Nitric oxide mimics transcriptional and post-translational regulation during α-Tocopherol cytoprotection against glycochenodeoxycholate-induced cell death in hepatocytes

Raúl González, Adolfo Cruz, Gustavo Ferrín, Pedro López-Cillero, Rubén Fernández-Rodríguez, Javier Briceño, Miguel A. Gómez, Sebastián Rufián, Manuel De La Mata, Antonio Martínez-Ruiz, Jose J.G. Marin, Jordi Muntané

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Background & Aims: Reactive oxygen species (ROS) and nitric oxide (NO) exert a relevant role during bile acid-induced hepatotoxicity. Whether α-Tocopherol regulates oxidative and nitrosative stress, bile acid transporter expression and their NO-dependent post-translational modifications, and cell death were assessed in vitro and in vivo. Methods: α-Tocopherol and/or NO donors (DETA-NONOate or CSNO, and V-PYRRO/NO) were administered to glycochenodeoxycholic acid (GCDCA)-treated cultured human hepatocytes or to bile duct obstructed rats. Cell injury, superoxide anion (O2-) production, as well as inducible nitric oxide synthase (NOS-2), cytochrome P4507A1 (CYP7A1), heme oxygenase-1, (HO-1) and bile acid transporter expression were determined. Cysteine S-nitrosylation and tyrosine nitration of Na +-taurocholate co-transporting polypeptide (NTCP), as well as taurocholic acid (TC) uptake were also evaluated. Results: GCDCA-induced cell death was associated with increased (O2-) production, NTCP and HO-1 expression, and with a reduction of CYP7A1 and NOS-2 expression. α-Tocopherol reduced cell death, (O2-) production, CYP7A1, NTCP, and HO-1 expression, as well as increased NOS-2 expression and NO production in GCDCA-treated hepatocytes. α-Tocopherol and NO donors increased NTCP cysteine S-nitrosylation and tyrosine nitration, and reduced TC uptake in hepatocytes. α-Tocopherol and V-PYRRO/NO reduced liver injury and NTCP expression in obstructed rats. Conclusions: The regulation of CYP7A1, NTCP, and HO-1 expression may be relevant for the cytoprotective properties of α-Tocopherol and NO against mitochondrial dysfunction, oxidative stress and cell death in GCDCA-treated hepatocytes. The regulation of NO-dependent post-translational modifications of NTCP by α-Tocopherol and NO donors reduces the uptake of toxic bile acids by hepatocytes.

Original languageEnglish
Pages (from-to)133-144
Number of pages12
JournalJournal of Hepatology
Volume55
Issue number1
DOIs
StatePublished - Jul 2011
Externally publishedYes

Keywords

  • Apoptosis
  • Bile acids
  • Cysteine S-nitrosylation
  • Free Radicals
  • Mitochondria
  • Necrosis
  • Transporters
  • Tyrosine nitration

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