Fructose Protects Against Acetaminophen-Induced Hepatotoxicity Mainly by Activating the Carbohydrate-Response Element-Binding Protein α-Fibroblast Growth Factor 21 Axis in Mice.
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ABSTRACT:
SUBMITTER: Zhang D
PROVIDER: S-EPMC8183176 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Acetaminophen (APAP) is a commonly used analgesic and antipyretic that can cause hepatotoxicity due to production of toxic metabolites via cytochrome P450 (Cyp) 1a2 and Cyp2e1. Previous studies have shown conflicting effects of fructose (the major component in Western diet) on the susceptibility to APAP-induced hepatotoxicity. To evaluate the role of fructose-supplemented diet in modulating the extent of APAP-induced liver injury, male C57BL/6J mice were given 30% (w/v) fructose in water (or regular water) for 8 weeks, followed by oral administration of APAP. APAP-induced liver injury (determined by serum levels of liver enzymes) was decreased by two-fold in mice pretreated with fructose. Fructose-treated mice exhibited (~1.5 fold) higher basal glutathione levels and (~2 fold) lower basal (mRNA and activity) levels of Cyp1a2 and Cyp2e1, suggesting decreased bioactivation of APAP and increased detoxification of toxic metabolite in fructose-fed mice. Hepatic mRNA expression of heat shock protein 70 was also found increased in fructose-fed mice. Analysis of bacterial 16S rRNA gene amplicons from the cecal samples of vehicle groups showed that the fructose diet altered gut bacterial community, leading to increased ?-diversity. The abundance of several bacterial taxa including the genus Anaerostipes was found to be significantly correlated with the levels of hepatic Cyp2e1, Cyp1a2 mRNA, and glutathione. Together, these results suggest that the fructose-supplemented diet decreases APAP-induced liver injury in mice, in part by reducing metabolic activation of APAP and inducing detoxification of toxic metabolites, potentially through altered composition of gut microbiota.
| S-EPMC5568217 | biostudies-literature
Project description:Acetaminophen (APAP) is a widely used analgesic and antipyretic drug, but its overdose can cause acute liver failure. The dosage-sensitive sex reversal adrenal hypoplasia congenita critical region on the X chromosome, gene 1 (DAX-1, NR0B1), is an orphan nuclear receptor that acts as a transcriptional co-repressor of various genes. In this study, we identified the role of DAX-1 in APAP-induced liver injury using hepatocyte-specific Dax-1 knockout (Dax-1 LKO) mice. Mouse primary hepatocytes were used as a comparative in vitro study. APAP overdose led to decreased plasma alanine aminotransferase and aspartate aminotransferase levels in Dax-1 LKO mice compared to C57BL/6J (WT) controls, accompanied by reduced liver necrosis. The expression of the genes encoding the enzymes catalyzing glutathione (GSH) synthesis and metabolism and antioxidant enzymes was increased in the livers of APAP-treated Dax-1 LKO mice. The rapid recovery of GSH levels in the mitochondrial fraction of APAP-treated Dax-1 LKO mice led to reduced reactive oxygen species levels, resulting in the inhibition of the prolonged JNK activation. The hepatocyte-specific DAX-1 deficiency increased the protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) compared with WT controls after APAP administration. These results indicate that DAX-1 deficiency in hepatocytes protects against APAP-induced liver injury by Nrf2-regulated antioxidant defense.
| S-EPMC9570285 | biostudies-literature
Project description:UNLABELLED:Autophagy can selectively remove damaged organelles, including mitochondria, and, in turn, protect against mitochondria-damage-induced cell death. Acetaminophen (APAP) overdose can cause liver injury in animals and humans by inducing mitochondria damage and subsequent necrosis in hepatocytes. Although many detrimental mechanisms have been reported to be responsible for APAP-induced hepatotoxicity, it is not known whether APAP can modulate autophagy to regulate hepatotoxicity in hepatocytes. To test the hypothesis that autophagy may play a critical protective role against APAP-induced hepatotoxicity, primary cultured mouse hepatocytes and green fluorescent protein/light chain 3 transgenic mice were treated with APAP. By using a series of morphological and biochemical autophagic flux assays, we found that APAP induced autophagy both in the in vivo mouse liver and in primary cultured hepatocytes. We also found that APAP treatment might suppress mammalian target of rapamycin in hepatocytes and that APAP-induced autophagy was suppressed by N-acetylcysteine, suggesting APAP mitochondrial protein binding and the subsequent production of reactive oxygen species may play an important role in APAP-induced autophagy. Pharmacological inhibition of autophagy by 3-methyladenine or chloroquine further exacerbated APAP-induced hepatotoxicity. In contrast, induction of autophagy by rapamycin inhibited APAP-induced hepatotoxicity. CONCLUSION:APAP overdose induces autophagy, which attenuates APAP-induced liver cell death by removing damaged mitochondria.
| S-EPMC3245329 | biostudies-literature
Project description:Acetaminophen (N-acetyl-para-aminophenol (APAP)) toxicity causes acute liver failure by inducing centrilobular hepatic damage as a consequence of mitochondrial oxidative stress. Sterile inflammation, triggered by hepatic damage, facilitates gut bacterial translocation leading to systemic inflammation; TLR4-mediated activation by LPS has been shown to have a critical role in APAP-mediated hepatotoxicity. In this study, we demonstrate significant protection mediated by chitohexaose (Chtx) in mice challenged with a lethal dose of APAP (400 mg/kg b.w.). Decreased mortality by Chtx was associated with reduced hepatic damage, increased peritoneal migration of neutrophils, decreased mRNA expression of IL-1β as well as inhibition of inflammasome activation in liver. Further, an alternate mouse model of co-administration of a sublethal doses of APAP (200 mg/kg b.w.) and LPS (5 mg/kg b.w.) operating synergistically and mediating complete mortality was developed. Overwhelming inflammation, characterized by increased inflammatory cytokines (TNF-α, IL-1β and so on) in liver as well as in circulation and mortality was demonstrable in this model. Also, Chtx administration mediated significant reversal of mortality in APAP+LPS co-administered mice, which was associated with reduced IL-1β in liver and plasma cytokines in this model. In conclusion, Chtx being a small molecular weight linear carbohydrate offers promise for clinical management of liver failure associated with APAP overdose.
| S-EPMC4917664 | biostudies-literature
Project description:Kupffer cells (KCs) play a key part in the pathological process of acetaminophen (APAP)-induced acute liver injury (ALI), the leading cause of acute liver failure in the world. CXC motif chemokine ligand 5 (CXCL5) exerts proinflammatory effects in acute respiratory distress syndrome and arthritis. In the current study, we aim to reveal the effects of CXCL5 on the activation of KCs and the role of CXCL5 in the pathogenesis of APAP-induced hepatotoxicity. The in vivo study, conducted on mice intraperitoneally injected with APAP (300 mg/kg) to establish the ALI model and then treated with Anti-CXCL5 mAb at 30 min and 12 h after the APAP challenge, showed that CXCL5 expression significantly increased in injured livers, and Anti-CXCL5 mAb mitigated the degree of APAP-evoked ALI in mice which was proven through biochemicals and histological examination. Also, neutralization of CXCL5 had no significant effect on APAP metabolism in the liver but exhibited anti-inflammatory effects and ameliorated hepatocellular death in the injured liver. The in vitro data displayed that recombinant mouse CXCL5 treatment promoted APAP-induced cellular toxicity in primary hepatocytes co-cultured with KCs, compared with single-cultured hepatocytes. Consistent with the result, we found that the Anti-CXCL5 mAb gradient decreased LPS-induced expression of inflammatory cytokines in single-cultured KCs. Therefore, CXCL5 could stimulate KCs to produce inflammatory mediators, therefore damaging hepatocytes from APAP toxicity.
| S-EPMC10419303 | biostudies-literature
Project description:Acetaminophen (APAP) hepatotoxicity is characterized by an extensive mitochondrial oxidant stress. However, its importance as a drug target has not been clarified. To investigate this, fasted C57BL/6J mice were treated with 300 mg/kg APAP and the mitochondria-targeted antioxidant Mito-Tempo (MT) was given 1.5 h later. APAP caused severe liver injury in mice, as indicated by the increase in plasma ALT activities and centrilobular necrosis. MT dose-dependently reduced the injury. Importantly, MT did not affect APAP-protein adducts formation, glutathione depletion or c-jun N-terminal kinase activation and its mitochondrial translocation. In contrast, hepatic glutathione disulfide and peroxynitrite formation were dose-dependently reduced by MT, indicating its effective mitochondrial oxidant stress scavenging capacity. Consequently, mitochondrial translocation of Bax and release of mitochondrial intermembrane proteins such as apoptosis-inducing factor were prevented, and nuclear DNA fragmentation was eliminated. To demonstrate the importance of mitochondria-specific antioxidant property of MT, we compared its efficacy with Tempo, which has the same pharmacological mode of action as MT but lacks the mitochondria targeting moiety. In contrast to the dramatic protection by MT, the same molar dose of Tempo did not significantly reduce APAP hepatotoxicity. In contrast, even a 3 h post-treatment with MT reduced 70 % of the injury, and the combination of MT with N-acetylcysteine (NAC) provided superior protection than NAC alone. We conclude that MT protects against APAP overdose in mice by attenuating the mitochondrial oxidant stress and preventing peroxynitrite formation and the subsequent mitochondrial dysfunction. MT is a promising therapeutic agent for APAP overdose patients.
| S-EPMC5033665 | biostudies-literature
Project description:To examine the effects of formononetin (FMN) on Acetaminophen (APAP)-induced liver injury in vitro and in vivo. Human non-tumor hepatic cells LO2 were pretreated with either vehicle or FMN (20, 40 ?M), for 6 h, followed by incubation with or without APAP (10 mM) for 24 h. In an in vivo assay, male BALB/c mice were randomly divided into four groups: (1) control group; (2) APAP group; (3) APAP + FMN (50 mg/Kg); (4) APAP + FMN (100 mg/Kg). The mice in the control and APAP groups were pre-treated with vehicle; the other two groups were pretreated daily with FMN (50, 100 mg/Kg) orally for 7 consecutive days. After the final treatment, acute liver injury was induced in all groups, except the control group, by intraperitoneal (i.p.) injection of 300 mg/Kg APAP. In LO2 cells, APAP exposure decreased the cell viability and glutathione (GSH) content, which were both greatly restored by FMN pretreatment. Overdose of APAP increased hepatic malondialdehyde (MDA) content, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) activity in experimental mice. Supplementation with 100 mg/Kg FMN significantly reduced APAP-induced elevated levels of MDA (1.97 ± 0.27 vs 0.55 ± 0.14 nmol/mg protein, p < 0.001), ALT (955.80 ± 209.40 vs 46.90 ± 20.40 IU/L, p < 0.001) and AST (1533.80 ± 244.80 vs 56.70 ± 28.80 IU/L, p < 0.001), and hepatic GSH level (5.54 ± 0.93 vs 8.91 ± 1.11 ?mol/mg protein, p < 0.001) was significantly increased. These results were further validated by histopathology and TdT-mediated biotin-dUTP nick-endlabeling (TUNEL) staining, pretreatment with 100 mg/Kg FMN significant decreased APAP-induced hepatocellular damage and cell apoptosis (36.55 ± 3.82 vs 2.58 ± 1.80%, p < 0.001). Concomitantly, FMN stimulated the expression of Nrf2 and antioxidant gene expression in the presence of APAP. These data provide an experimental basis for the use of FMN in the treatment of patients with APAP-induced hepatotoxicity.
| S-EPMC5325199 | biostudies-literature
Project description:The alleviation of oxidative stress is considered an effective treatment for acetaminophen (APAP)-induced acute liver injury (AILI). However, it remains unknow whether the potential antioxidant Smilax china L. polysaccharide (SCLP) protects against AILI. In this study, in vitro and in vivo experiments were conducted to verify the hepatoprotective effect of SCLP against AILI and explore the potential mechanism. We found that SCLP relieved liver histopathological changes; reversed the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA) and reactive oxygen species (ROS); reversed the change in liver myeloperoxidase (MPO) activity; and enhanced liver antioxidant (GSH, GSH-Px, and t-SOD) levels in APAP-treated mice, thereby significantly reducing APAP-induced liver toxicity. SCLP rescued the cell viability and alleviated oxidative stress in H2O2-treated mouse AML12 (Alpha mouse liver 12) hepatocytes. The results of the mechanistic studies showed that SCLP upregulated nuclear factor E2 related factor (Nrf2) expression, promoted Nrf2 nuclear translocation, and enhanced the ability of Nrf2 to bind antioxidant response elements (AREs). Furthermore, SCLP activated Nrf2-ARE pathway, thus upregulating the expression of oxidative stress-related proteins heme oxygenase 1(HO-1), NAD(P)H quinone dehydrogenase 1(NQO-1) and glutamic acid cysteine ligase catalytic subunit (GCLC). In conclusion, this study confirmed the close correlation between liver protection by SCLP upon exposure to APAP and activated of the Nrf2-ARE pathway. These findings suggest that SCLP is an attractive therapeutic candidate drug for the treatment of AILI.
| S-EPMC9098950 | biostudies-literature
Project description:ObjectiveFructose consumption is a risk factor for metabolic disease. We recently demonstrated that fibroblast growth factor 21 (FGF21), a metabolic hormone involved in lipid and glucose metabolism, is acutely stimulated in humans by 75 g oral fructose, with peak levels occurring 2 h after consumption. This study reports on the dose dependency and reproducibility of the FGF21 response to fructose.MethodsLean, healthy adults drank either five different doses of fructose dissolved in water, each separated by 2 weeks, or the same dose on three occasions, each separated by 1 week.ResultsFibroblast growth factor 21 levels peaked at 2 h in a dose-dependent manner. No significant increase in FGF21 was seen after consumption of 10 g fructose, while robust increases were seen after drinking solutions containing 30, 50 and 75 g. At 2 h, the minimal fold change of FGF21 was highest following a 75 g fructose drink, and all subjects demonstrated at least a doubling of FGF21 levels following consumption of this dose.ConclusionsThe increase in FGF21 following an oral fructose challenge is dose dependent, with levels peaking at 2 h independent of dose. The FGF21 response to 75 g fructose is also highly reproducible within individuals.Clinical implicationsBy demonstrating that the FGF21 response to fructose is dose dependent and reproducible, this study deepens current understanding of FGF21 fructose dynamics and physiology in humans. This is an important area of clinical interest given associations between fructose intake and a wide variety of metabolic derangements.
| S-EPMC6180711 | biostudies-literature
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.
| S-EPMC6800176 | biostudies-literature