Abstract:
BACKGROUND & AIMS:Cerebral oxidative stress plays an important role in the pathogenesis of hepatic encephalopathy (HE), but the underlying mechanisms are incompletely understood. Herein, we analyzed a role of heme oxygenase (HO)1, iron and NADPH oxidase 4 (Nox4) for the induction of oxidative stress and senescence in HE. METHODS:Gene and protein expression in human post-mortem brain samples was analyzed by gene array and western blot analysis. Mechanisms and functional consequences of HO1 upregulation were studied in NH4Cl-exposed astrocytes in vitro by western blot, qPCR and super-resolution microscopy. RESULTS:HO1 and the endoplasmic reticulum (ER) stress marker grp78 were upregulated, together with changes in the expression of multiple iron metabolism-related genes, in post-mortem brain samples from patients with liver cirrhosis and HE. NH4Cl elevated HO1 protein and mRNA in cultured astrocytes through glutamine synthetase (GS)-dependent upregulation of glutamine/fructose amidotransferases 1/2 (GFAT1/2), which blocked the transcription of the HO1-targeting miR326-3p in a O-GlcNAcylation dependent manner. Upregulation of HO1 by NH4Cl triggered ER stress and was associated with elevated levels of free ferrous iron and expression changes in iron metabolism-related genes, which were largely abolished after knockdown or inhibition of GS, GFAT1/2, HO1 or iron chelation. NH4Cl, glucosamine (GlcN) and inhibition of miR326-3p upregulated Nox4, while knockdown of Nox4, GS, GFAT1/2, HO1 or iron chelation prevented NH4Cl-induced RNA oxidation and astrocyte senescence. Elevated levels of grp78 and O-GlcNAcylated proteins were also found in brain samples from patients with liver cirrhosis and HE. CONCLUSION:The present study identified glucosamine synthesis-dependent protein O-GlcNAcylation as a novel mechanism in the pathogenesis of HE that triggers oxidative and ER stress, as well as senescence, through upregulation of HO1 and Nox4. LAY SUMMARY:Patients with liver cirrhosis frequently exhibit hyperammonemia and suffer from cognitive and motoric dysfunctions, which at least in part involve premature ageing of the astrocytes in the brain. This study identifies glucosamine and an O-GlcNAcylation-dependent disruption of iron homeostasis as novel triggers of oxidative stress, thereby mediating ammonia toxicity in the brain.
journal_name
J Hepatoljournal_title
Journal of hepatologyauthors
Görg B,Karababa A,Schütz E,Paluschinski M,Schrimpf A,Shafigullina A,Castoldi M,Bidmon HJ,Häussinger Ddoi
10.1016/j.jhep.2019.06.020subject
Has Abstractpub_date
2019-11-01 00:00:00pages
930-941issue
5eissn
0168-8278issn
1600-0641pii
S0168-8278(19)30392-7journal_volume
71pub_type
杂志文章abstract::Hydroxyethyl starch (HES) has gained wide clinical acceptance as a colloidal plasma substitute. We were able to study the liver biopsies of two patients with renal failure who developed ascites after repeated infusions of HES. All types of liver cells displayed massive accumulation of HES with the morphologic resembla...
journal_title:Journal of hepatology
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doi:10.1016/s0168-8278(86)80030-7
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abstract::The effectiveness of recombinant alpha-interferon was evaluated in chronic non-A, non-B hepatitis of parenteral transmission. Thirty patients were randomly allocated two groups: control group (without treatment) and treatment group (alpha-interferon 5 mega units thrice weekly for 2 months, and then 1.5 mega units unti...
journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章,随机对照试验
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更新日期:1990-01-01 00:00:00
abstract:BACKGROUND & AIMS:Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease in Western countries. It is unclear how infiltrating leukocytes affect NASH-development. Our study aims to investigate the role of the homing/receptor, pair mucosal addressin cell adhesion molecule-1 (MAdCAM-1)/β7-Integri...
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更新日期:2017-06-01 00:00:00
abstract:BACKGROUND & AIMS:CD4(+) CD25(+) Foxp3(+) regulatory T cells (Tregs) have a profound ability to control immune responses. We have previously shown that the liver is a major source of peripherally induced Tregs. Here, we investigate the liver cell types and molecular mechanisms responsible for hepatic Treg induction. M...
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abstract:BACKGROUND & AIMS:Hepatic stellate cell activation is a wound-healing response to liver injury. However, continued activation of stellate cells during chronic liver damage causes excessive matrix deposition and the formation of pathological scar tissue leading to fibrosis and ultimately cirrhosis. The importance of sus...
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更新日期:2015-09-01 00:00:00
abstract:BACKGROUND & AIMS:Robust data on hepatocellular carcinoma (HCC) incidence among HIV/hepatitis B virus (HBV)-coinfected individuals on antiretroviral therapy (ART) are needed to inform HCC screening strategies. We aimed to evaluate the incidence and risk factors of HCC among HIV/HBV-coinfected individuals on tenofovir d...
journal_title:Journal of hepatology
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doi:10.1016/j.jhep.2019.03.032
更新日期:2019-08-01 00:00:00
abstract::Hepatic fibrosis represents an important stage in the progression of chronic liver disease to cirrhosis. In the present paper we have investigated whether capsaicin-sensitive neuropeptide-containing sensory neurons may participate in the development of liver fibrosis. The expression of hepatic fibrosis induced by comm...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/0168-8278(90)90212-a
更新日期:1990-11-01 00:00:00
abstract::The etiologic agent responsible for epidemics of enterically-transmitted non-A, non-B hepatitis has been molecularly characterized as the hepatitis E virus (HEV). The cloning of a portion of the Burma strain of HEV (HEV(B); 'Old World' strain) has been described together with the isolation of a contiguous overlapping ...
journal_title:Journal of hepatology
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journal_title:Journal of hepatology
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journal_title:Journal of hepatology
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更新日期:1994-01-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
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更新日期:2017-10-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
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更新日期:2020-06-01 00:00:00
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journal_title:Journal of hepatology
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doi:10.1016/j.jhep.2017.01.006
更新日期:2017-06-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/s0168-8278(00)00068-4
更新日期:2001-01-01 00:00:00
abstract::The clinical relevance of a new antimitochondrial antibody, anti-M9, reacting with an outer membrane-associated antigen on liver mitochondria is described. Sera from 22 anti-M2-negative patients with histologically proven primary biliary cirrhosis (PBC) who had been followed for 5-15 years were tested for anti-M9 in t...
journal_title:Journal of hepatology
pub_type: 杂志文章
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更新日期:1988-06-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/0168-8278(91)90036-b
更新日期:1991-01-01 00:00:00
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journal_title:Journal of hepatology
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更新日期:2004-08-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章,随机对照试验
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pub_type: 杂志文章
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更新日期:1992-05-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
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更新日期:2013-10-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章,评审
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abstract:BACKGROUND/AIMS:The glycosphingolipid alpha-galactosylceramide has been shown to activate invariant natural killer T cells when presented in the context of CD1d and induces powerful antiviral immune responses via the production of inflammatory cytokines. The aim of this study was to investigate the safety and the antiv...
journal_title:Journal of hepatology
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1016/j.jhep.2007.04.018
更新日期:2007-09-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2015.10.015
更新日期:2016-03-01 00:00:00
abstract:BACKGROUND/AIMS:The independent role of soft drink consumption in non-alcoholic fatty liver disease (NAFLD) patients remains unclear. We aimed to assess the association between consumption of soft drinks and fatty liver in patients with or without metabolic syndrome. METHODS:We recruited 31 patients (age: 43+/-12 year...
journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2009.05.033
更新日期:2009-11-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2004.11.033
更新日期:2005-03-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2014.04.007
更新日期:2014-08-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
doi:10.1016/j.jhep.2010.04.022
更新日期:2010-10-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章,评审
doi:10.1016/j.jhep.2017.09.021
更新日期:2018-02-01 00:00:00