Fructose Protects Murine Hepatocytes from Tumor Necrosis Factor-induced Apoptosis by Modulating JNK Signaling

Speicher, Tobias; Köhler, Ulrike A.; Choukèr, Alexander; Werner, Sabine; Weiland, Timo; Wendel, Albrecht

doi:10.1074/jbc.m111.266742

Cited by 8 publications

(6 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this study, the gene expression levels of PGC-1α and FoxO1 immediately increased after fructose, but not glucose, administration. It has been previously reported that fructose activates the cAMP-PKA signaling pathway through reduction of hepatic intracellular ATP concentration, which further activates CREB [ 44 ]. The CREB pathway might be involved in the increase of FoxO1 and PGC-1α expression after fructose administration, suggesting that fructose intake regulates the gene expression levels of the gluconeogenic genes through both AKT-FoxO1 and CREB pathway.…”

Section: Discussionmentioning

confidence: 99%

Acute fructose intake suppresses fasting-induced hepatic gluconeogenesis through the AKT-FoxO1 pathway

Watanabe

Nishimura

Inoue

et al. 2019

Biochemistry and Biophysics Reports

View full text Add to dashboard Cite

Excessive intake of fructose increases lipogenesis in the liver, leading to hepatic lipid accumulation and development of fatty liver disease. Metabolic alterations in the liver due to fructose intake have been reported in many studies, but the effect of fructose administration on hepatic gluconeogenesis is not fully understood. The aim of this study was to evaluate the acute effects of fructose administration on fasting-induced hepatic gluconeogenesis. C57BL/6J mice were administered fructose solution after 14 h of fasting and plasma insulin, glucose, free fatty acids, and ketone bodies were analysed. We also measured phosphorylated AKT and forkhead box O (FoxO) 1 protein levels and gene expression related to gluconeogenesis in the liver. Furthermore, we measured glucose production from pyruvate after fructose administration. Glucose-administered mice were used as controls. Fructose administration enhanced phosphorylation of AKT in the liver, without increase of blood insulin levels. Blood free fatty acids and ketone bodies concentrations were as high as those in the fasting group after fructose administration, suggesting that insulin-induced inhibition of lipolysis did not occur in mice administered with fructose. Fructose also enhanced phosphorylation of FoxO1 and suppressed gluconeogenic gene expression, glucose-6-phosphatase activity, and glucose production from pyruvate. The present study suggests that acute fructose administration suppresses fasting-induced hepatic gluconeogenesis in an insulin-independent manner.

show abstract

Section: Discussionmentioning

confidence: 99%

Acute fructose intake suppresses fasting-induced hepatic gluconeogenesis through the AKT-FoxO1 pathway

Watanabe

Nishimura

Inoue

et al. 2019

Biochemistry and Biophysics Reports

View full text Add to dashboard Cite

show abstract

“…Here we found that IFNβ produced by LPS‐stimulated HSCs causes apoptosis of hepatocytes. LPS/HSC as well as IFNβ activated JNK, an established signaling pathway of hepatocyte apoptosis (Ding and Yin, ; Gunawan et al, ; Ni et al, ; Speicher et al, ). Interestingly, anti‐IFNβ Ab prevented JNK1 activation but strongly increased JNK2 activation beyond that by LPS/HSC.…”

Section: Discussionmentioning

confidence: 99%

Endotoxin‐stimulated Rat Hepatic Stellate Cells Induce Autophagy in Hepatocytes as a Survival Mechanism

Dangi

Huang

Tandon

et al. 2015

Journal Cellular Physiology

View full text Add to dashboard Cite

Bacterial lipopolysaccharide (LPS)-stimulated hepatic stellate cells (HSCs) produce many cytokines including IFNβ, TNFα, and IL6, strongly inhibit DNA synthesis, but induce apoptosis of a small number of hepatocytes. In vivo administration of LPS (up to 10 mg/mL) causes modest inflammation and weight loss in rats but not mortality. We determined whether LPS-stimulated HSCs instigate mechanisms of hepatocyte survival. Rats received 10 mg/kg LPS (i.p.) and determinations were made at 6 h. In vitro, HSCs were treated with 100 ng/mL LPS till 24 h. The medium was transferred to hepatocytes, and determinations were made at 0–12 h. Controls were HSC-conditioned medium or medium-containing LPS. LPS treatment of rats caused autophagy in hepatocytes, a physiological process for clearance of undesirable material including injured or damaged organelles. This was accompanied by activation of c-Jun NH2 terminal kinase (JNK) and apoptosis of ~4–5% of hepatocytes. In vitro, LPS-conditioned HSC medium (LPS/HSC) induced autophagy in hepatocytes but apoptosis of only ~10% of hepatocytes. While LPS/HSC stimulated activation of JNK (associated with cell death), it also activated NFkB and ERK1/2 (associated with cell survival). LPS-stimulated HSCs produced IFNβ, and LPS/HSC-induced autophagy in hepatocytes and their apoptosis were significantly inhibited by anti-IFNβ antibody. Blockade of autophagy, on the other hand, strongly augmented hepatocyte apoptosis. While LPS-stimulated HSCs cause apoptosis of a subpopulation of hepatocytes by producing IFNβ, they also induce cell survival mechanisms, which may be of critical importance in resistance to liver injury during endotoxemia.

show abstract

“…9,20 As shown in Figure 3b, serum transaminase activities in TNF-α/ActD mice were reduced upon galactose treatment via oral administration, while i.v. injection led to reduction of ALT and LDH activities, but not AST.…”

Section: The Protective Effect Of Galactose Is Not Attributed To Compmentioning

confidence: 98%

“…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.…”

mentioning

confidence: 99%

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

View full text Add to dashboard Cite

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...

show abstract

Fructose Protects Murine Hepatocytes from Tumor Necrosis Factor-induced Apoptosis by Modulating JNK Signaling

Cited by 8 publications

References 21 publications

Acute fructose intake suppresses fasting-induced hepatic gluconeogenesis through the AKT-FoxO1 pathway

Acute fructose intake suppresses fasting-induced hepatic gluconeogenesis through the AKT-FoxO1 pathway

Endotoxin‐stimulated Rat Hepatic Stellate Cells Induce Autophagy in Hepatocytes as a Survival Mechanism

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

Contact Info

Product

Resources

About