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Please use this identifier to cite or link to this item: http://hdl.handle.net/10564/2940

Title: Reduction of endotoxin attenuates liver fibrosis through suppression of hepatic stellate cell activation and remission of intestinal permeability in a rat non-alcoholic steatohepatitis model.
Other Titles: 非アルコール性脂肪肝炎(NASH)モデルのラットにおいて、エンドトキシンの減少が肝星細胞の活性化抑制と腸管透過性改善を介して肝線維化進展を抑制する。
Authors: Douhara, Akitoshi
Moriya, Kei
Yoshiji, Hitoshi
Noguchi, Ryuichi
Namisaki, Tadashi
Kitade, Mitsuteru
Kaji, Kosuke
Aihara, Yosuke
Nishimura, Norihisa
Takeda, Kosuke
Okura, Yasushi
Kawaratani, Hideto
Fukui, Hiroshi
Keywords: endotoxin
toll‑like receptor 4
hepatic stellate cell
liver fibrosis
intestinal permeability
non‑alcoholic steatohepatitis
Issue Date: Mar-2015
Publisher: Spandidos
Citation: Molecular medicine reports Vol.11 No.3 p.1693-1700
Abstract: Previous clinical studies have demonstrated that endotoxin/toll‑like receptor 4 (TLR4) signaling is critical in the inflammatory pathways associated with non‑alcoholic steatohepatitis (NASH). In human and animal studies, NASH was associated with portal lipopolysaccharide (LPS) and the plasma LPS level was hypothesized to be associated with small intestinal bacterial overgrowth, change in composition of the microbiota and increased intestinal permeability. The aim of the present study was to investigate the roles of endogenous endotoxin and TLR4 in the pathogenesis of NASH. The effects of antibiotics were assessed in vivo using a choline deficiency amino acid (CDAA)‑induced experimental liver fibrosis model. Antibiotics, including polymyxins and neomycins, were orally administered in drinking water. Antibiotics attenuated hepatic stellate cell (HSC) activation and liver fibrosis via TGF‑β and collagen in an experimental hepatic fibrosis model. The mechanism by which antibiotics attenuated LPS‑TLR4 signaling and liver fibrosis was assessed. Notably, TLR4 mRNA level in the liver was elevated in the CDAA group and the CDAA‑induced increase was significantly reduced by antibiotics. However, no significant differences were observed in the intestine among all groups. Elevated mRNA levels of LPS binding protein, which was correlated with serum endotoxin levels, were recognized in the CDAA group and the CDAA‑induced increase was significantly reduced by antibiotics. The intestinal permeability of the CDAA group was increased compared with the choline‑supplemented amino acid group. The tight junction protein (TJP) in the intestine, determined by immunohistochemical analysis was inversely associated with intestinal permeability. Antibiotics improved the intestinal permeability and enhanced TJP expression. Inhibition of LPS‑TLR4 signaling with antibiotics attenuated liver fibrosis development associated with NASH via the inhibition of HSC activation. These results indicated that reduction of LPS and restoration of intestinal TJP may be a novel therapeutic strategy for treatment of liver fibrosis development in NASH.
Description: 博士(医学)・甲第628号・平成27年3月16日
Copyright: © Douhara et al. This is an open access article distributed under the terms of a Creative Commons Attribution License.
The definitive version is available at " http://dx.doi.org/10.3892/mmr.2014.2995 "
URI: http://hdl.handle.net/10564/2940
ISSN: 17912997
Academic Degrees and number: 24601A628
Degree-granting date: 2015-03-16
Degree name: 博士(医学)
Degree-granting institutions: 奈良県立医科大学
Appears in Collections:2014年度

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