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Li J, Yang D, Ge S, Liu L, Huo Y, Hu Z. Identifying hub genes of sepsis-associated and hepatic encephalopathies based on bioinformatic analysis-focus on the two common encephalopathies of septic cirrhotic patients in ICU. BMC Med Genomics 2024; 17:19. [PMID: 38212812 PMCID: PMC10785360 DOI: 10.1186/s12920-023-01774-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2023] [Accepted: 12/12/2023] [Indexed: 01/13/2024] Open
Abstract
BACKGROUND In the ICU ward, septic cirrhotic patients are susceptible to suffering from sepsis-associated encephalopathy and/or hepatic encephalopathy, which are two common neurological complications in such patients. However, the mutual pathogenesis between sepsis-associated and hepatic encephalopathies remains unclear. We aimed to identify the mutual hub genes, explore effective diagnostic biomarkers and therapeutic targets for the two common encephalopathies and provide novel, promising insights into the clinical management of such septic cirrhotic patients. METHODS The precious human post-mortem cerebral tissues were deprived of the GSE135838, GSE57193, and GSE41919 datasets, downloaded from the Gene Expression Omnibus database. Furthermore, we identified differentially expressed genes and screened hub genes with weighted gene co-expression network analysis. The hub genes were then subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway functional enrichment analyses, and protein-protein interaction networks were constructed. Receiver operating characteristic curves and correlation analyses were set up for the hub genes. Finally, we explored principal and common signaling pathways by using Gene Set Enrichment Analysis and the association between the hub genes and immune cell subtype distribution by using CIBERSORT algorithm. RESULTS We identified seven hub genes-GPR4, SOCS3, BAG3, ZFP36, CDKN1A, ADAMTS9, and GADD45B-by using differentially expressed gene analysis and weighted gene co-expression network analysis method. The AUCs of these genes were all greater than 0.7 in the receiver operating characteristic curves analysis. The Gene Set Enrichment Analysis results demonstrated that mutual signaling pathways were mainly enriched in hypoxia and inflammatory response. CIBERSORT indicated that these seven hub genes were closely related to innate and adaptive immune cells. CONCLUSIONS We identified seven hub genes with promising diagnostic value and therapeutic targets in septic cirrhotic patients with sepsis-associated encephalopathy and/or hepatic encephalopathy. Hypoxia, inflammatory, and immunoreaction responses may share the common downstream pathways of the two common encephalopathies, for which earlier recognition and timely intervention are crucial for management of such septic cirrhotic patients in ICU.
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Affiliation(s)
- Juan Li
- Department of Intensive Care Unit, Hebei Key Laboratory of Critical Disease Mechanism and Intervention, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, China
| | - Dong Yang
- Department of Emergency (Xiangjiang Hospital), The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, Hebei, China
| | - Shengmei Ge
- Department of Intensive Care Unit, Hebei Key Laboratory of Critical Disease Mechanism and Intervention, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, China
| | - Lixia Liu
- Department of Intensive Care Unit, Hebei Key Laboratory of Critical Disease Mechanism and Intervention, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, China
| | - Yan Huo
- Department of Intensive Care Unit, Hebei Key Laboratory of Critical Disease Mechanism and Intervention, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, China
| | - Zhenjie Hu
- Department of Intensive Care Unit, Hebei Key Laboratory of Critical Disease Mechanism and Intervention, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, Hebei, China.
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Cellular Pathogenesis of Hepatic Encephalopathy: An Update. Biomolecules 2023; 13:biom13020396. [PMID: 36830765 PMCID: PMC9953810 DOI: 10.3390/biom13020396] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/01/2023] [Accepted: 02/17/2023] [Indexed: 02/22/2023] Open
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome derived from metabolic disorders due to various liver failures. Clinically, HE is characterized by hyperammonemia, EEG abnormalities, and different degrees of disturbance in sensory, motor, and cognitive functions. The molecular mechanism of HE has not been fully elucidated, although it is generally accepted that HE occurs under the influence of miscellaneous factors, especially the synergistic effect of toxin accumulation and severe metabolism disturbance. This review summarizes the recently discovered cellular mechanisms involved in the pathogenesis of HE. Among the existing hypotheses, ammonia poisoning and the subsequent oxidative/nitrosative stress remain the mainstream theories, and reducing blood ammonia is thus the main strategy for the treatment of HE. Other pathological mechanisms mainly include manganese toxicity, autophagy inhibition, mitochondrial damage, inflammation, and senescence, proposing new avenues for future therapeutic interventions.
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Häussinger D, Dhiman RK, Felipo V, Görg B, Jalan R, Kircheis G, Merli M, Montagnese S, Romero-Gomez M, Schnitzler A, Taylor-Robinson SD, Vilstrup H. Hepatic encephalopathy. Nat Rev Dis Primers 2022; 8:43. [PMID: 35739133 DOI: 10.1038/s41572-022-00366-6] [Citation(s) in RCA: 108] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/12/2022] [Indexed: 01/18/2023]
Abstract
Hepatic encephalopathy (HE) is a prognostically relevant neuropsychiatric syndrome that occurs in the course of acute or chronic liver disease. Besides ascites and variceal bleeding, it is the most serious complication of decompensated liver cirrhosis. Ammonia and inflammation are major triggers for the appearance of HE, which in patients with liver cirrhosis involves pathophysiologically low-grade cerebral oedema with oxidative/nitrosative stress, inflammation and disturbances of oscillatory networks in the brain. Severity classification and diagnostic approaches regarding mild forms of HE are still a matter of debate. Current medical treatment predominantly involves lactulose and rifaximin following rigorous treatment of so-called known HE precipitating factors. New treatments based on an improved pathophysiological understanding are emerging.
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Affiliation(s)
- Dieter Häussinger
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
| | - Radha K Dhiman
- Department of Hepatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, (Uttar Pradesh), India
| | - Vicente Felipo
- Laboratory of Neurobiology, Centro de Investigación Principe Felipe, Valencia, Spain
| | - Boris Görg
- Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Rajiv Jalan
- Liver Failure Group ILDH, Division of Medicine, UCL Medical School, Royal Free Campus, London, UK.,European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
| | - Gerald Kircheis
- Department of Gastroenterology, Diabetology and Hepatology, University Hospital Brandenburg an der Havel, Brandenburg Medical School, Brandenburg an der Havel, Germany
| | - Manuela Merli
- Department of Translational and Precision Medicine, Universita' degli Studi di Roma - Sapienza, Roma, Italy
| | | | - Manuel Romero-Gomez
- UCM Digestive Diseases, Virgen del Rocío University Hospital, Institute of Biomedicine of Seville (HUVR/CSIC/US), University of Seville, Seville, Spain
| | - Alfons Schnitzler
- Institute of Clinical Neuroscience and Medical Psychology, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Simon D Taylor-Robinson
- Department of Surgery and Cancer, St. Mary's Hospital Campus, Imperial College London, London, UK
| | - Hendrik Vilstrup
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark
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Arjunan A, Sah DK, Jung YD, Song J. Hepatic Encephalopathy and Melatonin. Antioxidants (Basel) 2022; 11:837. [PMID: 35624703 PMCID: PMC9137547 DOI: 10.3390/antiox11050837] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 04/06/2022] [Accepted: 04/24/2022] [Indexed: 11/25/2022] Open
Abstract
Hepatic encephalopathy (HE) is a severe metabolic syndrome linked with acute/chronic hepatic disorders. HE is also a pernicious neuropsychiatric complication associated with cognitive decline, coma, and death. Limited therapies are available to treat HE, which is formidable to oversee in the clinic. Thus, determining a novel therapeutic approach is essential. The pathogenesis of HE has not been well established. According to various scientific reports, neuropathological symptoms arise due to excessive accumulation of ammonia, which is transported to the brain via the blood-brain barrier (BBB), triggering oxidative stress and inflammation, and disturbing neuronal-glial functions. The treatment of HE involves eliminating hyperammonemia by enhancing the ammonia scavenging mechanism in systemic blood circulation. Melatonin is the sole endogenous hormone linked with HE. Melatonin as a neurohormone is a potent antioxidant that is primarily synthesized and released by the brain's pineal gland. Several HE and liver cirrhosis clinical studies have demonstrated impaired synthesis, secretion of melatonin, and circadian patterns. Melatonin can cross the BBB and is involved in various neuroprotective actions on the HE brain. Hence, we aim to elucidate how HE impairs brain functions, and elucidate the precise molecular mechanism of melatonin that reverses the HE effects on the central nervous system.
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Affiliation(s)
- Archana Arjunan
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea;
| | - Dhiraj Kumar Sah
- Department of Biochemistry, Chonnam National University Medical School, Hwasun 58128, Korea;
| | - Young Do Jung
- Department of Biochemistry, Chonnam National University Medical School, Hwasun 58128, Korea;
| | - Juhyun Song
- Department of Anatomy, Chonnam National University Medical School, Hwasun 58128, Korea;
- BioMedical Sciences Graduate Program (BMSGP), Chonnam National University, 264 Seoyangro, Hwasun 58128, Korea
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Schrimpf A, Knappe O, Qvartskhava N, Poschmann G, Stühler K, Bidmon HJ, Luedde T, Häussinger D, Görg B. Hyperammonemia-induced changes in the cerebral transcriptome and proteome. Anal Biochem 2022; 641:114548. [DOI: 10.1016/j.ab.2022.114548] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 10/10/2021] [Accepted: 01/06/2022] [Indexed: 02/07/2023]
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Häussinger D, Butz M, Schnitzler A, Görg B. Pathomechanisms in hepatic encephalopathy. Biol Chem 2021; 402:1087-1102. [PMID: 34049427 DOI: 10.1515/hsz-2021-0168] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 05/12/2021] [Indexed: 02/06/2023]
Abstract
Hepatic encephalopathy (HE) is a frequent neuropsychiatric complication in patients with acute or chronic liver failure. Symptoms of HE in particular include disturbances of sensory and motor functions and cognition. HE is triggered by heterogeneous factors such as ammonia being a main toxin, benzodiazepines, proinflammatory cytokines and hyponatremia. HE in patients with liver cirrhosis is triggered by a low-grade cerebral edema and cerebral oxidative/nitrosative stress which bring about a number of functionally relevant alterations including posttranslational protein modifications, oxidation of RNA, gene expression changes and senescence. These alterations are suggested to impair astrocyte/neuronal functions and communication. On the system level, a global slowing of oscillatory brain activity and networks can be observed paralleling behavioral perceptual and motor impairments. Moreover, these changes are related to increased cerebral ammonia, alterations in neurometabolite and neurotransmitter concentrations and cortical excitability in HE patients.
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Affiliation(s)
- Dieter Häussinger
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich Heine University, Moorenstr. 5, D-40225 Düsseldorf, Germany
| | - Markus Butz
- Department of Neurology/Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich Heine University, Moorenstr. 5, D-40225 Düsseldorf, Germany
| | - Alfons Schnitzler
- Department of Neurology/Institute of Clinical Neuroscience and Medical Psychology, Medical Faculty, Heinrich Heine University, Moorenstr. 5, D-40225 Düsseldorf, Germany
| | - Boris Görg
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich Heine University, Moorenstr. 5, D-40225 Düsseldorf, Germany
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Chen J, Wang H, He Z, Li T. Analysis of Risk Factors for Postoperative Delirium After Liver Transplantation. Neuropsychiatr Dis Treat 2020; 16:1645-1652. [PMID: 32753870 PMCID: PMC7343290 DOI: 10.2147/ndt.s254920] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Accepted: 06/17/2020] [Indexed: 01/29/2023] Open
Abstract
PURPOSE The study aimed to analyze the incidence of postoperative delirium (POD) and associated risk factors after liver transplantation (LT). PATIENTS AND METHODS We identified and enrolled patients undergoing LT at the Second Xiangya Hospital, Central South University between August 2018 and May 2019. We abstracted their relevant clinical information and assigned the patients into a POD group and non-POD group to compare differences in clinical information. Risk factors of POD were analyzed using logistic regression. RESULTS A total of 159 LT patients were enrolled. Forty-two patients exhibited delirium (26.4%). Of the 42 with delirium, 33 (78.6%) had delirium within 3 days postoperatively and a median duration of 5 days (quartile 3-7 days). The results of binary logistic regression are as follows: preoperative ammonia (≥46 vs <46 μmol/L; OR 3.51, 95% CI [1.31-9.46], P<0.05), Model for End-Stage Liver Disease (MELD) score (≥15 vs.<15; OR 3.33, 95% CI [1.27-8.79], P<0.05), presence of hepatic encephalopathy (OR 3.30, 95% CI [1.20-9.07], P<0.05), aspartate aminotransferase (AST) on day 1 postoperatively (OR 1.33, 95% CI [1.06 -1.68], P<0.05), anhepatic period (OR 1.04, 95% CI [1.02 -1.06], P<0.01). The POD group had a longer intubation time (2925.0 vs 1410.0 min, P<0.01), ICU length of stay (6 vs 4 d, P<0.01) and increased medical costs (43.96 vs 33.74 ten thousand yuan, P<0.01). CONCLUSION The incidence of POD in LT patients is a significant clinical feature. Ammonia ≥46 μmol/l, MELD score ≥15, hepatic encephalopathy, anhepatic period, and AST at 1 day postoperatively were independent risk factors for POD.
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Affiliation(s)
- Junguo Chen
- Department of Organ Transplantation, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Hao Wang
- Department of Organ Transplantation, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Zhijun He
- Department of Organ Transplantation, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
| | - Ting Li
- Department of Organ Transplantation, The Second Xiangya Hospital, Central South University, Changsha, People's Republic of China
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Görg B, Karababa A, Schütz E, Paluschinski M, Schrimpf A, Shafigullina A, Castoldi M, Bidmon HJ, Häussinger D. O-GlcNAcylation-dependent upregulation of HO1 triggers ammonia-induced oxidative stress and senescence in hepatic encephalopathy. J Hepatol 2019; 71:930-941. [PMID: 31279900 DOI: 10.1016/j.jhep.2019.06.020] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2018] [Revised: 06/24/2019] [Accepted: 06/27/2019] [Indexed: 01/18/2023]
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.
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Affiliation(s)
- Boris Görg
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
| | - Ayşe Karababa
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, 40225 Düsseldorf, Germany
| | - Elina Schütz
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, 40225 Düsseldorf, Germany
| | - Martha Paluschinski
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, 40225 Düsseldorf, Germany
| | - Alina Schrimpf
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, 40225 Düsseldorf, Germany
| | - Aygul Shafigullina
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, 40225 Düsseldorf, Germany
| | - Mirco Castoldi
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, 40225 Düsseldorf, Germany
| | - Hans J Bidmon
- C.&O. Vogt Institute for Brain Research, Heinrich-Heine-University, 40225 Düsseldorf, Germany
| | - Dieter Häussinger
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, 40225 Düsseldorf, Germany
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Lu K, Zimmermann M, Görg B, Bidmon HJ, Biermann B, Klöcker N, Häussinger D, Reichert AS. Hepatic encephalopathy is linked to alterations of autophagic flux in astrocytes. EBioMedicine 2019; 48:539-553. [PMID: 31648987 PMCID: PMC6838440 DOI: 10.1016/j.ebiom.2019.09.058] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 09/18/2019] [Accepted: 09/19/2019] [Indexed: 02/07/2023] Open
Abstract
Background Hepatic encephalopathy (HE) is a severe neuropsychiatric syndrome caused by various types of liver failure resulting in hyperammonemia-induced dysfunction of astrocytes. It is unclear whether autophagy, an important pro-survival pathway, is altered in the brains of ammonia-intoxicated animals as well as in HE patients. Methods Using primary rat astrocytes, a co-culture model of primary mouse astrocytes and neurons, an in vivo rat HE model, and post mortem brain samples of liver cirrhosis patients with HE we analyzed whether and how hyperammonemia modulates autophagy. Findings We show that autophagic flux is efficiently inhibited after administration of ammonia in astrocytes. This occurs in a fast, reversible, time-, dose-, and ROS-dependent manner and is mediated by ammonia-induced changes in intralysosomal pH. Autophagic flux is also strongly inhibited in the cerebral cortex of rats after acute ammonium intoxication corroborating our results using an in vivo rat HE model. Transglutaminase 2 (TGM2), a factor promoting autophagy, is upregulated in astrocytes of in vitro- and in vivo-HE models as well as in post mortem brain samples of liver cirrhosis patients with HE, but not in patients without HE. LC3, a commonly used autophagy marker, is significantly increased in the brain of HE patients. Ammonia also modulated autophagy moderately in neuronal cells. We show that taurine, known to ameliorate several parameters caused by hyperammonemia in patients suffering from liver failure, is highly potent in reducing ammonia-induced impairment of autophagic flux. This protective effect of taurine is apparently not linked to inhibition of mTOR signaling but rather to reducing ammonia-induced ROS formation. Interpretation Our data support a model in which autophagy aims to counteract ammonia-induced toxicity, yet, as acidification of lysosomes is impaired, possible protective effects thereof, are hampered. We propose that modulating autophagy in astrocytes and/or neurons, e.g. by taurine, represents a novel strategy to treat liver diseases associated with HE. Funding Supported by the DFG, CRC974 “Communication and Systems Relevance in Liver Injury and Regeneration“, Düsseldorf (Project number 190586431) Projects A05 (DH), B04 (BG), B05 (NK), and B09 (ASR).
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Affiliation(s)
- Kaihui Lu
- Institute of Biochemistry and Molecular Biology I, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany
| | - Marcel Zimmermann
- Institute of Biochemistry and Molecular Biology I, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany
| | - Boris Görg
- Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany
| | - Hans-Jürgen Bidmon
- C. & O. Vogt Institute for Brain Research, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany
| | - Barbara Biermann
- Institute of Neural and Sensory Physiology, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany
| | - Nikolaj Klöcker
- Institute of Neural and Sensory Physiology, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany
| | - Dieter Häussinger
- Department of Gastroenterology, Hepatology and Infectious Diseases, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany
| | - Andreas S Reichert
- Institute of Biochemistry and Molecular Biology I, Heinrich Heine University Düsseldorf, Medical Faculty, Düsseldorf, Germany.
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Sergeeva OA, Chepkova AN, Görg B, Rodrigues Almeida F, Bidmon HJ, Haas HL, Häussinger D. Histamine-induced plasticity and gene expression in corticostriatal pathway under hyperammonemia. CNS Neurosci Ther 2019; 26:355-366. [PMID: 31571389 PMCID: PMC7052803 DOI: 10.1111/cns.13223] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Revised: 08/10/2019] [Accepted: 09/04/2019] [Indexed: 01/13/2023] Open
Abstract
Aims Histamine H3 receptor (H3R) antagonists/inverse agonists increase vigilance. We studied brain histaminergic pathways under hyperammonemia and the transcriptome of receptors and their signaling cascades to provide a rationale for wake‐promoting therapies. Methods We analyzed histamine‐induced long‐lasting depression of corticostriatal synaptic transmission (LLDhist). As the expression of dopamine 1 receptors (D1R) is upregulated in LGS‐KO striatum where D1R‐H3R dimers may exist, we investigated actions of H3R and D1R agonists and antagonists. We analyzed transcription of selected genes in cortex and dorsal striatum in a mouse model of inborn hyperammonemia (liver‐specific glutamine synthetase knockout: LGS‐KO) and compared it with human hepatic encephalopathy. Results LGS‐KO mice showed significant reduction of the direct depression (DD) but not the long‐lasting depression (LLD) by histamine. Neither pharmacological activation nor inhibition of D1R significantly affected DDhist and LLDhist in WT striatum, while in LGS‐KO mice D1R activation suppressed LLDhist. Histaminergic signaling was found unchanged at the transcriptional level except for the H2R. A study of cAMP‐regulated genes indicated a significant reduction in the molecular signature of wakefulness in the diseased cortex. Conclusions Our findings provide a rationale for the development of aminergic wake‐promoting therapeutics in hyperammonemic disorders.
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Affiliation(s)
- Olga A Sergeeva
- Molecular Neurophysiology, Medical Faculty, Institute of Neural and Sensory Physiology, Heinrich-Heine University, Duesseldorf, Germany.,Medical Faculty, Institute of Clinical Neurosciences and Medical Psychology, Heinrich-Heine University, Duesseldorf, Germany
| | - Aisa N Chepkova
- Molecular Neurophysiology, Medical Faculty, Institute of Neural and Sensory Physiology, Heinrich-Heine University, Duesseldorf, Germany.,Clinic of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich-Heine University, Duesseldorf, Germany
| | - Boris Görg
- Clinic of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich-Heine University, Duesseldorf, Germany
| | - Filipe Rodrigues Almeida
- Medical Faculty, Institute of Clinical Neurosciences and Medical Psychology, Heinrich-Heine University, Duesseldorf, Germany
| | - Hans-Jürgen Bidmon
- Medical Faculty, C.&O. Vogt Institute for Brain Research, Heinrich-Heine University, Duesseldorf, Germany
| | - Helmut L Haas
- Molecular Neurophysiology, Medical Faculty, Institute of Neural and Sensory Physiology, Heinrich-Heine University, Duesseldorf, Germany
| | - Dieter Häussinger
- Clinic of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich-Heine University, Duesseldorf, Germany
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11
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Lima LCD, Miranda AS, Ferreira RN, Rachid MA, Simões E Silva AC. Hepatic encephalopathy: Lessons from preclinical studies. World J Hepatol 2019; 11:173-185. [PMID: 30820267 PMCID: PMC6393717 DOI: 10.4254/wjh.v11.i2.173] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 11/19/2018] [Accepted: 01/28/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatic encephalopathy (HE) is a major complication that is closely related to the progression of end-stage liver disease. Metabolic changes in advanced liver failure can promote cognition impairment, attention deficits and motor dysfunction that may result in coma and death. HE can be subdivided according to the type of hepatic injury, namely, type A, which results from acute liver failure, type B, which is associated with a portosystemic shunting without intrinsic liver disease, and type C, which is due to chronic liver disease. Several studies have investigated the pathogenesis of the disease, and most of the mechanisms have been explored using animal models. This article aimed to review the use of preclinical models to investigate HE. The most used animal species are rats and mice. Experimental models of type A HE include surgical procedures and the administration of hepatotoxic medications, whereas models of types B and C HE are generally surgically induced lesions in liver tissue, which evolve to hepatic cirrhosis. Preclinical models have allowed the comprehension of the pathways related to HE.
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Affiliation(s)
- Luiza Cioglia Dias Lima
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais 31270-901, Brasil
| | - Aline Silva Miranda
- Departamento de Morfologia, Instituto de Ciências Biológicas, UFMG, Belo Horizonte, Minas Gerais 30130-100, Brasil
| | - Rodrigo Novaes Ferreira
- Departamento de Morfologia, Instituto de Ciências Biológicas, UFMG, Belo Horizonte, Minas Gerais 30130-100, Brasil
| | - Milene Alvarenga Rachid
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais 31270-901, Brasil
| | - Ana Cristina Simões E Silva
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, UFMG, Belo Horizonte, Minas Gerais 30130-100, Brasil.
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Görg B, Karababa A, Häussinger D. Hepatic Encephalopathy and Astrocyte Senescence. J Clin Exp Hepatol 2018; 8:294-300. [PMID: 30302047 PMCID: PMC6175776 DOI: 10.1016/j.jceh.2018.05.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 05/08/2018] [Indexed: 02/07/2023] Open
Abstract
Hepatic Encephalopathy (HE) is a severe complication of acute or chronic liver diseases with a broad spectrum of neurological symptoms including motor disturbances and cognitive impairment of different severity. Contrary to former beliefs, a growing number of studies suggest that cognitive impairment may not fully reverse after an acute episode of overt HE in patients with liver cirrhosis. The reasons for persistent cognitive impairment in HE are currently unknown but recent observations raise the possibility that astrocyte senescence may play a role here. Astrocyte senescence is closely related to oxidative stress and correlate with irreversible cognitive decline in aging and neurodegenerative diseases. In line with this, surrogate marker for oxidative stress and senescence were upregulated in ammonia-exposed cultured astrocytes and in post mortem brain tissue from patients with liver cirrhosis with but not without HE. Ammonia-induced senescence in astrocytes involves glutamine synthesis-dependent formation of reactive oxygen species (ROS), p53 activation and upregulation of cell cycle inhibitory factors p21 and GADD45α. More recent studies also suggest a role of ROS-induced downregulation of Heme Oxygenase (HO)1-targeting micro RNAs and upregulation of HO1 for ammonia-induced proliferation inhibition in cultured astrocytes. Further studies are required to identify the precise sequence of events that lead to astrocyte senescence and to elucidate functional implications of senescence for cognitive performance in patients with liver cirrhosis and HE.
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Key Words
- ARE, Antioxidant Response Elements
- BDNF, Brain-Derived Neurotrophic Factor
- Eph, Ephrine
- EphR, Ephrine Receptor
- GADD45α, Growth Arrest and DNA Damage Inducible 45α
- GS, Glutamine Synthetase
- HE, Hepatic Encephalopathy
- HO1, Heme Oxygenase 1
- LOLA, l-Ornithine-l-Aspartate
- MAP, Mitogen Activated Protein Kinases
- NAPDH, Reduced Form of Nicotinamide Adenine Dinucleotide Phosphate
- Nox, NADPH Oxidase
- Nrf2, Nuclear Factor-Like 2
- PBR, Peripheral-Type Benzodiazepine Receptor
- PTN, Protein Tyrosine Nitration
- RNOS, Reactive Nitrogen and Oxygen Species
- ROS, Reactive Oxygen Species
- SA-β-Gal, Senescence-Associated β-d-Galactosidase
- TSP, Trombospondin
- TrkBT, Truncated Tyrosine Receptor Kinase B
- ZnPP, Zinc Protoporphyrin
- ammonia
- astrocytes
- heme oxygenase 1
- hepatic encephalopathy
- mPT, Mitochondrial Permeability Transition
- miRNAs
- nNOS, Neuronal-Type Nitric-Oxide Synthase
- oxidative stress
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Affiliation(s)
| | | | - Dieter Häussinger
- Address for correspondence: Dieter Häussinger, Universitätsklinikum Düsseldorf, Klinik für Gastroenterologie, Hepatologie und Infektiologie, Moorenstrasse 5, 40225 Düsseldorf, Germany. Tel.: +49 211 811 7569; fax: +49 211 811 8838.
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Jayakumar A, Norenberg MD. Hyperammonemia in Hepatic Encephalopathy. J Clin Exp Hepatol 2018; 8:272-280. [PMID: 30302044 PMCID: PMC6175739 DOI: 10.1016/j.jceh.2018.06.007] [Citation(s) in RCA: 64] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 06/10/2018] [Indexed: 12/12/2022] Open
Abstract
The precise mechanism underlying the neurotoxicity of Hepatic Encephalopathy (HE) is remains unclear. The dominant view has been that gut-derived nitrogenous toxins are not extracted by the diseased liver and thereby enter the brain. Among the various toxins proposed, the case for ammonia is most compelling. Events that lead to increased levels of blood or brain ammonia have been shown to worsen HE, whereas reducing blood ammonia levels alleviates HE. Clinical, pathological, and biochemical changes observed in HE can be reproduced by increasing blood or brain ammonia levels in experimental animals, while exposure of cultured astrocytes to ammonium salts reproduces the morphological and biochemical findings observed in HE. However, factors other than ammonia have recently been proposed to be involved in the development of HE, including cytokines and other blood and brain immune factors. Moreover, recent studies have questioned the critical role of ammonia in the pathogenesis of HE since blood ammonia levels do not always correlate with the level/severity of encephalopathy. This review summarizes the vital role of ammonia in the pathogenesis of HE in humans, as well as in experimental models of acute and chronic liver failure. It further emphasizes recent advances in the molecular mechanisms involved in the progression of neurological complications that occur in acute and chronic liver failure.
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Key Words
- AHE, Acute Hepatic Encephalopathy
- ALF, Acute Liver Failure
- CHE, Chronic Hepatic Encephalopathy
- CNS, Central Nervous System
- CSF, Cerebrospinal Fluid
- ECs, Endothelial Cells
- HE, Hepatic Encephalopathy
- IL, Interleukin
- LPS, Lipopolysaccharide
- MAPKs, Mitogen-Activated Protein Kinases
- NCX, Sodium-Calcium Exchanger
- NF-κB, Nuclear Factor-kappaB
- NHE, Sodium/Hydrogen Exchanger-1 or SLC9A1 (SoLute Carrier Family 9A1)
- SUR1, The Sulfonylurea Receptor 1
- TDP-43 and tau proteinopathies
- TDP-43, TAR DNA-Binding Protein, 43 kDa
- TLR, Toll-like Receptor
- TNF-α, Tumor Necrosis Factor-Alpha
- TSP-1, Thrombospondin-1
- ammonia
- hepatic encephalopathy
- inflammation
- matricellular proteins
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Affiliation(s)
- A.R. Jayakumar
- General Medical Research, Neuropathology Section, R&D Service, Veterans Affairs Medical Center, Miami, FL 33125, United States
- South Florida VA Foundation for Research and Education Inc., Veterans Affairs Medical Center, Miami, FL 33125, United States
| | - Michael D. Norenberg
- Department of Pathology, University of Miami School of Medicine, Miami, FL 33125, United States
- Department of Biochemistry & Molecular Biology, University of Miami School of Medicine, Miami, FL 33125, United States
- Department of Neurology and Neurological Surgery, University of Miami School of Medicine, Miami, FL 33125, United States
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Abstract
Hepatic encephalopathy describes the array of neurological alterations that occur during acute liver failure or chronic liver injury. While key players in the pathogenesis of hepatic encephalopathy, such as increases in brain ammonia, alterations in neurosteroid levels, and neuroinflammation, have been identified, there is still a paucity in our knowledge of the precise pathogenic mechanism. This review gives a brief overview of our understanding of the pathogenesis of hepatic encephalopathy and then summarizes the significant recent advances made in clinical and basic research contributing to our understanding, diagnosis, and possible treatment of hepatic encephalopathy. A literature search using the PubMed database was conducted in May 2017 using "hepatic encephalopathy" as a keyword, and selected manuscripts were limited to those research articles published since May 2014. While the authors acknowledge that many significant advances have been made in the understanding of hepatic encephalopathy prior to May 2014, we have limited the scope of this review to the previous three years only.
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Affiliation(s)
- Victoria Liere
- Department of Medical Physiology, College of Medicine, Texas A&M Health Science Center, Temple, TX, USA
| | | | - Sharon DeMorrow
- Department of Medical Physiology, College of Medicine, Texas A&M Health Science Center, Temple, TX, USA
- Central Texas Veterans Healthcare System, Temple, TX, USA
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15
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Dai H, Jia G, Wang W, Liang C, Han S, Chu M, Mei X. Genistein inhibited ammonia induced astrocyte swelling by inhibiting NF-κB activation-mediated nitric oxide formation. Metab Brain Dis 2017; 32:841-848. [PMID: 28255863 DOI: 10.1007/s11011-017-9975-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Accepted: 02/15/2017] [Indexed: 11/27/2022]
Abstract
Our previous study has indicated the involvement of epidermal growth factor receptor (EGFR) transactivation in ammonia-induced astrocyte swelling, which represents a major pathogenesis of brain edema in hepatic encephalopathy. In this study, we examined the effect of genistein, a naturally occurred broad-spectrum protein tyrosine kinase (PTK) inhibitor, on ammonia-induced cell swelling. We found that genistein pretreatment significantly prevented ammonia-induced astrocyte swelling. Mechanistically, ammonia triggered EGFR/extracellular signal-regulated kinase (ERK) association and subsequent ERK phosphorylation were alleviated by genistein pretreatment. Moreover, ammonia-induced NF-κB nuclear location, iNOS expression, and consequent NO production were all prevented by AG1478 and genistein pretreatment. This study suggested that genistein could alleviate ammonia-induced astrocyte swelling, which may be, at least partly, related to its PTK-inhibiting activity and repression of NF-κB mediated iNOS-derived NO accumulation.
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Affiliation(s)
- Hongliang Dai
- School of Nursing, Jinzhou Medical University, No. 40, Section 3, Songpo Road, Jinzhou, Liaoning, 121001, China.
| | - Guizhi Jia
- Department of Physiology, Jinzhou Medical University, Jinzhou, Liaoning, 121001, People's Republic of China.
| | - Wei Wang
- Department of Orthopedics, First Affiliated Hospital, Jinzhou Medical University, Jinzhou, Liaoning, 121001, People's Republic of China
| | - Chunguang Liang
- School of Nursing, Jinzhou Medical University, No. 40, Section 3, Songpo Road, Jinzhou, Liaoning, 121001, China
| | - Siyu Han
- School of Nursing, Jinzhou Medical University, No. 40, Section 3, Songpo Road, Jinzhou, Liaoning, 121001, China
| | - Minghui Chu
- School of Nursing, Jinzhou Medical University, No. 40, Section 3, Songpo Road, Jinzhou, Liaoning, 121001, China
| | - Xifan Mei
- Department of Orthopedics, First Affiliated Hospital, Jinzhou Medical University, Jinzhou, Liaoning, 121001, People's Republic of China.
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Karababa A, Groos-Sahr K, Albrecht U, Keitel V, Shafigullina A, Görg B, Häussinger D. Ammonia Attenuates LPS-Induced Upregulation of Pro-Inflammatory Cytokine mRNA in Co-Cultured Astrocytes and Microglia. Neurochem Res 2016; 42:737-749. [PMID: 27655254 DOI: 10.1007/s11064-016-2060-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 09/03/2016] [Accepted: 09/08/2016] [Indexed: 12/19/2022]
Abstract
Hepatic encephalopathy (HE) is associated with cerebral microglia activation. Ammonia, a major toxin of HE, activates microglia in vitro but does not trigger pro-inflammatory cytokine synthesis. In the present study we analysed effects of ammonia on lipopolysaccharide (LPS)-induced upregulation of microglia activation and cytokine mRNA as well as on cytokine secretion in mono-cultured microglia and co-cultured astrocytes and microglia. In mono-cultured microglia LPS (100 ng/ml, 18 h) strongly elevated mRNA levels of the microglia activation marker CD14 and the pro-inflammatory cytokines IL-1α/β, IL-6 and TNF-α. NH4Cl (5 mmol/l) had no effect on LPS-induced upregulation of CD14, IL-1α/β and IL-6 mRNA but enhanced LPS-induced upregulation of TNF-α mRNA in mono-cultured microglia. In co-cultured astrocytes and microglia, however, LPS-induced upregulation of IL-1α/β, TNF-α, IL-6, CD14 but not of IL-10, IL-12A/B or TGFβ1-3 mRNA was attenuated by NH4Cl. LPS-induced upregulation of IL-1α/β, IL-6 and TNF-α was also diminished by the TGR5-ligands allopregnanolone and taurolithocholic acid in mono-cultured microglia. NH4Cl also attenuated LPS-induced release of MCP-1, IL-6 and IL-10 in mono-cultured microglia. mRNA level of surrogate marker for microglia activation (CD14) and for the anti-inflammatory M2-type microglia (CD163, CXCL1, CXCL2) were also elevated in post mortem brain tissue taken from the fusiforme gyrus of patients with liver cirrhosis and HE. The findings suggest that ammonia attenuates LPS-induced microglia reactivity in an astrocyte-dependent way. One may speculate that these anti-inflammatory effects of ammonia may be triggered by neurosteroids derived from astrocytes and may account for absence of microglia reactivity in cerebral cortex of cirrhotic patients with HE.
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Affiliation(s)
- Ayse Karababa
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, D-40225, Düsseldorf, Germany
| | - Katerina Groos-Sahr
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, D-40225, Düsseldorf, Germany
| | - Ute Albrecht
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, D-40225, Düsseldorf, Germany
| | - Verena Keitel
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, D-40225, Düsseldorf, Germany
| | - Aygul Shafigullina
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, D-40225, Düsseldorf, Germany
| | - Boris Görg
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, D-40225, Düsseldorf, Germany
| | - Dieter Häussinger
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, D-40225, Düsseldorf, Germany.
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Abstract
Hepatic encephalopathy (HE) is a commonly encountered sequela of chronic liver disease and cirrhosis with significant associated morbidity and mortality. Although ammonia is implicated in the pathogenesis of HE, the exact underlying mechanisms still remain poorly understood. Its role in the urea cycle, astrocyte swelling, and glutamine and gamma-amino-n-butyric acid systems suggests that the pathogenesis is multifaceted. Greater understanding in its underlying mechanism may offer more targeted therapeutic options in the future, and thus further research is necessary to fully understand the pathogenesis of HE.
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Affiliation(s)
- Parth J Parekh
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tulane University, New Orleans, LA, USA
| | - Luis A Balart
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tulane University, New Orleans, LA, USA.
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18
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Jördens MS, Keitel V, Karababa A, Zemtsova I, Bronger H, Häussinger D, Görg B. Multidrug resistance-associated protein 4 expression in ammonia-treated cultured rat astrocytes and cerebral cortex of cirrhotic patients with hepatic encephalopathy. Glia 2015; 63:2092-2105. [PMID: 26102310 DOI: 10.1002/glia.22879] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Accepted: 06/08/2015] [Indexed: 12/30/2022]
Abstract
Hepatic encephalopathy (HE) is a neuropsychiatric syndrome frequently accompanying liver cirrhosis and reflects the clinical manifestation of a low grade cerebral edema associated with cerebral oxidative/nitrosative stress. The multidrug resistance-associated protein (Mrp) 4 is an export pump which transports metabolites that were recently suggested to play a major role in the pathogenesis of HE such as neurosteroids and cyclic nucleotides. We therefore studied Mrp4 expression changes in ammonia-exposed cultured astrocytes and postmortem human brain samples of cirrhotic patients with HE. NH4 Cl increased Mrp4 mRNA and protein levels in astrocytes in a dose- and time-dependent manner up to threefold after 72 h of exposure and concurrently inhibited N-glycosylation of Mrp4 protein. Upregulation of Mrp4 mRNA and protein as well as impaired N-glycosylation of Mrp4 protein by ammonia were sensitive towards the glutamine-synthetase inhibitor l-methionine-S-sulfoximine and were not induced by CH3 NH3 Cl (5 mmol/L). Upregulation of Mrp4 mRNA required ammonia-induced activation of nitric oxide synthases or NADPH oxidase and p38MAPK -dependent activation of PPARα. Inhibition of Mrp4 by ceefourin 1 synergistically enhanced both, inhibition of astrocyte proliferation as well as transcription of the oxidative stress surrogate marker heme oxygenase 1 by forskolin (10 µmol/L, 72 h) or NH4 Cl (5 mmol/L, 72 h) in cultured rat astrocytes. Increased Mrp4 mRNA and protein levels were also found in postmortem brain samples from patients with liver cirrhosis with HE but not in those without HE. The data show that Mrp4 is upregulated in HE, which may be relevant for the handling of neurosteroids and cyclic nucleotides in response to ammonia. GLIA 2015;63:2092-2105.
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Affiliation(s)
- Markus S Jördens
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine University, Düsseldorf, Germany
| | - Verena Keitel
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine University, Düsseldorf, Germany
| | - Ayse Karababa
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine University, Düsseldorf, Germany
| | - Irina Zemtsova
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine University, Düsseldorf, Germany
| | - Holger Bronger
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine University, Düsseldorf, Germany
| | - Dieter Häussinger
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine University, Düsseldorf, Germany
| | - Boris Görg
- Clinic for Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine University, Düsseldorf, Germany
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