O-GlcNAcylation-dependent upregulation of HO1 triggers ammonia-induced oxidative stress and senescence in hepatic encephalopathy

Görg, Boris; Karababa, Ayşe; Schütz, E.; Paluschinski, Martha; Schrimpf, Alina; Шафигуллина, А. К.; Castoldi, Mirco; Bidmon, Hans‐Jürgen; Häussinger, Dieter

doi:10.1016/j.jhep.2019.06.020

Cited by 45 publications

(34 citation statements)

References 31 publications

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“…Further, another study reported that the O-GlcNAcylation-dependent upregulation of HO1 can induce ferrous iron release to promote the induction of oxidative stress. HO1 activity substantially affects iron homeostasis in ammonia-exposed astrocytes 36 . Generally, HO1 protein expression can be stimulated by O-GlcNAcylation, which is consistent with our finding.…”

Section: Discussionmentioning

confidence: 99%

O-GlcNAcylation enhances sensitivity to RSL3-induced ferroptosis via the YAP/TFRC pathway in liver cancer

Zhu

Murshed

et al. 2021

Cell Death Discov.

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Ferroptosis is a form of regulated cell death characterized by iron-dependent accumulation of lipid hydroperoxides to lethal levels. YAP has been reported to play a pivotal role in controlling ferroptotic death, and the expression of YAP is enhanced and stabilized by O-GlcNAcylation. However, whether O-GlcNAcylation can increase the sensitivity of hepatocellular carcinoma (HCC) cells to ferroptosis remains unknown. In the present study, we found that O-GlcNAcylation increased the sensitivity of HCC cells to ferroptosis via YAP. Moreover, YAP increased the iron concentration in HCC cells through transcriptional elevation of TFRC via its O-GlcNAcylation. With YAP knockdown or YAP-T241 mutation, the increased sensitivity to ferroptosis induced by O-GlcNAcylation was abolished. In addition, the xenograft assay confirmed that O-GlcNAcylation increased ferroptosis sensitivity via TFRC in vivo. In summary, we are the first to find that O-GlcNAcylation can increase ferroptosis sensitivity in HCC cells via YAP/TFRC. Our work will provide a new basis for clinical therapeutic strategies for HCC patients.

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Section: Discussionmentioning

confidence: 99%

O-GlcNAcylation enhances sensitivity to RSL3-induced ferroptosis via the YAP/TFRC pathway in liver cancer

Zhu

Murshed

et al. 2021

Cell Death Discov.

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“…Senescence is a non-proliferative state of cells, in which cells obtain a specific secretory profile, markedly more inflammatory than baseline, a process called 'inflammaging (117). Multiple papers from Görg et al nicely show that ammonia can induce astrocyte senescence in an ONS dependent manner (111,116). Moreover, in vitro evidence suggests that ammonia could accelerate the inflammaging phenotype in adult astrocytes (Figure 4C) (117).…”

Section: Astrocytes Are Subject To Oxidative and Nitrosative Stressmentioning

confidence: 96%

“…Multiple putative mechanisms for generating ONS in HE are suggested, namely overactivation of N-Methyl-D-Aspartate receptors (109,110), activation of NAPDH oxidase (30,111) and the abovementioned Trojan Horse hypothesis (Figure 4A and 4C) (90). The pathophysiological consequences of ROS/RNS generation are numerous (111)(112)(113). ONS has also been suggested to link to proinflammatory signaling (reviewed in (114)).…”

Section: Astrocytes Are Subject To Oxidative and Nitrosative Stressmentioning

confidence: 99%

The neurogliovascular unit in hepatic encephalopathy

et al. 2021

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…The group unraveled the molecular mechanisms of oxidative-nitrosative stress with Tyrnitration of different proteins including glutamine synthetase, and RNA oxidation and identified glutamine formation as a prerequisite of ammonia toxicity which caused mitochondrial swelling and O-GlcN-Acylation of proteins. 11,12 Most relevant, all pathogenetic steps unraveled in experimental animals could be demonstrated in the cerebra of patients with cirrhosis and HE, but not in the cerebra of patients with cirrhosis without HE. In collaboration with neuroscientists, Dieter Häussinger and his coworkers demonstrated that these molecular pathobiochemical changes lead to disturbance of oscillatory networks and, thereby, the clinical symptoms of HEa milestone in our understanding of HE.…”

mentioning

confidence: 99%

EASL recognition award recipient 2021: Prof. Dieter Häussinger

Beuers

2021

Journal of Hepatology

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Prof. Häussinger was born in 1951 in the medieval town of Nördlingen in Bavaria. His family's house in Nördlingen has remained an important place for him to retreat and relax. Dieter Häussinger studied Medicine in Munich, where he also completed his dissertation and met first with his long-term research partner, the biochemist Helmut Sies. In 1979 he started his academic career in Freiburg at the Medical Department under the mentorship of Prof. Wolfgang Gerok ( † 2020) and focused from the beginning on the pathobiochemistry of liver diseases. He became a professor of

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O-GlcNAcylation-dependent upregulation of HO1 triggers ammonia-induced oxidative stress and senescence in hepatic encephalopathy

Cited by 45 publications

References 31 publications

O-GlcNAcylation enhances sensitivity to RSL3-induced ferroptosis via the YAP/TFRC pathway in liver cancer

O-GlcNAcylation enhances sensitivity to RSL3-induced ferroptosis via the YAP/TFRC pathway in liver cancer

The neurogliovascular unit in hepatic encephalopathy

EASL recognition award recipient 2021: Prof. Dieter Häussinger

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