RRC ID 69744
Author Ishida K, Kaji K, Sato S, Ogawa H, Takagi H, Takaya H, Kawaratani H, Moriya K, Namisaki T, Akahane T, Yoshiji H.
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.
Journal J Nutr Biochem
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.
Volume 89
Pages 108573
Published 2021-3-1
DOI 10.1016/j.jnutbio.2020.108573
PII S0955-2863(20)30605-7
PMID 33388347
MeSH Acetaldehyde / metabolism* Aldehyde Dehydrogenase, Mitochondrial / metabolism Animals Anti-Inflammatory Agents / pharmacology Antioxidants / metabolism Antioxidants / pharmacology Carbon Tetrachloride / adverse effects Cell Line Ethanol / adverse effects Female Hep G2 Cells Hepatic Stellate Cells / pathology Humans Isothiocyanates / pharmacology* Kupffer Cells / metabolism Lipopolysaccharides / metabolism* Liver / metabolism Liver Cirrhosis / drug therapy* Liver Cirrhosis / pathology Liver Diseases, Alcoholic / pathology Mice Mice, Inbred C57BL NF-E2-Related Factor 2 / metabolism* Signal Transduction / drug effects Sulfoxides / pharmacology* Toll-Like Receptor 4 / metabolism*
IF 4.873
Human and Animal Cells Hep G2(RCB1886)