Nrf2 counteracts cholestatic liver injury via stimulation of hepatic defense systems

Okada, Kōsuke; Shoda, Junichi; Taguchi, Keiko; Maher, Jonathan; Ishizaki, Kaoru; Inoue, Yoshimi; Ohtsuki, M; Gotô, Nobuharu; Sugimoto, Hirokazu; Utsunomiya, Hirotoshi; Oda, Koji; Warabi, Eiji; Ishii, Tetsuro; Yamamoto, Masayuki

doi:10.1016/j.bbrc.2009.08.156

Cited by 77 publications

(55 citation statements)

References 28 publications

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“…There are conflicting data on the effect of cholestatic liver injury in Nrf2 knockout (KO) mice. While some reported no worsening in liver injury after BDL in Nrf2 KO mice (30), others reported Nrf2 KO mice were more susceptible to LCA treatmentinduced liver injury (25) and increased Nrf2 functionality was protective against cholestatic liver injury, such as in Keap1 KO mice subjected to BDL (22). Thus, the results from the Nrf2 KO mice are mixed.…”

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confidence: 61%

Activation of a Novel c-Myc-miR27-Prohibitin 1 Circuitry in Cholestatic Liver Injury Inhibits Glutathione Synthesis in Mice

Yang

Zhou

et al. 2015

Antioxidants & Redox Signaling

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Aims: We showed that chronic cholestatic liver injury induced the expression of c-Myc but suppressed that of glutamate-cysteine ligase (GCL, composed of catalytic and modifier subunits GCLC and GCLM, respectively). This was associated with reduced nuclear antioxidant response element (ARE) binding by nuclear factorerythroid 2 related factor 2 (Nrf2). Here, we examined whether c-Myc is involved in this process. Results: Similar to bile duct ligation (BDL), lithocholic acid (LCA) treatment in vivo induced c-Myc but suppressed GCL subunits expression at day 14. Nrf2 expression and Nrf2 ARE binding fell markedly. However, Nrf2 heterodimerization with MafG was enhanced by LCA, which prompted us to examine whether LCA treatment in vivo altered proteins that bind to ARE using biotinylated ARE in pull-down assay followed by proteomics. LCA treatment enhanced c-Myc but lowered prohibitin 1 (PHB1) binding to ARE. This was a result of c-Mycmediated induction of microRNA 27a/b (miR27a/b), which target both PHB1 and Nrf2 to reduce their expression. Knockdown of c-Myc or miR27a/b attenuated LCA-mediated suppression of Nrf2, PHB1, and GCL subunit expression, whereas overexpression of PHB1 protected against the fall in Nrf2 and GCL subunits. Both c-Myc and PHB1 directly interact with Nrf2 but c-Myc lowers Nrf2 binding to ARE while PHB1 enhances it. Innovation: This is the first work that shows how activation of this circuit in cholestatic liver injury inhibits GCL expression. Conclusions: LCA feeding and BDL activate c-Myc-miR27a/b-PHB1 circuit, with the consequence of inhibiting Nrf2 expression and ARE binding, resulting in decreased reduced glutathione synthesis and antioxidant capacity. Antioxid. Redox Signal. 22,[259][260][261][262][263][264][265][266][267][268][269][270][271][272][273][274]

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mentioning

confidence: 61%

Activation of a Novel c-Myc-miR27-Prohibitin 1 Circuitry in Cholestatic Liver Injury Inhibits Glutathione Synthesis in Mice

Yang

Zhou

et al. 2015

Antioxidants & Redox Signaling

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“…Nrf2, in turn, is an important modifier of susceptibility to cholestasis. Sustained activation of Nrf2 signaling, such as that provoked in Keap1 F/F mice, protects against liver injury in a bile duct ligation model of cholestasis (42). Treatment of mice with lithocholic acid, a toxic bile acid, produces cholestatic liver injury that is exacerbated in Nrf2-disrupted mice (43).…”

Section: Discussionmentioning

confidence: 99%

Notch-Nrf2 Axis: Regulation of Nrf2 Gene Expression and Cytoprotection by Notch Signaling

Wakabayashi

Skoko

Chartoumpekis

et al. 2014

Molecular and Cellular Biology

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115

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“…Nrf2 can regulate the expression and activation of variety of enzymes that counteract oxidative stress and promote cell survival [30,31]. In addition, studies have shown that the activation of Nrf2 can safeguard against cholestasis caused by bile duct ligation and alphanaphthyl isocyanate models via the induction of many anti-oxidative genes [5,32,33].…”

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Effects of Vardenafil Against Cholestatic Liver Damage in Mice: a Mechanistic Study

El‐Agamy

Almaramhy

Ahmed

et al. 2018

Cell Physiol Biochem

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Background/Aims: Phosphodiesterase-5 inhibitors have beneficial effects in multiple liver diseases possibly through the reduction of oxidative stress and inflammatory response. However, these effects have not yet been examined in cholestatic liver dysfunction. Hence, this study aimed to explore the ability of vardenafil, a known phosphodiesterase-5 inhibitor, to repress lithocholic acid (LCA)-induced cholestatic liver injury and investigate the possible molecular pathways. Methods: Male Swiss albino mice were treated with LCA (0.125 mg/g) twice daily for 7 days to induce cholestatic liver damage. Vardenafil was administered 3 days before and throughout the administration of LCA. Serum markers of hepatotoxicity and hepatic nitro-oxidative stress along with antioxidant parameters were measured, and the histopathology of liver tissues was assessed. The expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its target genes was examined using PCR. The activation of nuclear factor kappa-B (NF-κB) and the levels of inflammatory cytokines were determined. NLRP3 inflammasome and its components were studied by PCR and western blot. Results: LCA induced marked cholestatic liver damage as demonstrated by increased serum transaminases, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), bilirubin, and bile acids. Examination of liver specimens confirmed the biochemical results. Nitro-oxidative stress parameters were significantly elevated along with reduced antioxidant capacity in hepatic tissue following LCA administration. LCA suppressed Nrf2 and its target genes and decreased the mRNA expression and binding capacity of Nrf2 as well as the mRNA expression of GCLm, GCLc, Nqo1, and HO-1. Additionally, LCA enhanced the activation of NF-κB, which was accompanied by elevations of inflammatory cytokines. Importantly, LCA induced the activation of NLRP3 inflammasome. LCA increased the expression of NLRP3, ASC, caspase-1, and IL-1β genes and proteins in hepatic tissue. The activities of IL-1β and caspase-1 were increased in the LCA group. Interestingly, vardenafil ameliorated LCA-induced hepatic injury and alleviated all biochemical, histopathological, and inflammatory parameters. Conclusions: These data elucidated the effects of Nrf2 inhibition and NLRP3 inflammasome activation in LCA-induced liver injury. The hepatoprotective activity of vardenafil in LCA-induced cholestatic damage may result from the drug’s ability to activate Nrf2 signaling and prevent the activation of NLRP3, which could suppress the inflammatory responses in hepatic tissue. Thus, vardenafil can be considered a novel anti-inflammatory remedy for cholestatic liver damage.

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Nrf2 counteracts cholestatic liver injury via stimulation of hepatic defense systems

Cited by 77 publications

References 28 publications

Activation of a Novel c-Myc-miR27-Prohibitin 1 Circuitry in Cholestatic Liver Injury Inhibits Glutathione Synthesis in Mice

Activation of a Novel c-Myc-miR27-Prohibitin 1 Circuitry in Cholestatic Liver Injury Inhibits Glutathione Synthesis in Mice

Notch-Nrf2 Axis: Regulation of Nrf2 Gene Expression and Cytoprotection by Notch Signaling

Anti-Inflammatory Effects of Vardenafil Against Cholestatic Liver Damage in Mice: a Mechanistic Study

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