinant Ahr and Arnt alleles, we have shown that AHR activation, AHR translocation to the nucleus, AHR dimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT), and AHR-ARNT binding to dioxin responsive elements within the genome are required for adaptive metabolism, dioxin toxicity, and closure of the DV within the developing liver (3,4,7,8,10).The question of how the AHR is able to produce multiple biological events from a similar signal transduction mechanism remains unclear. We hypothesize that receptor signaling in distinct cell types is responsible ...

Anticancer effects of amooranin in human colon carcinoma cell line in vitro and in nude mice xenografts

“…Specifically, AMR is found to activate the aromatic hydrocarbon receptor (AHR) which might indicate the signaling molecule and upstream physiological events induced by AMR. 35,36 AMR also caused up-regulation of several genes with active roles in programmed cell death such as PDCD5, 37,38 CCNB1, CCNB2, RB1, ATP5G3, PLSCR1, COX6A1 and CDKN2C. Cyclin B1 (CCNB1) and Cyclin B2 (CCNB2) are reported to be involved in apoptosis, especially the former one being involved in Golgi apparatus disassembly and in p53-mediated cell cycle arrest at the G 2 /M transition phase.…”

Aryl Hydrocarbon Receptor Plays Protective Roles against High Fat Diet (HFD)-induced Hepatic Steatosis and the Subsequent Lipotoxicity via Direct Transcriptional Regulation of Socs3 Gene Expression

“…Mice homozygous for the floxed allele and hemizygous for the Cre transgene (AhR LKO) were obtained by crossing AhR flox/Ϫ /Cre Alb mice to AhR flox/flox mice. Deletion of the Ahr gene was observed specifically in hepatocytes but not in non-parenchymal cells and other tissues (26). Littermates that were negative for the Cre transgenes (AhR flox/flox ) were used as experimental controls.…”

“…Animals, Diet, Drug Treatment, and Histology-AhR LKO mice were generated as described previously (26). Briefly, AhR flox/flox mice were crossed to C57BL/6J mice carrying the Cre recombinase gene driven by the albumin promoter (The Jackson Laboratory, Bar Harbor, ME).…”

The Aryl hydrocarbon receptor is activated by modified low-density lipoprotein

“…Experiments using Ahr and Arnt hypomorphic mice have demonstrated that, similar to its role in xenobiotic metabolism, the developmental role of AHR requires activation of the receptor and formation of an AHR/ARNT dimer complex (7,8). Additionally, experiments using tissue-specific AHR null mice have demonstrated that AHR expression within endothelial and/or hematopoietic cells is necessary for closure of the DV (9). Overall, these findings are consistent with the idea that an endogenous activator exists for the AHR and that this signaling pathway is important in vascular physiology.…”