Nrf2 Ameliorates DDC-Induced Sclerosing Cholangitis and Biliary Fibrosis and Improves the Regenerative Capacity of the Liver

Athanassios Fragoulis, Julia Schenkel, Miriam Herzog, Tim Schellenberg, Holger Jahr, Thomas Pufe, Christian Trautwein, Thomas W Kensler, Konrad L. Streetz, Christoph Jan Wruck

Research output: Contribution to journalArticle

Abstract

The Nrf2 pathway protects against oxidative stress and induces regeneration of various tissues. Here, we investigated whether Nrf2 protects from sclerosing cholangitis and biliary fibrosis and simultaneously induces liver regeneration. Diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) was fed to Nrf2-KO mice (Nrf2-/-), mice with liver-specific hyperactivated Nrf2 (HKeap1-/-) and wild-type (WT) littermates to induce cholangitis, liver fibrosis, and oval cell expansion. HKeap1-/--mice were protected from almost all DDC-induced injury compared with WT and Nrf2-/-. Liver injury in Nrf2-/- and WT mice was mostly similar, albeit Nrf2-/- suffered more from DDC diet as seen for several parameters. Nrf2 activity was especially important for the expression of the hepatic efflux transporters Abcg2 and Abcc2-4, which are involved in hepatic toxin elimination. Surprisingly, cell proliferation was more enhanced in Nrf2-/-- and HKeap1-/--mice compared with WT. Interestingly, Nrf2-/--mice failed to sufficiently activate oval cell expansion after DDC treatment and showed almost no resident oval cell population under control conditions. The resident oval cell population of untreated HKeap1-/--mice was increased and DDC treatment resulted in a stronger oval cell expansion compared with WT. We provide evidence that Nrf2 activation protects from DDC-induced sclerosing cholangitis and biliary fibrosis. Moreover, our data establish a possible role of Nrf2 in oval cell expansion.

Original languageEnglish (US)
Pages (from-to)485-498
Number of pages14
JournalToxicological sciences : an official journal of the Society of Toxicology
Volume169
Issue number2
DOIs
StatePublished - Jun 1 2019

Fingerprint

Sclerosing Cholangitis
Liver
Fibrosis
Nutrition
Cells
Oxidative stress
Cell proliferation
3,5-diethoxycarbonyl-1,4-dihydrocollidine
Chemical activation
Tissue
Diet
Liver Regeneration
Cholangitis
Population Control
Wounds and Injuries
Liver Cirrhosis
Regeneration
Oxidative Stress

Keywords

  • cholangitis
  • liver fibrosis
  • Nrf2
  • oval cell expansion
  • porphyrin clearance

ASJC Scopus subject areas

  • Toxicology

Cite this

Nrf2 Ameliorates DDC-Induced Sclerosing Cholangitis and Biliary Fibrosis and Improves the Regenerative Capacity of the Liver. / Fragoulis, Athanassios; Schenkel, Julia; Herzog, Miriam; Schellenberg, Tim; Jahr, Holger; Pufe, Thomas; Trautwein, Christian; Kensler, Thomas W; Streetz, Konrad L.; Wruck, Christoph Jan.

In: Toxicological sciences : an official journal of the Society of Toxicology, Vol. 169, No. 2, 01.06.2019, p. 485-498.

Research output: Contribution to journalArticle

Fragoulis, Athanassios ; Schenkel, Julia ; Herzog, Miriam ; Schellenberg, Tim ; Jahr, Holger ; Pufe, Thomas ; Trautwein, Christian ; Kensler, Thomas W ; Streetz, Konrad L. ; Wruck, Christoph Jan. / Nrf2 Ameliorates DDC-Induced Sclerosing Cholangitis and Biliary Fibrosis and Improves the Regenerative Capacity of the Liver. In: Toxicological sciences : an official journal of the Society of Toxicology. 2019 ; Vol. 169, No. 2. pp. 485-498.
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AU - Schenkel, Julia

AU - Herzog, Miriam

AU - Schellenberg, Tim

AU - Jahr, Holger

AU - Pufe, Thomas

AU - Trautwein, Christian

AU - Kensler, Thomas W

AU - Streetz, Konrad L.

AU - Wruck, Christoph Jan

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N2 - The Nrf2 pathway protects against oxidative stress and induces regeneration of various tissues. Here, we investigated whether Nrf2 protects from sclerosing cholangitis and biliary fibrosis and simultaneously induces liver regeneration. Diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) was fed to Nrf2-KO mice (Nrf2-/-), mice with liver-specific hyperactivated Nrf2 (HKeap1-/-) and wild-type (WT) littermates to induce cholangitis, liver fibrosis, and oval cell expansion. HKeap1-/--mice were protected from almost all DDC-induced injury compared with WT and Nrf2-/-. Liver injury in Nrf2-/- and WT mice was mostly similar, albeit Nrf2-/- suffered more from DDC diet as seen for several parameters. Nrf2 activity was especially important for the expression of the hepatic efflux transporters Abcg2 and Abcc2-4, which are involved in hepatic toxin elimination. Surprisingly, cell proliferation was more enhanced in Nrf2-/-- and HKeap1-/--mice compared with WT. Interestingly, Nrf2-/--mice failed to sufficiently activate oval cell expansion after DDC treatment and showed almost no resident oval cell population under control conditions. The resident oval cell population of untreated HKeap1-/--mice was increased and DDC treatment resulted in a stronger oval cell expansion compared with WT. We provide evidence that Nrf2 activation protects from DDC-induced sclerosing cholangitis and biliary fibrosis. Moreover, our data establish a possible role of Nrf2 in oval cell expansion.

AB - The Nrf2 pathway protects against oxidative stress and induces regeneration of various tissues. Here, we investigated whether Nrf2 protects from sclerosing cholangitis and biliary fibrosis and simultaneously induces liver regeneration. Diet containing 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) was fed to Nrf2-KO mice (Nrf2-/-), mice with liver-specific hyperactivated Nrf2 (HKeap1-/-) and wild-type (WT) littermates to induce cholangitis, liver fibrosis, and oval cell expansion. HKeap1-/--mice were protected from almost all DDC-induced injury compared with WT and Nrf2-/-. Liver injury in Nrf2-/- and WT mice was mostly similar, albeit Nrf2-/- suffered more from DDC diet as seen for several parameters. Nrf2 activity was especially important for the expression of the hepatic efflux transporters Abcg2 and Abcc2-4, which are involved in hepatic toxin elimination. Surprisingly, cell proliferation was more enhanced in Nrf2-/-- and HKeap1-/--mice compared with WT. Interestingly, Nrf2-/--mice failed to sufficiently activate oval cell expansion after DDC treatment and showed almost no resident oval cell population under control conditions. The resident oval cell population of untreated HKeap1-/--mice was increased and DDC treatment resulted in a stronger oval cell expansion compared with WT. We provide evidence that Nrf2 activation protects from DDC-induced sclerosing cholangitis and biliary fibrosis. Moreover, our data establish a possible role of Nrf2 in oval cell expansion.

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KW - porphyrin clearance

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