Activation of the Ah Receptor Signal Transduction Pathway by Bilirubin and Biliverdin

Phelan, D.; Winter, G.M.; Rogers, William J.; Lam, Jenny; Denison, Michael S.

doi:10.1006/abbi.1998.0814

Cited by 276 publications

(168 citation statements)

References 33 publications

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“…The aryl hydrocarbon receptor (Ahr) is the only binding site known for which bilirubin/biliverdin have been shown to be agonists. 38,39 Ahr appears to have a prominent role of in cell cycle progression in general. Mouse embryonic fibroblasts from Ahr genetically deficient mice, 40 Ahr defective mouse hepatoma Hepa 1c1c7 cells 41 and VSMCs cultured from Ahr deficient mouse aortas have a prolonged cell cycle time when compared to wild type cells.…”

Section: Discussionmentioning

confidence: 99%

Bilirubin and Biliverdin Treatment of Atherosclerotic Diseases

Öllinger¹,

Yamashita²,

Bilban³

et al. 2007

Cell Cycle

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We have recently shown that the natural bile pigment bilirubin has antiproliferative effects on vascular smooth muscle cells (VSMCs). Bilirubin is the end product of heme catabolism mediated by heme oxygenases and has for decades been considered a toxic waste product of our bodies. However, 14 separate studies and a meta-analysis have documented an inverse correlation between atherosclerosis and the levels of bilirubin in normal individuals. Having high normal or supranormal levels of bilirubin is associated with less atherosclerotic-type disease as compared with that in individuals with low normal levels of bilirubin. This combined with experimental data showing anti-atherosclerotic properties of the enzyme heme oxygenase-1 encouraged us to hypothesize that bilirubin and its precursor biliverdin, would act to ameliorate components of atherosclerosis, in a manner similar to what has been shown with HO-1. Both did so in an animal model of restenosis in which vascular smooth muscle cell proliferation leads to intimal proliferation and causes narrowing of the vessels. We also analyzed the antiproliferative effects of the bile pigments in an in vitro system where bilirubin/biliverdin caused p53 dependent cell cycle arrest by hypophosphorylation of the retinoblastoma tumor suppressor protein in growth factor stimulated VSMCs.

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Section: Discussionmentioning

confidence: 99%

Bilirubin and Biliverdin Treatment of Atherosclerotic Diseases

Öllinger¹,

Yamashita²,

Bilban³

et al. 2007

Cell Cycle

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show abstract

“…13 There are at least 2 possible mechanisms by which biliverdin may be exerting its effects on the NF-jB. By analogy with its effects on the Ah receptor, 42,48 biliverdin may bind directly to NF- jB and inhibit its function. Activation of the Ah receptor leads to the repression of transcription and to cell-cycle arrest.…”

Section: Discussionmentioning

confidence: 99%

Biliverdin inhibits activation of NF‐κB: Reversal of inhibition by human biliverdin reductase

Gibbs

Maines

2007

Intl Journal of Cancer

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hBVR functions in the cell as a reductase and as a kinase. In the first capacity, it reduces biliverdin, the product of HO activity, to the effective intracellular antioxidant, bilirubin; as a dual-specificity kinase (S/T/Y) it activates the MAPK and IGF/IRK receptor signal transduction pathways. NF-jB and the MAPK pathway are activated by ROS, which results in the activation of stress-inducible genes, including ho-1. Presently, we report on the negative effect of biliverdin on NF-jB activation and the converse effect of hBVR. Biliverdin, in a concentration-and time-dependent manner, inhibited transcriptional activity of NF-jB in HEK293A cells. Nuclear extracts from biliverdin-treated cells show reduced DNA binding of NF-jB in an electromobility shift assay, whereas extracts from cells treated with TNF-a showed enhanced binding. Coimmunoprecipitation data show hBVR binds to the 65 kDa subunit of NF-jB, and that this is dependent on activation by TNF-a. Overexpression of hBVR enhanced both the basal and TNF-amediated activation of NF-jB and also that of the NF-jB-activated iNOS gene. Also, overexpression of hBVR arrested the cell cycle in the G 1 /G 0 phase and reduced the number of cells in S phase. Similar results were observed with MCF-7 cells. Because of the Janus nature of NF-jB activity in the cell and the inhibitory action of biliverdin, the present findings provide a foundation for therapeutic intervention in inflammatory diseases and cancer that may be attained by preventing reduction of biliverdin. On the other hand, by increasing BVR levels beneficial functions of NF-jB might be augmented. ' 2007 Wiley-Liss, Inc.

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“…26 Also, bilirubin and biliverdin can function as AhR ligands. 27,28 It is possible that AhR-dependent increase in CAR levels is one of the mechanisms by which bilirubin indirectly increases CAR activity to protect the body from the adverse effects of elevated bilirubin levels. Recent reports have also associated CAR activity with thyroid hormone homeostasis during states of restricted calorie intake 16 as well as with hepatocyte proliferation 29 and tumor formation.…”

Section: Discussionmentioning

confidence: 99%

Aryl-hydrocarbon receptor activation regulates constitutive androstane receptor levels in murine and human liver

et al. 2007

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The aryl-hydrocarbon receptor (AhR) is a basic helix-loop-helix/Per-Arnt-Sim transcription factor that can be activated by exogenous as well as endogenous ligands. AhR is traditionally associated with xenobiotic metabolism. In an attempt to identify novel target genes, C57BL/6J mice were treated with ␤-naphthoflavone (BNF), a known AhR ligand, and genome-wide expression analysis studies were performed using high-density microarrays. Constitutive androstane receptor (CAR) was found to be one of the differentially regulated genes. Real-time quantitative polymerase chain reaction (qPCR) verified the increase in CAR messenger RNA (mRNA) level. BNF treatment did not increase CAR mRNA in AhR-null mice. Time-course studies in mice revealed that the regulation of CAR mRNA mimicked that of Cyp1A1, a known AhR target gene. To demonstrate that the increase in CAR mRNA translates to an increase in functional CAR protein, mice were sequentially treated with BNF (6 hours) followed by the selective CAR agonist, TCPOBOP (3 hours). qPCR revealed an increase in the mRNA level of Cyp2b10, previously known to be regulated by CAR. This also suggests that CAR protein is present in limiting amounts with respect to its transactivation ability.

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Activation of the Ah Receptor Signal Transduction Pathway by Bilirubin and Biliverdin

Cited by 276 publications

References 33 publications

Bilirubin and Biliverdin Treatment of Atherosclerotic Diseases

Bilirubin and Biliverdin Treatment of Atherosclerotic Diseases

Biliverdin inhibits activation of NF‐κB: Reversal of inhibition by human biliverdin reductase

Aryl-hydrocarbon receptor activation regulates constitutive androstane receptor levels in murine and human liver

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