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

Wen Su,Mingji Feng,Junyao Tang,Yuan Liu,Rongfeng Lan,Ke Pan,Yiao Liu,Rong Cao,Zhuo Mao

doi:10.3389/fphar.2021.721471

Abstract

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.

Highlights

Zinc transporter 8 (ZnT8), encoded by the human SLC30A8 gene, is a zinc transporter closely associated with type 1 and type 2 diabetes (Barragán-Álvarez et al, 2021)
To investigate whether ZnT8 plays a role in drug-induced hepatotoxicity, we injected APAP intraperitoneally into ZnT8 KO and wild-type mice
Histological analysis showed that ZnT8 KO mice had less typical bridging necrosis within the centrilobular region and smaller areas of necrosis compared with wild-type controls (Figure 1C)

Summary

Introduction

Zinc transporter 8 (ZnT8), encoded by the human SLC30A8 gene, is a zinc transporter closely associated with type 1 and type 2 diabetes (Barragán-Álvarez et al, 2021). ZnT8 is expressed almost exclusively in pancreatic β cells and is responsible for the uptake of zinc ions into insulin granules. Zinc ions in the pancreas are co-secreted with insulin into the portal vein and the liver to assist in primary insulin. Previous studies in rodent models have shown that ZnT8 deficiency leads to a significant decrease in zinc levels in the pancreatic islets, resulting in degradation of insulin by the liver due to the lack of zinc (Tamaki et al, 2013). The pancreas is closely related to the liver in term of anatomy and function. We hypothesized that dysregulation of zinc homeostasis in ZnT8 knockout (KO) mice may contribute to altered liver function

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