title: S-Adenosylmethionine attenuates lipopolysaccharide-induced liver injury by downregulating the Toll-like receptor 4 signal in Kupffer cells.
abstract: OBJECTIVE
  S-Adenosylmethionine (SAM) is beneficial for lipopolysaccharide (LPS)-induced liver injury, but its molecular basis is not fully understood. The present study was carried out to investigate the effects of SAM on LPS signal transduction and its possible mechanism.
  
  
  METHODS
  An animal model of LPS-induced liver injury was established by intraperitoneally injecting mice with 10 mg/kg LPS pretreatment with or without SAM (170 μmol/kg body weight). Toll-like receptor 4 (TLR4) protein expression in liver tissues and the tumor necrosis factor alpha (TNF-α) secretion level in serum were detected by immunohistochemistry and enzyme-linked immunosorbent assay, respectively. Then, Kupffer cells (KCs) were isolated and challenged with LPS, with or without SAM pretreatment (1,000 μM), and the expressions of TLR4 and myeloid differentiation primary response protein (MYD88) were assayed at the mRNA and protein levels. The activities of nuclear factor-kappa B (NF-κB) and p38 mitogen-activated protein kinase (MAPK) were also analyzed using Western blotting.
  
  
  RESULTS
  SAM significantly improved the survival rate of endotoxemic mice (p < 0.05) and decreased TNF-α levels in serum (p < 0.05). Simultaneously, SAM also attenuated LPS-induced liver injury and expression of TLR4 and MYD88 in the hepatic sinusoid. Moreover, TLR4 and MYD88 gene and protein expressions were downregulated by SAM pretreatment in LPS-stimulated KCs. Finally, SAM did not affect NF-κB-p65 translocation into the nucleus (p > 0.05), but significantly inhibited p38 MAPK activation (p < 0.05).
  
  
  CONCLUSIONS
  SAM attenuated liver injury and improved the survival rate in endotoxemic mice by decreasing the TNF-α expression. The downregulative effect of SAM on TNF-α was mediated by suppressing activation of the TLR4/MAPK signaling pathway.
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, 74# Linjiang Road, Chongqing, 400010, China. lipeizhi@163.com.
authors.forename: Peizhi
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, 74# Linjiang Road, Chongqing, 400010, China. djxiaosen@sohu.com.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, 74# Linjiang Road, Chongqing, 400010, China. gongjianping11@126.com.
authors.forename: Jianping
authors.initials: J
authors.lastname: Gong
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, 74# Linjiang Road, Chongqing, 400010, China. candy8001@126.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Chongqing Medical University, 74# Linjiang Road, Chongqing, 400010, China. doctor115@126.com.
authors.forename: Xiwen
authors.initials: X
authors.lastname: Zhu
keywords: Liver injury; S-Adenosylmethionine; Toll-like receptor 4; Tumor necrosis factor-α