Diet–Host–Microbiota Interactions Shape Aryl Hydrocarbon Receptor Ligand Production to Modulate Intestinal Homeostasis

The aryl hydrocarbon receptor (AhR) is a transcription factor that regulates a wide range of biological and toxicological effects by binding to specific ligands. AhR ligands exist in various internal and external ecological systems, such as in a wide variety of hydrophobic environmental contaminants and naturally occurring chemicals. Most of these ligands have shown differential responses among different species. Understanding the differences and their mechanisms helps in designing better experimental animal models, improves our understanding of the environmental toxicants related to AhR, and helps to screen and develop new drugs. This review systematically discusses the species differences in AhR activation effects and their modes of action. We focus on the species differences following AhR activation from two aspects: (1) the molecular configuration and activation of AhR and (2) the contrast of cis-acting elements corresponding to AhR. The variations in the responses seen in humans and other species following the activation of the AhR signaling pathway can be attributed to both factors.

Download Full-text

The Basic Helix-Loop-Helix Domain of the Aryl Hydrocarbon Receptor Nuclear Transporter (ARNT) Can Oligomerize and Bind E-box DNA Specifically

Journal of Biological Chemistry ◽

10.1074/jbc.m105675200 ◽

2001 ◽

Vol 276 (44) ◽

pp. 40537-40544 ◽

Cited By ~ 25

Author(s):

Joy L. Huffman ◽

Asawari Mokashi ◽

Hans Peter Bächinger ◽

Richard G. Brennan

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Basic Helix Loop Helix ◽

Helix Loop Helix ◽

Aryl Hydrocarbon ◽

E Box

Download Full-text

Antioxidant Functions of the Aryl Hydrocarbon Receptor

Stem Cells International ◽

10.1155/2016/7943495 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 36

Author(s):

Cornelia Dietrich

Keyword(s):

Polycyclic Aromatic Hydrocarbons ◽

Aryl Hydrocarbon Receptor ◽

Aromatic Hydrocarbons ◽

Transcriptional Activation ◽

Antioxidant Response ◽

Protective Role ◽

Helix Loop Helix ◽

Aryl Hydrocarbon ◽

Polycyclic Aromatic

The aryl hydrocarbon receptor (AhR) is a transcription factor belonging to the basic helix-loop-helix/PER-ARNT-SIM family. It is activated by a variety of ligands, such as environmental contaminants like polycyclic aromatic hydrocarbons or dioxins, but also by naturally occurring compounds and endogenous ligands. Binding of the ligand leads to dimerization of the AhR with aryl hydrocarbon receptor nuclear translocator (ARNT) and transcriptional activation of several xenobiotic phase I and phase II metabolizing enzymes. It is generally accepted that the toxic responses of polycyclic aromatic hydrocarbons, dioxins, and structurally related compounds are mediated by activation of the AhR. A multitude of studies indicate that the AhR operates beyond xenobiotic metabolism and exerts pleiotropic functions. Increasing evidence points to a protective role of the AhR against carcinogenesis and oxidative stress. Herein, I will highlight data demonstrating a causal role of the AhR in the antioxidant response and present novel findings on potential AhR-mediated antioxidative mechanisms.

Download Full-text

Suppression of adipocyte differentiation by Cordyceps militaris through activation of the aryl hydrocarbon receptor

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90373.2008 ◽

2008 ◽

Vol 295 (4) ◽

pp. E859-E867 ◽

Cited By ~ 15

Author(s):

Tsuyoshi Shimada ◽

Nobuhiko Hiramatsu ◽

Ayumi Kasai ◽

Mai Mukai ◽

Maro Okamura ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Mammalian Cells ◽

Adipocyte Differentiation ◽

Biological Activities ◽

Cordyceps Militaris ◽

Dominant Negative ◽

Peroxisome Proliferator ◽

Monocyte Chemoattractant Protein 1 ◽

Aryl Hydrocarbon ◽

Wide Range

Mycelial extracts have a wide range of biological activities that modulate functions of mammalian cells. In this report, we sought to identify antiadipogenic mycelia with the use of 3T3-L1 cells and found that the extract of Cordyceps militaris exclusively suppressed differentiation of 3T3-L1 preadipocytes into mature adipocytes without affecting cell viability. This inhibitory effect was dose dependent, reversible, and associated with 1) a decrease in lipid accumulation, 2) blunted induction of adipocyte markers including adiponectin, peroxisome proliferator-activated receptor-γ, and CCAAT/enhancer binding protein-α, and 3) sustained expression of a preadipocyte marker, monocyte chemoattractant protein-1. C. militaris also significantly decreased accumulation of lipid and hypertrophy in mature adipocytes and preserved their response to insulin (phosphorylation of Akt) during prolonged culture. Subsequent experiments revealed that C. militaris has the potential to activate the aryl hydrocarbon receptor (AhR). In 3T3-L1 cells, treatment with AhR agonists including benzo[ a]pyrene and 3-methylcholanthrene reproduced the antiadipogenic effect of C. militaris. Furthermore, dominant-negative inhibition of AhR abrogated the suppressive effect of C. militaris on adipocyte differentiation. These results suggest that C. militaris has the potential to interfere with adipocyte differentiation through activation of AhR.

Download Full-text

Identification of functional domains of the aryl hydrocarbon receptor nuclear translocator protein (ARNT)

Molecular and Cellular Biology ◽

10.1128/mcb.14.9.6075-6086.1994 ◽

1994 ◽

Vol 14 (9) ◽

pp. 6075-6086

Author(s):

S Reisz-Porszasz ◽

M R Probst ◽

B N Fukunaga ◽

O Hankinson

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Mutant Cell ◽

Translocator Protein ◽

Functional Domains ◽

Recognition Sequence ◽

Dimerization Domain ◽

Alpha Helices ◽

Helix Loop Helix ◽

Aryl Hydrocarbon

The activated aryl hydrocarbon receptor (AHR) and the AHR nuclear translocator (ARNT) bind DNA as a heterodimer. Both proteins represent a novel class of basic helix-loop-helix (bHLH)-containing transcription factors in that (i) activation of AHR requires the binding of ligand (e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]), (ii) the xenobiotic responsive element (XRE) recognized by the AHR/ARNT heterodimer differs from the recognition sequence for nearly all other bHLH proteins, and (iii) both proteins contain a PAS homology region, which in the Drosophila PER and SIM proteins functions as a dimerization domain. A cDNA for mouse ARNT has been cloned, and potential functional domains of ARNT were investigated by deletion analysis. A mutant lacking all regions of ARNT other than the bHLH and PAS regions is unimpaired in TCDD-dependent dimerization and subsequent XRE binding and only modestly reduced in ability to complement an ARNT-deficient mutant cell line, c4, in vivo. Both the first and second alpha helices of the bHLH region are required for dimerization. The basic region is required for XRE binding but not for dimerization. Deletion of either the A or B segments of the PAS region slightly affects TCDD-induced heterodimerization, while deletion of the complete PAS region severely affects (but does not eliminate) dimerization. Thus, ARNT possesses multiple domains required for maximal heterodimerization. Mutants deleted for PAS A, PAS B, and the complete PAS region all retain some degree of XRE binding, yet none can rescue the c4 mutant. Therefore, both the PAS A and PAS B segments, besides contributing to dimerization, apparently fulfill additional, unknown functions required for biological activity of ARNT.

Download Full-text

cDNA cloning and tissue-specific expression of a novel basic helix-loop-helix/PAS factor (Arnt2) with close sequence similarity to the aryl hydrocarbon receptor nuclear translocator (Arnt).

Molecular and Cellular Biology ◽

10.1128/mcb.16.4.1706 ◽

1996 ◽

Vol 16 (4) ◽

pp. 1706-1713 ◽

Cited By ~ 182

Author(s):

K Hirose ◽

M Morita ◽

M Ema ◽

J Mimura ◽

H Hamada ◽

...

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Sequence Similarity ◽

Cdna Clones ◽

Mobility Shift ◽

Phylogenetic Groups ◽

Specific Expression ◽

Basic Helix Loop Helix ◽

Helix Loop Helix ◽

Aryl Hydrocarbon ◽

Adult Mice

We isolated mouse cDNA clones (Arnt2) that are highly similar to but distinct from the aryl hydrocarbon receptor (AhR) nuclear translocator (Arnt). The composite cDNA covered a 2,443-bp sequence consisting of a putative 2,136-bp open reading frame encoding a polypeptide of 712 amino acids. The predicted Arnt2 polypeptide carries a characteristic basic helix-loop-helix (bHLH)/PAS motif in its N-terminal region with close similarity (81% identity) to that of mouse Arnt and has an overall sequence identity of 57% with Arnt. Biochemical properties and interaction of Arnt2 with other bHLH/PAS proteins were investigated by coimmunoprecipitation assays, gel mobility shift assays, and the yeast two-hybrid system. Arnt2 interacted with AhR and mouse Sim as efficiently as Arnt, and the Arnt2-AhR complex recognized and bound specifically the xenobiotic responsive element (XRE) sequence. Expression of Arnt2 successfully rescued XRE-driven reporter gene activity in the Arnt-defective c4 mutant of Hepa-1 cells. RNA blot analysis revealed that expression of Arnt2 mRNA was restricted to the brains and kidneys of adult mice, while Arnt mRNA was expressed ubiquitously. In addition, whole-mount in situ hybridization of 9.5-day mouse embryos showed that Arnt2 mRNA was expressed in the dorsal neural tube and branchial arch 1, while Arnt transcripts were detected broadly in various tissues of mesodermal and endodermal origins. These results suggest that Arnt2 may play different roles from Arnt both in adult mice and in developing embryos. Finally, sequence comparison of the currently known bHLH/PAS proteins indicates a division into two phylogenetic groups: the Arnt group, containing Arnt, Arnt2, and Per, and the AhR group, consisting of AhR, Sim, and Hif-1alpha.

Download Full-text

The Aryl Hydrocarbon Receptor and the Maintenance of Lung Health

International Journal of Molecular Sciences ◽

10.3390/ijms19123882 ◽

2018 ◽

Vol 19 (12) ◽

pp. 3882 ◽

Cited By ~ 12

Author(s):

Necola Guerrina ◽

Hussein Traboulsi ◽

David Eidelman ◽

Carolyn Baglole

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Cigarette Smoke ◽

Respiratory Illness ◽

Chronic Obstructive ◽

Environmental Toxicants ◽

Obstructive Pulmonary Disease ◽

Aryl Hydrocarbon ◽

Disease States ◽

Physiological Processes ◽

Lung Health

Much of what is known about the Aryl Hydrocarbon Receptor (AhR) centers on its ability to mediate the deleterious effects of the environmental toxicant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; dioxin). However, the AhR is both ubiquitously-expressed and evolutionarily-conserved, suggesting that it evolved for purposes beyond strictly mediating responses to man-made environmental toxicants. There is growing evidence that the AhR is required for the maintenance of health, as it is implicated in physiological processes such as xenobiotic metabolism, organ development and immunity. Dysregulation of AhR expression and activity is also associated with a variety of disease states, particularly those at barrier organs such as the skin, gut and lungs. The lungs are particularly vulnerable to inhaled toxicants such as cigarette smoke. However, the role of the AhR in diseases such as chronic obstructive pulmonary disease (COPD)—a respiratory illness caused predominately by cigarette smoking—and lung cancer remains largely unexplored. This review will discuss the growing body of literature that provides evidence that the AhR protects the lungs against the damaging effects of cigarette smoke.

Download Full-text

Identification of functional domains of the aryl hydrocarbon receptor nuclear translocator protein (ARNT).

Molecular and Cellular Biology ◽

10.1128/mcb.14.9.6075 ◽

1994 ◽

Vol 14 (9) ◽

pp. 6075-6086 ◽

Cited By ~ 172

Author(s):

S Reisz-Porszasz ◽

M R Probst ◽

B N Fukunaga ◽

O Hankinson

Keyword(s):

Aryl Hydrocarbon Receptor ◽

Mutant Cell ◽

Translocator Protein ◽

Functional Domains ◽

Recognition Sequence ◽

Dimerization Domain ◽

Alpha Helices ◽

Helix Loop Helix ◽

Aryl Hydrocarbon

The activated aryl hydrocarbon receptor (AHR) and the AHR nuclear translocator (ARNT) bind DNA as a heterodimer. Both proteins represent a novel class of basic helix-loop-helix (bHLH)-containing transcription factors in that (i) activation of AHR requires the binding of ligand (e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin [TCDD]), (ii) the xenobiotic responsive element (XRE) recognized by the AHR/ARNT heterodimer differs from the recognition sequence for nearly all other bHLH proteins, and (iii) both proteins contain a PAS homology region, which in the Drosophila PER and SIM proteins functions as a dimerization domain. A cDNA for mouse ARNT has been cloned, and potential functional domains of ARNT were investigated by deletion analysis. A mutant lacking all regions of ARNT other than the bHLH and PAS regions is unimpaired in TCDD-dependent dimerization and subsequent XRE binding and only modestly reduced in ability to complement an ARNT-deficient mutant cell line, c4, in vivo. Both the first and second alpha helices of the bHLH region are required for dimerization. The basic region is required for XRE binding but not for dimerization. Deletion of either the A or B segments of the PAS region slightly affects TCDD-induced heterodimerization, while deletion of the complete PAS region severely affects (but does not eliminate) dimerization. Thus, ARNT possesses multiple domains required for maximal heterodimerization. Mutants deleted for PAS A, PAS B, and the complete PAS region all retain some degree of XRE binding, yet none can rescue the c4 mutant. Therefore, both the PAS A and PAS B segments, besides contributing to dimerization, apparently fulfill additional, unknown functions required for biological activity of ARNT.

Download Full-text