Involvement of connexin43 in acetaminophen-induced liver injury

Michaël Maes; Mitchell R. Mcgill; Tereza Cristina da Silva; Chloé Abels; Margitta Lebofsky; Cintia Maria Monteiro de Araújo; Taynã Tiburcio; Isabel Veloso Alves Pereira; Joost Willebrords; Sara Crespo Yanguas; Anwar Farhood; Alain Beschin; Jo Van Ginderachter; Maria Lucia Zaidan Dagli; Hartmut Jaeschke; Bruno Cogliati; Mathieu Vinken

doi:10.1016/j.bbadis.2016.02.007

Involvement of connexin43 in acetaminophen-induced liver injury

Michaël Maes, Mitchell R. Mcgill, Tereza Cristina da Silva, Chloé Abels, Margitta Lebofsky, Cintia Maria Monteiro de Araújo, Taynã Tiburcio, Isabel Veloso Alves Pereira, Joost Willebrords, Sara Crespo Yanguas, Anwar Farhood, Alain Beschin, Jo Van Ginderachter, Maria Lucia Zaidan Dagli, Hartmut Jaeschke, Bruno Cogliati, Mathieu Vinken

Research output: Contribution to journal › Article › peer-review

31 Citations (Scopus)

Abstract

Background and aims

Being goalkeepers of liver homeostasis, gap junctions are also involved in hepatotoxicity. However, their role in this process is ambiguous, as gap junctions can act as both targets and effectors of liver toxicity. This particularly holds true for drug-induced liver insults. In the present study, the involvement of connexin 26, connexin32 and connexin43, the building blocks of liver gap junctions, was investigated in acetaminophen-induced hepatotoxicity.

Methods

C57BL/6 mice were overdosed with 300 mg/kg body weight acetaminophen followed by analysis of the expression and localization of connexins as well as monitoring of hepatic gap junction functionality. Furthermore, acetaminophen-induced liver injury was compared between mice genetically deficient in connexin43 and wild type littermates. Evaluation of the toxicological response was based on a set of clinically relevant parameters, including protein adduct formation, measurement of alanine aminotransferase activity, cytokines and glutathione.

Results

It was found that gap junction communication deteriorates upon acetaminophen intoxication in wild type mice, which is associated with a switch in mRNA and protein production from connexin32 and connexin26 to connexin43. The upregulation of connexin43 expression is due, at least in part, to de novo production by hepatocytes. Connexin43-deficient animals tended to show increased liver cell death, inflammation and oxidative stress in comparison with wild type counterparts.

Conclusion

These results suggest that hepatic connexin43-based signaling may protect against acetaminophen-induced liver toxicity.

Original language	English
Pages (from-to)	1111-1121
Number of pages	11
Journal	Biochimica et Biophysica Acta - Molecular Basis of Disease
Volume	1862
Issue number	6
DOIs	https://doi.org/10.1016/j.bbadis.2016.02.007
Publication status	Published - 1 Jun 2016

Keywords

connexin
acetaminophen
hepatotoxicity

Access to Document

10.1016/j.bbadis.2016.02.007

1 Active
5 Finished

OZR2651: International Joint Research Group - Liver Connexin and Pannexin Research Group (LCPR)
Vinken, M., Rogiers, V., Cogliati, B. & Dagli, M. L.
1/08/14 → 1/07/26
Project: Fundamental
OZR2813: Bilaterale samenwerking ikv gemeenschappelijke doctoraatsproject: Bench Fee voor Joint PhD VUB-Universidade de Sao Paulo, Michael Maes
Vinken, M.
10/06/15 → 31/07/17
Project: Fundamental
EU457: CONNECT: Connexin and pannexin channels as drug targets and biomarkers in acute and chronic liver disease
Vinken, M.
1/03/14 → 28/02/19
Project: Fundamental

31 Citations
4 Article
1 Meeting abstract (Journal)

Connexins and pannexins in liver damage
Crespo Yanguas, S., Willebrords, J., Maes, M., da Silva, T. C., Alves Pereira, I. V., Cogliati, B., Zaidan Dagli, M. L. & Vinken, M., 18 Feb 2016, In: EXCLI Journal. 15, p. 177-186 10 p.
Research output: Contribution to journal › Article › peer-review
Experimental models of hepatotoxicity related to acute liver failure
Maes, M., Vinken, M. & Jaeschke, H., 1 Jan 2016, In: Toxicology and Applied Pharmacology. 290, p. 86-97 12 p.
Research output: Contribution to journal › Article › peer-review

File
162 Citations (Scopus)

283 Downloads (Pure)
Connexin and pannexin signaling in gastrointestinal and liver disease
Maes, M., Crespo Yanguas, S., Willebrords, J., Cogliati, B. & Vinken, M., 1 Oct 2015, In: Translational Research. 166, 4, p. 332-343
Research output: Contribution to journal › Article › peer-review
41 Citations (Scopus)

Protective effects of connexin43 signaling against experimentally induced acute liver failure in mouse.
Maes, M. (Recipient), 28 Mar 2015
Prize: Prize (including medals and awards)

Cite this

Maes, M., Mcgill, M. R., da Silva, T. C., Abels, C., Lebofsky, M., Monteiro de Araújo, C. M., Tiburcio, T., Alves Pereira, I. V., Willebrords, J., Crespo Yanguas, S., Farhood, A., Beschin, A., Van Ginderachter, J., Zaidan Dagli, M. L., Jaeschke, H., Cogliati, B., & Vinken, M. (2016). Involvement of connexin43 in acetaminophen-induced liver injury. Biochimica et Biophysica Acta - Molecular Basis of Disease, 1862(6), 1111-1121. https://doi.org/10.1016/j.bbadis.2016.02.007

Maes, Michaël ; Mcgill, Mitchell R. ; da Silva, Tereza Cristina ; Abels, Chloé ; Lebofsky, Margitta ; Monteiro de Araújo, Cintia Maria ; Tiburcio, Taynã ; Alves Pereira, Isabel Veloso ; Willebrords, Joost ; Crespo Yanguas, Sara ; Farhood, Anwar ; Beschin, Alain ; Van Ginderachter, Jo ; Zaidan Dagli, Maria Lucia ; Jaeschke, Hartmut ; Cogliati, Bruno ; Vinken, Mathieu. / Involvement of connexin43 in acetaminophen-induced liver injury. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2016 ; Vol. 1862, No. 6. pp. 1111-1121.

@article{06e4b056f2a947e29f81fbade1f87162,

title = "Involvement of connexin43 in acetaminophen-induced liver injury",

abstract = "Background and aimsBeing goalkeepers of liver homeostasis, gap junctions are also involved in hepatotoxicity. However, their role in this process is ambiguous, as gap junctions can act as both targets and effectors of liver toxicity. This particularly holds true for drug-induced liver insults. In the present study, the involvement of connexin 26, connexin32 and connexin43, the building blocks of liver gap junctions, was investigated in acetaminophen-induced hepatotoxicity.MethodsC57BL/6 mice were overdosed with 300 mg/kg body weight acetaminophen followed by analysis of the expression and localization of connexins as well as monitoring of hepatic gap junction functionality. Furthermore, acetaminophen-induced liver injury was compared between mice genetically deficient in connexin43 and wild type littermates. Evaluation of the toxicological response was based on a set of clinically relevant parameters, including protein adduct formation, measurement of alanine aminotransferase activity, cytokines and glutathione.ResultsIt was found that gap junction communication deteriorates upon acetaminophen intoxication in wild type mice, which is associated with a switch in mRNA and protein production from connexin32 and connexin26 to connexin43. The upregulation of connexin43 expression is due, at least in part, to de novo production by hepatocytes. Connexin43-deficient animals tended to show increased liver cell death, inflammation and oxidative stress in comparison with wild type counterparts.ConclusionThese results suggest that hepatic connexin43-based signaling may protect against acetaminophen-induced liver toxicity.",

keywords = "connexin, acetaminophen, hepatotoxicity",

author = "Micha{\"e}l Maes and Mcgill, {Mitchell R.} and {da Silva}, {Tereza Cristina} and Chlo{\'e} Abels and Margitta Lebofsky and {Monteiro de Ara{\'u}jo}, {Cintia Maria} and Tayn{\~a} Tiburcio and {Alves Pereira}, {Isabel Veloso} and Joost Willebrords and {Crespo Yanguas}, Sara and Anwar Farhood and Alain Beschin and {Van Ginderachter}, Jo and {Zaidan Dagli}, {Maria Lucia} and Hartmut Jaeschke and Bruno Cogliati and Mathieu Vinken",

year = "2016",

month = jun,

day = "1",

doi = "10.1016/j.bbadis.2016.02.007",

language = "English",

volume = "1862",

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Maes, M, Mcgill, MR, da Silva, TC, Abels, C, Lebofsky, M, Monteiro de Araújo, CM, Tiburcio, T, Alves Pereira, IV, Willebrords, J, Crespo Yanguas, S, Farhood, A, Beschin, A , Van Ginderachter, J, Zaidan Dagli, ML, Jaeschke, H, Cogliati, B & Vinken, M 2016, 'Involvement of connexin43 in acetaminophen-induced liver injury', Biochimica et Biophysica Acta - Molecular Basis of Disease, vol. 1862, no. 6, pp. 1111-1121. https://doi.org/10.1016/j.bbadis.2016.02.007

Involvement of connexin43 in acetaminophen-induced liver injury. / Maes, Michaël; Mcgill, Mitchell R.; da Silva, Tereza Cristina; Abels, Chloé; Lebofsky, Margitta; Monteiro de Araújo, Cintia Maria; Tiburcio, Taynã; Alves Pereira, Isabel Veloso; Willebrords, Joost; Crespo Yanguas, Sara; Farhood, Anwar; Beschin, Alain ; Van Ginderachter, Jo; Zaidan Dagli, Maria Lucia; Jaeschke, Hartmut; Cogliati, Bruno; Vinken, Mathieu.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, Vol. 1862, No. 6, 01.06.2016, p. 1111-1121.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Involvement of connexin43 in acetaminophen-induced liver injury

AU - Maes, Michaël

AU - Mcgill, Mitchell R.

AU - da Silva, Tereza Cristina

AU - Abels, Chloé

AU - Lebofsky, Margitta

AU - Monteiro de Araújo, Cintia Maria

AU - Tiburcio, Taynã

AU - Alves Pereira, Isabel Veloso

AU - Willebrords, Joost

AU - Crespo Yanguas, Sara

AU - Farhood, Anwar

AU - Beschin, Alain

AU - Van Ginderachter, Jo

AU - Zaidan Dagli, Maria Lucia

AU - Jaeschke, Hartmut

AU - Cogliati, Bruno

AU - Vinken, Mathieu

PY - 2016/6/1

Y1 - 2016/6/1

N2 - Background and aimsBeing goalkeepers of liver homeostasis, gap junctions are also involved in hepatotoxicity. However, their role in this process is ambiguous, as gap junctions can act as both targets and effectors of liver toxicity. This particularly holds true for drug-induced liver insults. In the present study, the involvement of connexin 26, connexin32 and connexin43, the building blocks of liver gap junctions, was investigated in acetaminophen-induced hepatotoxicity.MethodsC57BL/6 mice were overdosed with 300 mg/kg body weight acetaminophen followed by analysis of the expression and localization of connexins as well as monitoring of hepatic gap junction functionality. Furthermore, acetaminophen-induced liver injury was compared between mice genetically deficient in connexin43 and wild type littermates. Evaluation of the toxicological response was based on a set of clinically relevant parameters, including protein adduct formation, measurement of alanine aminotransferase activity, cytokines and glutathione.ResultsIt was found that gap junction communication deteriorates upon acetaminophen intoxication in wild type mice, which is associated with a switch in mRNA and protein production from connexin32 and connexin26 to connexin43. The upregulation of connexin43 expression is due, at least in part, to de novo production by hepatocytes. Connexin43-deficient animals tended to show increased liver cell death, inflammation and oxidative stress in comparison with wild type counterparts.ConclusionThese results suggest that hepatic connexin43-based signaling may protect against acetaminophen-induced liver toxicity.

AB - Background and aimsBeing goalkeepers of liver homeostasis, gap junctions are also involved in hepatotoxicity. However, their role in this process is ambiguous, as gap junctions can act as both targets and effectors of liver toxicity. This particularly holds true for drug-induced liver insults. In the present study, the involvement of connexin 26, connexin32 and connexin43, the building blocks of liver gap junctions, was investigated in acetaminophen-induced hepatotoxicity.MethodsC57BL/6 mice were overdosed with 300 mg/kg body weight acetaminophen followed by analysis of the expression and localization of connexins as well as monitoring of hepatic gap junction functionality. Furthermore, acetaminophen-induced liver injury was compared between mice genetically deficient in connexin43 and wild type littermates. Evaluation of the toxicological response was based on a set of clinically relevant parameters, including protein adduct formation, measurement of alanine aminotransferase activity, cytokines and glutathione.ResultsIt was found that gap junction communication deteriorates upon acetaminophen intoxication in wild type mice, which is associated with a switch in mRNA and protein production from connexin32 and connexin26 to connexin43. The upregulation of connexin43 expression is due, at least in part, to de novo production by hepatocytes. Connexin43-deficient animals tended to show increased liver cell death, inflammation and oxidative stress in comparison with wild type counterparts.ConclusionThese results suggest that hepatic connexin43-based signaling may protect against acetaminophen-induced liver toxicity.

KW - connexin

KW - acetaminophen

KW - hepatotoxicity

U2 - 10.1016/j.bbadis.2016.02.007

DO - 10.1016/j.bbadis.2016.02.007

M3 - Article

VL - 1862

SP - 1111

EP - 1121

JO - Biochimica et Biophysica Acta - Molecular Basis of Disease

JF - Biochimica et Biophysica Acta - Molecular Basis of Disease

SN - 0925-4439

IS - 6

ER -

Involvement of connexin43 in acetaminophen-induced liver injury

Abstract

Keywords

Access to Document

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Projects

OZR2651: International Joint Research Group - Liver Connexin and Pannexin Research Group (LCPR)

OZR2813: Bilaterale samenwerking ikv gemeenschappelijke doctoraatsproject: Bench Fee voor Joint PhD VUB-Universidade de Sao Paulo, Michael Maes

EU457: CONNECT: Connexin and pannexin channels as drug targets and biomarkers in acute and chronic liver disease

Research output

Connexins and pannexins in liver damage

Experimental models of hepatotoxicity related to acute liver failure

Connexin and pannexin signaling in gastrointestinal and liver disease

Prizes

Protective effects of connexin43 signaling against experimentally induced acute liver failure in mouse.

Cite this