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

Abstract

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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