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Fructose Protects Against Acetaminophen-Induced Hepatotoxicity Mainly by Activating the Carbohydrate-Response Element-Binding Protein α-Fibroblast Growth Factor 21 Axis in Mice.

ABSTRACT: Acetaminophen (N-acetyl-para-aminophenol [APAP]) overdose is the most common cause of drug-induced liver injury in the Western world and has limited therapeutic options. As an important dietary component intake, fructose is mainly metabolized in liver, but its impact on APAP-induced liver injury is not well established. We aimed to examine whether fructose supplementation could protect against APAP-induced hepatotoxicity and to determine potential fructose-sensitive intracellular mediators. We found that both high-fructose diet feeding before APAP injection and fructose gavage after APAP injection reduced APAP-induced liver injury with a concomitant induction of the hepatic carbohydrate-response element-binding protein α (ChREBPα)-fibroblast growth factor 21 (FGF21) pathway. In contrast, Chrebpα liver-specific-knockout (Chrebpα-LKO) mice failed to respond to fructose following APAP overdose, suggesting that ChREBPα is the essential intracellular mediator of fructose-induced hepatoprotective action. Primary mouse hepatocytes with deletion of Fgf21 also failed to show fructose protection against APAP hepatotoxicity. Furthermore, overexpression of FGF21 in the liver was sufficient to reverse liver toxicity in APAP-injected Chrebpα-LKO mice. Conclusion: Fructose protects against APAP-induced hepatotoxicity likely through its ability to activate the hepatocyte ChREBPα-FGF21 axis.

SUBMITTER: Zhang D

PROVIDER: S-EPMC8183176 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Fructose Protects Against Acetaminophen-Induced Hepatotoxicity Mainly by Activating the Carbohydrate-Response Element-Binding Protein α-Fibroblast Growth Factor 21 Axis in Mice.

Zhang Deqiang D Wang Sujuan S Ospina Erin E Shabandri Omar O Lank Daniel D Akakpo Jephte Y JY Zhao Zifeng Z Yang Meichan M Wu Jun J Jaeschke Hartmut H Saha Pradip P Tong Xin X Yin Lei L

Hepatology communications 20210223 6

Acetaminophen (N-acetyl-para-aminophenol [APAP]) overdose is the most common cause of drug-induced liver injury in the Western world and has limited therapeutic options. As an important dietary component intake, fructose is mainly metabolized in liver, but its impact on APAP-induced liver injury is not well established. We aimed to examine whether fructose supplementation could protect against APAP-induced hepatotoxicity and to determine potential fructose-sensitive intracellular mediators. We f ...[more]

PMID: 34141985

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Project description:Acetaminophen (APAP) is one of the most popular and safe pain medications worldwide. However, due to its wide availability, it is frequently implicated in intentional or unintentional overdoses where it can cause severe liver injury and even acute liver failure (ALF). In fact, APAP toxicity is responsible for 46% of all ALF cases in the United States. Early mechanistic studies in mice demonstrated the formation of a reactive metabolite, which is responsible for hepatic glutathione depletion and initiation of the toxicity. This insight led to the rapid introduction of N-acetylcysteine as a clinical antidote. However, more recently, substantial progress was made in further elucidating the detailed mechanisms of APAP-induced cell death. Mitochondrial protein adducts trigger a mitochondrial oxidant stress, which requires amplification through a MAPK cascade that ultimately results in activation of c-jun N-terminal kinase (JNK) in the cytosol and translocation of phospho-JNK to the mitochondria. The enhanced oxidant stress is responsible for the membrane permeability transition pore opening and the membrane potential breakdown. The ensuing matrix swelling causes the release of intermembrane proteins such as endonuclease G, which translocate to the nucleus and induce DNA fragmentation. These pathophysiological signaling mechanisms can be additionally modulated by removing damaged mitochondria by autophagy and replacing them by mitochondrial biogenesis. Importantly, most of the mechanisms have been confirmed in human hepatocytes and indirectly through biomarkers in plasma of APAP overdose patients. The extensive necrosis caused by APAP overdose leads to a sterile inflammatory response. Although recruitment of inflammatory cells is necessary for removal of cell debris in preparation for regeneration, these cells have the potential to aggravate the injury. This review touches on the newest insight into the intracellular mechanisms of APAP-induced cells death and the resulting inflammatory response. Furthermore, it discusses the translation of these findings to humans and the emergence of new therapeutic interventions.

Dataset Information

Fructose Protects Against Acetaminophen-Induced Hepatotoxicity Mainly by Activating the Carbohydrate-Response Element-Binding Protein α-Fibroblast Growth Factor 21 Axis in Mice.

Publications

Fructose Protects Against Acetaminophen-Induced Hepatotoxicity Mainly by Activating the Carbohydrate-Response Element-Binding Protein α-Fibroblast Growth Factor 21 Axis in Mice.

Similar Datasets

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