Hypothermia Advocates Functional Mitochondria and Alleviates Oxidative Stress to Combat Acetaminophen-Induced Hepatotoxicity.

Yeong Lan Tan,Han Kiat Ho

doi:10.3390/cells9112354

Abstract

For years, moderate hypothermia (32 °C) has been proposed as an unorthodox therapy for liver injuries, with proven hepatoprotective potential. Yet, limited mechanistic understanding has largely denied its acceptance over conventional pharmaceuticals for hepatoprotection. Today, facing a high prevalence of acetaminophen-induced liver injury (AILI) which accounts for the highest incidence of acute liver failure, hypothermia was evaluated as a potential therapy to combat AILI. For which, transforming growth factor-α transgenic mouse hepatocytes (TAMH) were subjected to concomitant 5 mM acetaminophen toxicity and moderate hypothermic conditioning for 24 h. Thereafter, its impact on mitophagy, mitochondrial biogenesis, glutathione homeostasis and c-Jun N-terminal kinase (JNK) signaling pathways were investigated. In the presence of AILI, hypothermia displayed simultaneous mitophagy and mitochondrial biogenesis to conserve functional mitochondria. Furthermore, antioxidant response was apparent with higher glutathione recycling and repressed JNK activation. These effects were, however, unremarkable with hypothermia alone without liver injury. This may suggest an adaptive response of hypothermia only to the injured sites, rendering it favorable as a potential targeted therapy. In fact, its cytoprotective effects were displayed in other DILI of similar pathology as acetaminophen i.e., valproate- and diclofenac-induced liver injury and this further corroborates the mechanistic findings of hypothermic actions on AILI.

Highlights

The discovery of acetaminophen (APAP), as an analgesic and antipyretic agent, can be dated back to the 1960s [1]
With moderate hypothermia, an increase in microtubule-associated proteins 1A/1B light chain 3B (LC3B)-II/β-actin ratio was observed in the presence of CQ, a lysosomal inhibitor, denoting the presence of autophagy (Figure 1A)
Aside from mitochondrial study, we further explored the changes in the hepatic GSH content in in vitro following hypothermia and APAP toxicity in transgenic mouse hepatocytes (TAMH)

Summary

Introduction

The discovery of acetaminophen (APAP), as an analgesic and antipyretic agent, can be dated back to the 1960s [1]. APAP-induced liver injury (AILI), among other pharmaceuticals, has engendered the highest incidence of acute liver failure (ALF) in Western countries [3]. With an alarming mortality rate of close to 50% [4], coupled with limited treatment options [5], the distressing notion of ALF has driven countless research on AILI over the years to uncover mechanistic insights and discover novel effective management strategies. The broad understanding on the toxico-pathological mechanism of AILI involves two key aspects—mitochondrial dysfunction and oxidative stress. These cellular perturbations are initiated by an accumulation of the reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), following the

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