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ZnT8 Deficiency Protects From APAP-Induced Acute Liver Injury by Reducing Oxidative Stress Through Upregulating Hepatic Zinc and Metallothioneins

Zinc transporter 8 (ZnT8) is an important zinc transporter highly expressed in pancreatic islets. Deficiency of ZnT8 leads to a marked decrease in islet zinc, which is thought to prevent liver diseases associated with oxidative stress. Herein, we aimed to investigate whether loss of islet zinc affec...

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Autores principales: Su, Wen, Feng, Mingji, Liu, Yuan, Cao, Rong, Liu, Yiao, Tang, Junyao, Pan, Ke, Lan, Rongfeng, Mao, Zhuo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369884/
https://www.ncbi.nlm.nih.gov/pubmed/34413780
http://dx.doi.org/10.3389/fphar.2021.721471
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author Su, Wen
Feng, Mingji
Liu, Yuan
Cao, Rong
Liu, Yiao
Tang, Junyao
Pan, Ke
Lan, Rongfeng
Mao, Zhuo
author_facet Su, Wen
Feng, Mingji
Liu, Yuan
Cao, Rong
Liu, Yiao
Tang, Junyao
Pan, Ke
Lan, Rongfeng
Mao, Zhuo
author_sort Su, Wen
collection PubMed
description Zinc transporter 8 (ZnT8) is an important zinc transporter highly expressed in pancreatic islets. Deficiency of ZnT8 leads to a marked decrease in islet zinc, which is thought to prevent liver diseases associated with oxidative stress. Herein, we aimed to investigate whether loss of islet zinc affects the antioxidant capacity of the liver and acute drug-induced liver injury. To address this question, we treated ZnT8 knockout (KO) or wild-type control mice with 300 mg/ kg acetaminophen (APAP) or phosphate-buffered saline (PBS). Unexpectedly, we found that loss of ZnT8 in mice ameliorated APAP-induced injury and was accompanied by inhibition of c-Jun N-terminal kinase (JNK) activation, reduced hepatocyte death, and decreased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). An increase in hepatic glutathione (GSH) was observed, corresponding to a decrease in malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels. APAP-induced inflammation and glycogen depletion were alleviated. In contrast, no significant changes were observed in cytochrome P450 family 2 subfamily E member 1 (CYP2E1), the main enzyme responsible for drug metabolism. Elevated levels of hepatic zinc and metallothionein (MT) were also observed, which may contribute to the hepatoprotective effect in ZnT8 KO mice. Taken together, these results suggest that ZnT8 deficiency protects the liver from APAP toxicity by attenuating oxidative stress and promoting hepatocyte proliferation. This study provides new insights into the functions of ZnT8 and zinc as key mediators linking pancreatic and hepatic functions.
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spelling pubmed-83698842021-08-18 ZnT8 Deficiency Protects From APAP-Induced Acute Liver Injury by Reducing Oxidative Stress Through Upregulating Hepatic Zinc and Metallothioneins Su, Wen Feng, Mingji Liu, Yuan Cao, Rong Liu, Yiao Tang, Junyao Pan, Ke Lan, Rongfeng Mao, Zhuo Front Pharmacol Pharmacology Zinc transporter 8 (ZnT8) is an important zinc transporter highly expressed in pancreatic islets. Deficiency of ZnT8 leads to a marked decrease in islet zinc, which is thought to prevent liver diseases associated with oxidative stress. Herein, we aimed to investigate whether loss of islet zinc affects the antioxidant capacity of the liver and acute drug-induced liver injury. To address this question, we treated ZnT8 knockout (KO) or wild-type control mice with 300 mg/ kg acetaminophen (APAP) or phosphate-buffered saline (PBS). Unexpectedly, we found that loss of ZnT8 in mice ameliorated APAP-induced injury and was accompanied by inhibition of c-Jun N-terminal kinase (JNK) activation, reduced hepatocyte death, and decreased serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST). An increase in hepatic glutathione (GSH) was observed, corresponding to a decrease in malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels. APAP-induced inflammation and glycogen depletion were alleviated. In contrast, no significant changes were observed in cytochrome P450 family 2 subfamily E member 1 (CYP2E1), the main enzyme responsible for drug metabolism. Elevated levels of hepatic zinc and metallothionein (MT) were also observed, which may contribute to the hepatoprotective effect in ZnT8 KO mice. Taken together, these results suggest that ZnT8 deficiency protects the liver from APAP toxicity by attenuating oxidative stress and promoting hepatocyte proliferation. This study provides new insights into the functions of ZnT8 and zinc as key mediators linking pancreatic and hepatic functions. Frontiers Media S.A. 2021-08-03 /pmc/articles/PMC8369884/ /pubmed/34413780 http://dx.doi.org/10.3389/fphar.2021.721471 Text en Copyright © 2021 Su, Feng, Liu, Cao, Liu, Tang, Pan, Lan and Mao. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Su, Wen
Feng, Mingji
Liu, Yuan
Cao, Rong
Liu, Yiao
Tang, Junyao
Pan, Ke
Lan, Rongfeng
Mao, Zhuo
ZnT8 Deficiency Protects From APAP-Induced Acute Liver Injury by Reducing Oxidative Stress Through Upregulating Hepatic Zinc and Metallothioneins
title ZnT8 Deficiency Protects From APAP-Induced Acute Liver Injury by Reducing Oxidative Stress Through Upregulating Hepatic Zinc and Metallothioneins
title_full ZnT8 Deficiency Protects From APAP-Induced Acute Liver Injury by Reducing Oxidative Stress Through Upregulating Hepatic Zinc and Metallothioneins
title_fullStr ZnT8 Deficiency Protects From APAP-Induced Acute Liver Injury by Reducing Oxidative Stress Through Upregulating Hepatic Zinc and Metallothioneins
title_full_unstemmed ZnT8 Deficiency Protects From APAP-Induced Acute Liver Injury by Reducing Oxidative Stress Through Upregulating Hepatic Zinc and Metallothioneins
title_short ZnT8 Deficiency Protects From APAP-Induced Acute Liver Injury by Reducing Oxidative Stress Through Upregulating Hepatic Zinc and Metallothioneins
title_sort znt8 deficiency protects from apap-induced acute liver injury by reducing oxidative stress through upregulating hepatic zinc and metallothioneins
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369884/
https://www.ncbi.nlm.nih.gov/pubmed/34413780
http://dx.doi.org/10.3389/fphar.2021.721471
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