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.

Suppression of hepatic ChREBP⍺-CYP2C50 axis-driven fatty acid oxidation sensitizes mice to diet-induced MASLD/MASH

“…Even though acute knockdown of liver Chrebpα using adenoviral transduction in db/db mice results in improved insulin sensitivity, glucose metabolism, and liver steatosis [ 37 ], the pathogenic role of hepatocyte ChREBP⍺ in diet-induced MAFLD/MASH remains unclear. To examine how hepatocyte Chrebp⍺ deficiency in adult mice impacts the onset and progression of this disease, we took advantage of AAV to generate adult-onset hepatocyte-specific Chrebp⍺ knockout ( Chrebp⍺-LKO ) mice [ 56 ]. This approach allowed us to bypass any developmental defects due to the loss of hepatocyte ChREBP⍺.…”

Fructose as a novel nutraceutical for acetaminophen (APAP)-induced hepatotoxicity

“…We further revealed that prompt fructose intake after APAP overdose could significantly mitigate liver damage through the activation of the ChREBP-FGF21 axis [53] . Based on literature and our report [52,53] , we propose that fructose could be utilized as a novel detoxification agent for drug-induced liver damage.…”

“…The mean fructose consumption in the United States is 54.7g/day, with the primary intake being from sugar-sweetened beverages [50] . Although fructose intake can promote de novo lipogenesis and cause insulin resistance, a prelude to diabetes, non-alcoholic fatty liver disease (NAFLD), and obesity, recent studies have highlighted fructose as a potential antidote against APAP-induced hepatotoxicity [51,52] . Our own study also found that fructose ingestion could ameliorate APAP-induced hepatotoxicity.…”

Recent progress in understanding mitokines as diagnostic and therapeutic targets in hepatocellular carcinoma

“…FGF21 forms a stable FGF21/KLB/FGFR complex via β-Klotho (KLB) and FGF receptor (FGFR) to activate downstream related signaling molecules, exerting biological effects and fulfilling corresponding specific functions. The binding of KLB to FGFR4 induces apoptosis and inhibits tumor cell proliferation[ 59 , 60 ]. As the concentration of FGF21 increases, KLB mRNA expression increases, and KLB protein content also increases in a consistent manner.…”