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Please use this identifier to cite or link to this item: http://hdl.handle.net/10564/3994

Title: Sulforaphane ameliorates ethanol plus carbon tetrachloride-induced liver fibrosis in mice through the Nrf2-mediated antioxidant response and acetaldehyde metabolization with inhibition of the LPS/TLR4 signaling pathway.
Other Titles: スルフォラファンはNrf2 活性化作用を介し抗酸化ストレス作用、アセトアルデヒド代謝作用およびLPS/TLR4 シグナル経路を阻害することで四塩化炭素およびエタノール投与により誘発されるアルコール肝線維症を改善する
Authors: Ishida, Koji
Kaji, Kosuke
Sato, Shinya
Ogawa, Hiroyuki
Takagi, Hirotetsu
Takaya, Hiroaki
Kawaratani, Hideto
Moriya, Kei
Namisaki, Tadashi
Akahane, Takemi
Yoshiji, Hitoshi
Keywords: Alcoholic liver injury
Mitochondrial aldehyde dehydrogenase
Toll-like receptor 4
Issue Date: Mar-2021
Publisher: Elsevier
Citation: The Journal of nutritional biochemistry Vol.89 Article No.108573 (2021 Mar)
Abstract: Alcoholic liver disease (ALD)-related fibrosis results from a variety of mechanisms including the accumulation of acetaldehyde, reactive oxygen species, and hepatic overload of endogenous lipopolysaccharide (LPS). Alcohol cessation is the therapeutic mainstay for patients with all stages of ALD, whereas pharmacological strategies for liver fibrosis have not been established. Sulforaphane, a phytochemical found in cruciferous vegetables, activates nuclear factor erythroid 2-related factor 2 (Nrf2) and exerts anticancer, antidiabetic, and antimicrobial effects; however, few studies investigated its efficacy in the development of ALD-related fibrosis. Herein, we investigated the effect of sulforaphane on acetaldehyde metabolism and liver fibrosis in HepaRG and LX-2 cells, human hepatoma and hepatic stellate cell lines, respectively, as well as in a mouse model of alcoholic liver fibrosis induced by ethanol plus carbon tetrachloride (EtOH/CCl₄). Sulforaphane treatment induced the activity of acetaldehyde-metabolizing mitochondrial aldehyde dehydrogenase in HepaRG cells and suppressed the acetaldehyde-induced proliferation and profibrogenic activity in LX-2 cells with upregulation of Nrf2-regulated antioxidant genes, including HMOX1, NQO1, and GSTM3. Moreover, sulforaphane attenuated the LPS/toll-like receptor 4-mediated sensitization to transforming growth factor-β with downregulation of NADPH oxidase 1 (NOX1) and NOX4. In EtOH/CCl₄-treated mice, oral sulforaphane administration augmented hepatic acetaldehyde metabolism. Additionally, sulforaphane significantly inhibited Kupffer cell infiltration and fibrosis, decreased fat accumulation and lipid peroxidation, and induced Nrf2-regulated antioxidant response genes in EtOH/CCl₄-treated mice. Furthermore, sulforaphane treatment blunted hepatic exposure of gut-derived LPS and suppressed hepatic toll-like receptor 4 signaling pathway. Taken together, these results suggest sulforaphane as a novel therapeutic strategy in ALD-related liver fibrosis.
Description: 博士(医学)・甲第811号・令和4年3月15日
© 2020 Elsevier Inc. All rights reserved.
URI: http://hdl.handle.net/10564/3994
ISSN: 09552863
Academic Degrees and number: 24601A811
Degree-granting date: 2022-03-15
Degree name: 博士(医学)
Degree-granting institutions: 奈良県立医科大学
Appears in Collections:2021年度

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