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

González, Raúl; Cruz, Antonio Míguez Santa; Ferrín, Gustavo; López‐Cillero, Pedro; Fernández‐Rodríguez, Rubén; Briceño, Javier; Gómez, M. A.; Rufián, Sebastián; Mata, Manuel de la; Martínez‐Ruiz, Antonio; Marin, José J.G.; Muntané, Jordi

doi:10.1016/j.jhep.2010.10.022

Cited by 32 publications

(19 citation statements)

References 51 publications

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“…The use of molecular treatments associated with the increase of NOS-3 expression and activity in CLD has shown a beneficial effect for the liver [6,7]. In addition, the administration of antioxidants reduces the hepatotoxicity of bile acids in vitro [8][9][10] and in vivo [3], through the prevention of NOS-3 expression decrease and the detoxification of ROS [11]. Thus, bioreactivity of NO mitigates the effect of ROS production [12].…”

Section: Introductionmentioning

confidence: 99%

“…Glycochenodeoxycholic acid (GCDCA) is a bile salt generated in the liver from chenodeoxycholic acid and glycine, whose relatively high toxicity and concentration in bile and serum after cholestasis has extended its use in cellular models of the disease [8][9][10]. Previously, we have reported that NOS-3 expression is decreased in the human hepatocarcinoma cell line HepG2 in response to GCDCA, and that the recovery of its expression and activity is related to the cytoprotective action of antioxidant molecules [8,9].…”

Section: Introductionmentioning

confidence: 99%

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GCDCA down-regulates gene expression by increasing Sp1 binding to the NOS-3 promoter in an oxidative stress dependent manner

González-Rubio

López‐Sánchez

Muñoz‐Castañeda

et al. 2015

Biochemical Pharmacology

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

GCDCA down-regulates gene expression by increasing Sp1 binding to the NOS-3 promoter in an oxidative stress dependent manner

González-Rubio

López‐Sánchez

Muñoz‐Castañeda

et al. 2015

Biochemical Pharmacology

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“…S-nitrosylation has emerged as an important posttranslational modification that has critical roles in regulating protein function in physiology and pathophysiology (11). S-nitrosylation of NTCP/Ntcp has been identified in NO donor-treated HuH-NTCP cells and also in liver from bile duct-ligated rats (13,33). It would be attractive to speculate that S-nitrosylation of Ntcp at C96 occurs when hepatocytes are exposed to pathological levels of NO and further that this modification may contribute to the development of cholestasis by inhibiting Ntcp function.…”

Section: Discussionmentioning

confidence: 99%

Cysteine 96 of Ntcp is responsible for NO-mediated inhibition of taurocholate uptake

Ramasamy

Anwer

Schonhoff

2013

American Journal of Physiology-Gastrointestinal and Liver Physi

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The Na(+) taurocholate (TC) cotransporting polypeptide Ntcp/NTCP mediates TC uptake across the sinusoidal membrane of hepatocytes. Previously, we demonstrated that nitric oxide (NO) inhibits TC uptake through S-nitrosylation of a cysteine residue. Our current aim was to determine which of the eight cysteine residues of Ntcp is responsible for NO-mediated S-nitrosylation and inhibition of TC uptake. Thus, we tested the effect of NO on TC uptake in HuH-7 cells transiently transfected with cysteine-to-alanine mutant Ntcp constructs. Of the eight mutants tested, only C44A Ntcp displayed decreased total and plasma membrane (PM) levels that were also reflected in decreased TC uptake. C266A Ntcp showed a decrease in TC uptake that was not explained by a decrease in total expression or PM localization, indicating that C266 is required for optimal uptake. We speculated that NO would target C266 since a previous report had shown the thiol reactive compound [2-(trimethylammonium) ethyl] methanethiosulfonate bromide (MTSET) inhibits TC uptake by wild-type NTCP but not by C266A NTCP. We confirmed that MTSET targets C266 of Ntcp, but, surprisingly, we found that C266 was not responsible for NO-mediated inhibition of TC uptake. Instead, we found that C96 was targeted by NO since C96A Ntcp was insensitive to NO-mediated inhibition of TC uptake. We also found that wild-type but not C96A Ntcp is S-nitrosylated by NO, suggesting that C96 is important in regulating Ntcp function in response to elevated levels of NO.

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“…They found that α-Tocopherol and NO donors increased NTCP S-nitrosylation, and reduced TC uptake in hepatocytes. α-Tocopherol and V-PYRRO/NO also reduced liver injury and rNtcp expression in obstructed rats [62]. Therefore, NO-dependent post-translational modifications of NTCP by α-Tocopherol and NO donors reduced the uptake of toxic bile acids by hepatocytes.…”

Section: Regulation Of Slc Family Of Drug Transportersmentioning

confidence: 99%

Loops and layers of post-translational modifications of drug transporters

You

2017

Advanced Drug Delivery Reviews

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Drug transporters encoded by solute carrier (SLC) family are distributed in multiple organs including kidney, liver, placenta, brain, and intestine, where they mediate the absorption, distribution, and excretion of a diverse array of environmental toxins and clinically important drugs. Alterations in the expression and function of these transporters play important roles in intra- and inter-individual variability of the therapeutic efficacy and the toxicity of many drugs. Consequently, the activity of these transporters must be highly regulated so as to carry out their normal functions. While it is clear that the regulation of these transporters tightly depends on genetic mechanisms, many studies have demonstrated that these transporters are the target of various post-translational modifications. This review article summarizes the recent advances in identifying the posttranslational modifications underlying the regulation of the drug transporters of SLC family. Such mechanisms are pivotal not only in physiological conditions, but also in diseases.

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

Cited by 32 publications

References 51 publications

GCDCA down-regulates gene expression by increasing Sp1 binding to the NOS-3 promoter in an oxidative stress dependent manner

GCDCA down-regulates gene expression by increasing Sp1 binding to the NOS-3 promoter in an oxidative stress dependent manner

Cysteine 96 of Ntcp is responsible for NO-mediated inhibition of taurocholate uptake

Loops and layers of post-translational modifications of drug transporters

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