Aryl Hydrocarbon Receptor–Dependent Induction of Liver Fibrosis by Dioxin

Pierre, Stéphane; Chevallier, Aline; Teixeira-Clerc, Fatima; Ambolet-Camoit, Ariane; Bui, Linh‐Chi; Bats, Anne-Sophie; Fournet, Jean‐Christophe; Fernandez-Salguero, Pedro; Aggerbeck, Μartine; Lotersztajn, Sophie; Barouki, Robert; Coumoul, Xavier

doi:10.1093/toxsci/kft236

Cited by 101 publications

(106 citation statements)

References 43 publications

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“…Development of periportal fibrosis as indicated by excess collagen deposition was determined by qualitative and quantitative assessment of PSR-stained liver sections. In agreement with previous studies (Nault et al, 2015a;Pierre et al, 2014), TCDD treatment significantly increased collagen deposition in the liver (Fig. 6A and B).…”

Section: Par-1 Deficiency Does Not Reduce Tcdd-elicited Hepatotoxicitysupporting

confidence: 93%

“…Recent studies also suggest exposure to environmental contaminants including persistent organic pollutants and organochlorines contributes to metabolic disease development (Cave et al, 2010;Lee et al, 2006Lee et al, , 2007Taylor et al, 2013). For example,2,3,7,, the prototypical aryl hydrocarbon receptor (AhR) ligand, has been shown to contribute to the progression of NAFLD spectrum from simple, reversible steatosis, to steatohepatitis and early signs of fibrosis in mice (Kopec et al, 2013;Nault et al, 2015a;Pierre et al, 2014). Notably, all of these pathologies are elements of the NAFLD spectrum in humans.…”

mentioning

confidence: 99%

“…Collectively, these studies indicate a central role for coagulation and thrombin signaling across the spectrum of NAFLD/NASH pathologies. Repeated TCDD exposure in mice has been shown to promote the development of steatosis, steatohepatitis, and fibrosis (Fader et al, 2015;Nault et al, 2015a;Pierre et al, 2014). However, no studies have examined whether the progression of liver pathologies elicited by TCDD is coupled to coagulation cascade activation, and the role of PAR-1 in this experimental context is unknown.…”

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confidence: 99%

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From the Cover: Coagulation-Driven Hepatic Fibrosis Requires Protease Activated Receptor-1 (PAR-1) in a Mouse Model of TCDD-Elicited Steatohepatitis

et al. 2016

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Emerging evidence supports a role for environmental chemical exposure in the pathology of non-alcoholic fatty liver disease (NAFLD), a disease process tightly linked to increased activity of the blood coagulation cascade. Exposure of C57BL/6 mice to the persistent environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) recapitulates features of the NAFLD spectrum, including steatosis, hepatic injury, inflammation, and fibrosis. We assessed coagulation cascade activation, and determined the role of the thrombin receptor protease activated receptor-1 (PAR-1) in experimental TCDDelicited NAFLD. Chronic exposure to TCDD (30 mg/kg every 4 days for 28 days) was associated with intrahepatic coagulation, indicated by increased plasma thrombin-antithrombin levels and hepatic fibrin(ogen) deposition. PAR-1 deficiency diminished TCDD-elicited body weight loss and relative liver weight was reduced in TCDD-exposed PAR-1 À/À mice compared with TCDD-exposed wild-type mice. PAR-1 deficiency did not affect TCDD-induced hepatic steatosis or hepatocellular injury, as indicated by serum alanine aminotransferase activity. Despite a lack of effect on these 2 features of NAFLD pathology, PAR-1 deficiency was associated with a reduction in hepatic inflammation evident in liver histopathology, and reflected by a reduction in serum levels of the proinflammatory cytokine interleukin-6. Moreover, TCDD-driven hepatic collagen deposition was markedly reduced in PAR-1-deficient mice. These results indicate that experimental TCDD-elicited steatohepatitis is associated with coagulation cascade activation and PAR-1-driven hepatic inflammation and fibrosis.

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Section: Par-1 Deficiency Does Not Reduce Tcdd-elicited Hepatotoxicitysupporting

confidence: 93%

mentioning

confidence: 99%

mentioning

confidence: 99%

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From the Cover: Coagulation-Driven Hepatic Fibrosis Requires Protease Activated Receptor-1 (PAR-1) in a Mouse Model of TCDD-Elicited Steatohepatitis

et al. 2016

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“…important role in TCDD-elicited fibrosis (Pierre et al, 2014) although the mechanisms involved in AhR-mediated fibrogenesis remain poorly understood.…”

mentioning

confidence: 99%

Dose-Dependent Metabolic Reprogramming and Differential Gene Expression in TCDD-Elicited Hepatic Fibrosis

Nault¹,

Fader²,

Ammendolia³

et al. 2016

Toxicol. Sci.

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We have previously shown that in response to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-elicited NAFLD progression, central carbon, glutaminolysis, and serine/folate metabolism are reprogrammed to support NADPH production and ROS defenses. To further investigate underlying dose-dependent responses associated with TCDD-induced fibrosis, female C57BL/6 mice were gavaged with TCDD every 4 days (d) for 28 d or 92 d. RNA-Seq, ChIP-Seq (2 h), and 28 d metabolomic (urine, serum, and hepatic extract) analyses were conducted with complementary serum marker assessments at 92 d. Additional vehicle and 30 mg/kg treatment groups were allowed to recover for 36 d following the 92-d treatment regimen to examine recovery from TCDD-elicited fibrosis. Histopathology revealed dose-dependent increases in hepatic fat accumulation, inflammation, and periportal collagen deposition at 92 days, with increased fibrotic severity in the recovery group. Serum proinflammatory and profibrotic interleukins-1b, -2, -4, -6, and -10, as well as TNF-a and IFN-c, exhibited dose-dependent induction. An increase in glucose tolerance was observed with a concomitant 3.0-fold decrease in hepatic glycogen linked to increased ascorbic acid biosynthesis and proline metabolism, consistent with increased fibrosis. RNASeq identified differential expression of numerous matrisome genes including an 8.8-fold increase in Tgfb2 indicating myofibroblast activation. Further analysis suggests reprogramming of glycogen, ascorbic acid, and amino acid metabolism in support of collagen deposition and the use of proline as a substrate for ATP production via the proline cycle. In summary, we demonstrate that glycogen, ascorbic acid, and amino acid metabolism are also reorganized to support remodeling of the extracellular matrix, progressing to hepatic fibrosis in response to chronic injury from TCDD.

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“…miR-29 family members, including miR-29a, are known to be downregulated in human fibrotic livers (39). Recently, it was reported that activation of AhR induces hepatic fibrosis by directly regulating pro-fibrotic pathways (40). It would be of interest to examine the role of miR-29a-mediated AhR regulation in the development of hepatic fibrosis.…”

Section: Discussionmentioning

confidence: 99%

RNA Editing Modulates Human Hepatic Aryl Hydrocarbon Receptor Expression by Creating MicroRNA Recognition Sequence

Nakano

Fukami

Gotoh

et al. 2016

Journal of Biological Chemistry

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Adenosine to inosine (A-to-I) RNA editing is the most frequent type of post-transcriptional nucleotide conversion in humans, and it is catalyzed by adenosine deaminase acting on RNA (ADAR) enzymes. In this study we investigated the effect of RNA editing on human aryl hydrocarbon receptor (AhR) expression because the AhR transcript potentially forms double-stranded structures, which are targets of ADAR enzymes. In human hepatocellular carcinoma-derived Huh-7 cells, the ADAR1 knockdown reduced the RNA editing levels in the 3-untranslated region (3-UTR) of the AhR transcript and increased the AhR protein levels. The ADAR1 knockdown enhanced the ligand-mediated induction of CYP1A1, a gene downstream of AhR. We investigated the possibility that A-to-I RNA editing creates miRNA targeting sites in the AhR mRNA and found that the miR-378-dependent down-regulation of AhR was abolished by ADAR1 knockdown. These results indicated that the ADAR1-mediated down-regulation of AhR could be attributed to the creation of a miR-378 recognition site in the AhR 3-UTR. The interindividual differences in the RNA editing levels within the AhR 3-UTR in a panel of 32 human liver samples were relatively small, whereas the differences in ADAR1 expression were large (220-fold). In the human liver samples a significant inverse association was observed between the miR-378 and AhR protein levels, suggesting that the RNA-editingdependent down-regulation of AhR by miR-378 contributes to the variability in the constitutive hepatic expression of AhR. In conclusion, this study uncovered for the first time that A-to-I RNA editing modulates the potency of xenobiotic metabolism in the human liver.

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Aryl Hydrocarbon Receptor–Dependent Induction of Liver Fibrosis by Dioxin

Cited by 101 publications

References 43 publications

From the Cover: Coagulation-Driven Hepatic Fibrosis Requires Protease Activated Receptor-1 (PAR-1) in a Mouse Model of TCDD-Elicited Steatohepatitis

From the Cover: Coagulation-Driven Hepatic Fibrosis Requires Protease Activated Receptor-1 (PAR-1) in a Mouse Model of TCDD-Elicited Steatohepatitis

Dose-Dependent Metabolic Reprogramming and Differential Gene Expression in TCDD-Elicited Hepatic Fibrosis

RNA Editing Modulates Human Hepatic Aryl Hydrocarbon Receptor Expression by Creating MicroRNA Recognition Sequence

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