Abstract
Increasing evidence suggests that NODs are involved in liver diseases; however, the underlying mechanisms remain obscure. In the present study, we analyzed the effect of NOD1 agonist pretreatment on acute liver failure induced by lipopolysaccharide (LPS) in D-galactosamine (D-GalN)-sensitized mice. We found that pretreatment with the NOD1 agonist markedly reduced LPS/D-GalN-induced mortality, elevation of serum ALT levels, and hepatocyte apoptosis. The protective effect of NOD1 agonist was independent of tumor necrosis factor (TNF)-α inhibition. NOD1 agonist pretreatment also attenuated TNF-α/D-GalN-induced apoptotic liver damage. The anti-apoptotic protein A20 expression was more pronounced in NOD1 agonist pretreated mice than in controls, and knockdown of A20 abrogated the protective effect of NOD1 agonist on LPS/D-GalN-induced liver injury and hepatocyte apoptosis. Further experiments showed that NOD1 agonist-induced A20 upregulation required the presence of kupffer cells and TNF-α. Taken together, our data strongly indicate that NOD1 is involved in the regulation of liver injury and could be a potential therapeutic target for liver diseases.
Highlights
Acute liver failure (ALF), caused by massive destruction of hepatocytes with resultant severe impairment of liver function, is a serious problem in clinical practice [1]
To investigate the effects of Nucleotide oligomerization domain receptor 1 (NOD1) agonist on LPS/D-GalN-induced liver injury, we treated the mice with C14-Tri-LAN-Gly (5 or 10 μg/mouse) 6 h before LPS/D-GalN challenge
Treatment of mice with LPS/D-GalN induces fulminant hepatitis, which is mediated by tumor necrosis factor (TNF)-α and characterized by massive hepatic apoptosis
Summary
Acute liver failure (ALF), caused by massive destruction of hepatocytes with resultant severe impairment of liver function, is a serious problem in clinical practice [1]. The LPS/D-GalN model has been widely used to explore the mechanisms of ALF and screen for potential hepatoprotective drugs [5, 6] In this model, LPS binds to and activates kupffer cells, resulting in a liberation of large amounts of proinflammatory cytokines, such as TNF-α, IL-1, and IL-6 [7]. TNF-α-induced hepatocyte apoptosis has been identified as an early and possibly causal event in LPS/D-GalN-induced acute liver failure [8,9,10]. Massive hepatocyte apoptosis induced by TNF-α was shown to be the central mechanism of liver damage in this model [11]. D-GalN, which induces a selective transcriptional block in hepatocytes, amplifies the toxicity of LPS and TNF-α to liver without damaging other organs or tissues [12]. Our data show that NOD1 agonist treatment prevented LPS/DGalN-induced fatal hepatitis through the upregulation of A20 expression in hepatocytes
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