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Please use this identifier to cite or link to this item: http://hdl.handle.net/10564/3903

Title: Bile Acid Sequestrant, Sevelamer Ameliorates Hepatic Fibrosis with Reduced Overload of Endogenous Lipopolysaccharide in Experimental Nonalcoholic Steatohepatitis.
Other Titles: 胆汁酸吸着薬であるセベラマーは、内因性のリポポリサッカライドの過負荷を軽減して、非アルコール性脂肪性肝炎の肝線維化を改善する。
Authors: Tsuji, Yuki
Kaji, Kosuke
Kitade, Mitsuteru
Kaya, Daisuke
Kitagawa, Koh
Ozutsumi, Takahiro
Fujinaga, Yukihisa
Takaya, Hiroaki
Kawaratani, Hideto
Namisaki, Tadashi
Moriya, Kei
Akahane, Takemi
Yoshiji, Hitoshi
Keywords: nonalcoholic steatohepatitis
sevelamer
lipopolysaccharide
toll-like receptor 4
Issue Date: 19-Jun-2020
Publisher: MDPI
Citation: Microorganisms Vol.8 No.6 Article No.925 (2020 Jun)
Abstract: Despite the use of various pharmacotherapeutic strategies, fibrosis due to nonalcoholic steatohepatitis (NASH) remains an unsatisfied clinical issue. We investigated the effect of sevelamer, a hydrophilic bile acid sequestrant, on hepatic fibrosis in a murine NASH model. Male C57BL/6J mice were fed a choline-deficient, L-amino acid-defined, high-fat (CDHF) diet for 12 weeks with or without orally administered sevelamer hydrochloride (2% per diet weight). Histological and biochemical analyses revealed that sevelamer prevented hepatic steatosis, macrophage infiltration, and pericellular fibrosis in CDHF-fed mice. Sevelamer reduced the portal levels of total bile acid and inhibited both hepatic and intestinal farnesoid X receptor activation. Gut microbiome analysis demonstrated that sevelamer improved a lower α-diversity and prevented decreases in Lactobacillaceae and Clostridiaceae as well as increases in Desulfovibrionaceae and Enterobacteriaceae in the CDHF-fed mice. Additionally, sevelamer bound to lipopolysaccharide (LPS) in the intestinal lumen and promoted its fecal excretion. Consequently, the sevelamer treatment restored the tight intestinal junction proteins and reduced the portal LPS levels, leading to the suppression of hepatic toll-like receptor 4 signaling pathway. Furthermore, sevelamer inhibited the LPS-mediated induction of fibrogenic activity in human hepatic stellate cells in vitro. Collectively, sevelamer inhibited the development of murine steatohepatitis by reducing hepatic LPS overload.
Description: 博士(医学)・甲第779号・令和3年3月15日
© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
URI: http://hdl.handle.net/10564/3903
ISSN: 20762607
Academic Degrees and number: 24601A779
Degree-granting date: 2021-03-15
Degree name: 博士(医学)
Degree-granting institutions: 奈良県立医科大学
Appears in Collections:2020年度

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