Intestinal Glucose Uptake Protects Liver from Lipopolysaccharide and d-Galactosamine, Acetaminophen, and Alpha-Amanitin in Mice

Zanobbio, Laura; Palazzo, Marco; Gariboldi, Silvia; Dusio, Giuseppina; Cardani, Diego; Mauro, Valentina; Marcucci, Fabrizio; Balsari, Andrea; Rumio, Cristiano

doi:10.2353/ajpath.2009.090071

Cited by 12 publications

(13 citation statements)

References 36 publications

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“…Rumio et al 8 However, we observed no improvements in survival rate or pathologic damage (Figures 1a and c), even when glucose was injected 1 h before LPS/D-GalN administration, as described by Rumio et al 8 (Supplementary Figure 3). These inconsistent results may be attributed to the different survival periods of model mice.…”

supporting

confidence: 78%

“…31 In the present study, we observed short-term phosphorylation of ERK1/2 within 30 min after TNF-α stimulation, which peaked at 15 min, consistent with previous findings. 8 Although galactose enhanced phosphorylation of ERK1/2 slightly at 30 min, we speculate that this effect is abated. On the other hand, activity of NF-κB was significantly affected by galactose in hepatocytes.…”

Section: Discussionmentioning

confidence: 79%

“…Moreover, galactose enhanced NF-κB activity within 30 min of TNF-α injection, and subsequently, increased the expression of anti-apoptotic genes within 3 h. It is conceivable that galactose functions at the early stages after liver injury. However, mice died between 10 and 40 h after LPS/D-GalN challenge in the study of Rumio et al 8 In view of the finding that glucose prevents ALF via activation of sodium-dependent glucose transporter-1 (SGLT-1), which is induced 6 h after LPS stimulation, 8,32 we prefer the hypothesis that glucose acts at a later stage of liver injury.…”

mentioning

confidence: 99%

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Galactose protects hepatocytes against TNF-α-induced apoptosis by promoting activation of the NF-κB signaling pathway in acute liver failure

Liu

Zhu

Liang

et al. 2015

Laboratory Investigation

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Saccharides are reported to protect hepatocytes from acute liver injury through distinct mechanisms. To date, the protective role of galactose against acute liver injury induced by lipopolysaccharide (LPS) and D-galactosamine (D-GalN) has been attributed to competition with D-GalN. Here, we showed that in addition to its effects on LPS/D-GalN and tumor necrosis factor alpha (TNF-α)/D-GalN models, galactose improves hepatic injury in mice challenged with LPS alone or TNF-α/actinomycin D. Consistent with this result, galactose enhanced the viability of TNF-α-stimulated Chang Liver and Hu7.5 hepatic cell lines. Specifically, galactose prevented TNF-α-induced apoptosis of hepatocytes through promoting phosphorylation of nuclear factor kappa B (NF-κB) p65. Additionally, galactose enhanced expression of the anti-apoptotic genes, c-IAP1 and A20, and inhibited cleavage of caspase-8 and caspase-3. These findings collectively suggest that galactose prevents TNF-α-induced liver injury through activation of the NF-κB signaling pathway. Considering that monosaccharides protect against liver injury via distinct mechanisms, these compounds may represent a promising clinical approach to treat acute liver failure. Acute liver failure (ALF), defined as rapid onset of severe hepatic dysfunction with poor prognosis, is a serious problem in clinical practice. 1 A model of hepatic injury induced by lipopolysaccharide (LPS) and D-galactosamine (D-GalN) has been widely used to explore the mechanisms of ALF and screen for potential hepatoprotective drugs. 2 In this model, LPS triggers innate immune responses and induces TNF-α, which subsequently activates the pro-apoptotic caspase reaction directly or indirectly via mitogen-activated protein (MAP) kinases, including p38, JNK1/2 and ERK1/2, as well as an anti-apoptotic signal via the transcription factor nuclear factor kappa B (NF-κB). 3-5 D-GalN, which acts as a sensitizing agent, amplifies the toxicity of LPS and TNF-α to liver. 6 Since liver has a central role in human metabolism, ALF may cause metabolic defects and energy imbalance. 7 As the main source of energy, saccharides have an important role in maintaining hepatocyte survival and physiological processes.A recent study revealed that oral administration of glucose prevents endotoxin-and drug-induced liver failure by promoting secretion of IL-10 to repress liver inflammation in LPS/D-GalN and acetaminophen-treated mice. 8 Another monosaccharide, fructose, prevents TNF-α/ actinomycin D (ActD)-induced apoptosis of hepatocytes through inhibiting JNK signaling in a PKA-dependent manner. 9 Earlier studies have reported that galactose prevents LPS/DGalN-induced liver damage in mice. 10 A recent metabolic profiling study revealed a significant decrease in galactose in the plasma of LPS/D-GalN-treated mice. 7 For decades, the protective role of galactose has been attributed to competition with D-GalN. 11 However, recent evidence has challenged this notion. First, galactose and glucose share the same enzyme machinery for conversion to...

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supporting

confidence: 78%

Section: Discussionmentioning

confidence: 79%

mentioning

confidence: 99%

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Galactose protects hepatocytes against TNF-α-induced apoptosis by promoting activation of the NF-κB signaling pathway in acute liver failure

Liu

Zhu

Liang

et al. 2015

Laboratory Investigation

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“…LPS/D-Gal treatment is an established model of targeted LPS-dependent liver injury accompanied by a massive hepatic apoptosis and release of amino transferases ALT and AST [12,13]. As seen on figure 1, rat liver injury induced by injection of bacterial LPS only (Figure 1A) or LPS and D-Gal combination (Figure 1D) was accompanied by a fast rise of serum ASS levels.…”

Section: Discussionmentioning

confidence: 99%

ASS and SULT2A1 are Novel and Sensitive Biomarkers of Acute Hepatic Injury-A Comparative Study in Animal Models

Prima¹,

Cao²,

Svetlov³

2013

J Liver

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Liver and kidney damage associated with polytrauma, endotoxic shock/sepsis, and organ transplantation, are among the leading causes of the multiple organ failure. Development of novel sensitive biomarkers that detect early stages of liver and kidney injury is vital for the effective diagnostics and treatment of these life-threatening conditions. Previously, we identified several hepatic proteins, including Argininosuccinate Synthase (ASS) and sulfotransferases which were degraded in the liver and rapidly released into circulation during Ischemia/Reperfusion (I/R) injury. Here we compared sensitivity and specificity of the newly developed sandwich ELISA assays for ASS and the sulfotransferase isoform SULT2A1 with the standard clinical liver and kidney tests Alanine Aminotransferase (ALT) and Aspartate Transaminase (AST) in various pre-clinical models of acute injury. Our data suggest that ASS and SULT2A1 have superior characteristics for liver and kidney health assessment in endotoxemia, Ischemia/ Reperfusion (I/R), chemical and drug-induced liver injury and may be of high potential value for clinical applications.

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“…It is associated with high overall mortality, ranging from 30 to 80%, depending on the underlying etiology. 1 The commonest causes are acute viral hepatitis, drug overdose, idiosyncratic drug reactions, and ingestion of other toxin. 2 Liver transplantation is the only therapy that has been proven beneficial, but the rapidity of progression and the variable course of ALF limit its application.…”

mentioning

confidence: 99%

Adenosine 5′-monophosphate ameliorates D-galactosamine/lipopolysaccharide-induced liver injury through an adenosine receptor-independent mechanism in mice

et al. 2014

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D-galactosamine (GalN)/lipopolysaccharide (LPS)-induced lethality and acute liver failure is dependent on endogenously produced inflammatory cytokines. Adenosine has been proven to be a central role in the regulation of inflammatory response. It is not entirely clear that which adenosine action is actually crucial to limiting inflammatory tissue destruction. Here we showed that GalN/LPS challenge elevated hepatic adenosine and induced lethality in adenosine receptor-deficient mice with equal efficiency as wild-type mice. In GalN/LPS-treated mice, pretreatment with adenosine 5′-monophosphate (5′-AMP) significantly elevated hepatic adenosine level and reduced mortality through decreasing cytokine and chemokine production. In RAW264.7 cells, 5′-AMP treatment inhibited the production of inflammatory cytokines, which is not mediated through adenosine receptors. 5′-AMP failed to attenuate LPS-induced nuclear factor-κB (NF-κB) p65 nuclear translocation, but reduced LPS-induced recruitment of NF-κB p65 to inflammatory gene promoters and decreased LPS-induced enrichment of H3K4 dimethylation at the tumor necrosis factor-α (TNF-α) promoter, which was involved in 5′-AMP-induced elevation of cellular adenosine and a decline of methylation potential. In vitro biochemical analysis revealed that adenosine directly attenuated recruitment of NF-κB to the TNF-α and interleukin-6 promoters. Our findings demonstrate that 5′-AMP-inhibiting inflammatory response is not mediated by adenosine receptors and it may represent a potential protective agent for amelioration of LPS-induced liver injury.

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Intestinal Glucose Uptake Protects Liver from Lipopolysaccharide and d-Galactosamine, Acetaminophen, and Alpha-Amanitin in Mice

Cited by 12 publications

References 36 publications

Galactose protects hepatocytes against TNF-α-induced apoptosis by promoting activation of the NF-κB signaling pathway in acute liver failure

Galactose protects hepatocytes against TNF-α-induced apoptosis by promoting activation of the NF-κB signaling pathway in acute liver failure

ASS and SULT2A1 are Novel and Sensitive Biomarkers of Acute Hepatic Injury-A Comparative Study in Animal Models

Adenosine 5′-monophosphate ameliorates D-galactosamine/lipopolysaccharide-induced liver injury through an adenosine receptor-independent mechanism in mice

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