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

Alcoholic liver disease (ALD)-related fibrosis results from a variety of mechanisms including the accumulation acetaldehyde, reactive oxygen species, and hepatic overload endogenous lipopolysaccharide (LPS). Alcohol cessation is therapeutic mainstay for patients with all stages ALD, whereas pharmacological strategies have not been established. Sulforaphane, phytochemical found in cruciferous vegetables, activates nuclear factor erythroid 2-related 2 (Nrf2) exerts anticancer, antidiabetic, antimicrobial effects; however, few studies investigated its efficacy development ALD-related fibrosis. Herein, we effect sulforaphane on acetaldehyde metabolism HepaRG LX-2 cells, human hepatoma stellate cell lines, respectively, as well mouse model alcoholic induced by ethanol plus carbon tetrachloride (EtOH/CCl4). Sulforaphane treatment activity acetaldehyde-metabolizing mitochondrial aldehyde dehydrogenase cells suppressed acetaldehyde-induced proliferation profibrogenic upregulation Nrf2-regulated antioxidant genes, HMOX1, NQO1, GSTM3. Moreover, attenuated LPS/toll-like receptor 4-mediated sensitization to transforming growth factor-β downregulation NADPH oxidase 1 (NOX1) NOX4. In EtOH/CCl4-treated mice, oral administration augmented metabolism. Additionally, significantly inhibited Kupffer infiltration fibrosis, decreased fat lipid peroxidation, response genes mice. Furthermore, blunted exposure gut-derived LPS toll-like 4 signaling pathway. Taken together, these suggest novel strategy