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  • 1
    In: Alcohol and Alcoholism, 2017, Vol. 52(suppl1), pp.i4-i30
    ISSN: 0735-0414
    E-ISSN: 1464-3502
    Source: Oxford University Press
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  • 2
    Language: English
    In: Gut, 16 July 2014, Vol.63(7), p.1039
    Description: The c-Jun-N-terminal kinase (JNK) is a member of the mitogen-activated protein kinase (MAPK) family. Upon activation, JNK regulates various cellular responses, such as differentiation, proliferation, migration, the immune reaction and cell death.1 JNK activation is also involved in multiple pathways in liver physiology and disease pathogenesis.2
    Keywords: Hepatic Fibrosis ; Hepatic Stellate Cell
    ISSN: 0017-5749
    ISSN: 00175749
    E-ISSN: 1468-3288
    E-ISSN: 14683288
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  • 3
    Language: English
    In: Pflügers Archiv - European Journal of Physiology, 2013, Vol.465(6), pp.775-778
    Description: Hepatic stellate cells (HSCs) are pericytes of liver in the space between parenchymal cells and sinusoidal endothelial cells of the hepatic lobule. HSCs comprise specialized functions such as vitamin A storage, hemodynamic functions, support of liver regeneration, and immunoregulation. In pathological conditions, HSCs transform to an activated myofibroblasts-like phenotype, start to proliferate, and de novo express several proinflammatory and profibrogenic genes. These processes are particularly important in the development of cirrhosis, portal hypertension, and hepatocellular cancer. This review highlights recent findings in understanding the biology of HSCs and discusses the physiological functions of HSCs and the role of activated HSCs in pathophysiology and disease.
    Keywords: Hepatic stellate cell ; Myofibroblast ; Pericyte ; Fibrosis ; Immunoregulation ; Vasoregulation ; Hepatocellular cancer
    ISSN: 0031-6768
    E-ISSN: 1432-2013
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  • 4
    Article
    Article
    BMJ Publishing Group Ltd and British Society of Gastroenterology
    Language: English
    In: Gut, 21 October 2010, Vol.59(10), p.1303
    Description: Lipid accumulation in hepatocytes and hepatoma cells induces cancer-related molecular signalling involving nuclear factor kappaB (NF-κB) and c-Jun N-terminal kinase(JNK)/activator protein-1 activity, and overexpression of tumour growth-promoting genes, respectively.11–14 For example, unsaturated fatty acids inhibit the expression of phosphatase and tensin homologue (PTEN) in hepatocytes via activation of an NF-κB/mammalian target of rapamycin (mTOR) complex.15 16 PTEN is a regulator of phosphoinositide 3-kinase (PI3K) signalling and an important tumour suppressor mutated/deleted in HCC, and consistently, HCC growth and progression were significantly increased in a xenograft model of mice fed with an oleic acid-enriched diet, even without weight gain.15
    Keywords: Hepatocellular Carcinoma ; Non-Alcoholic Steatohepatitis
    ISSN: 0017-5749
    ISSN: 00175749
    E-ISSN: 1468-3288
    E-ISSN: 14683288
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  • 5
    Language: English
    In: Alcoholism, clinical and experimental research, July 2011, Vol.35(7), pp.1361-7
    Description: Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are the most frequent conditions leading to elevated liver enzymes and liver cirrhosis, respectively, in the Western world. However, despite strong epidemiological evidence for combined effects on the progression of liver injury, the mutual interaction of the pathophysiological mechanisms is incompletely understood. The aim of this study was to establish and analyze an experimental murine model, where we combined chronic alcohol administration with a NASH-inducing high-fat (HF) diet. Balb/c mice were randomly allocated into 4 experimental groups receiving (i) standard chow, (ii) an HF diet, (iii) alcohol in drinking water (increasing concentrations up to 5%), or (iv) an HF diet and alcohol ad libitum for 6 weeks. An HF diet significantly induced hepatic triglyceride accumulation and expression of proinflammatory genes (p47(phox) and tumor necrosis factor), while the effects of alcohol alone were less pronounced. However, in combination with HF diet, alcohol significantly enhanced proinflammatory gene expression compared to the HF diet alone. Furthermore, alcohol as well as HF diet led to a marked increase in profibrogenic genes (collagen type I and transforming growth factor-β), activation of hepatic stellate cells, and extracellular matrix deposition in the liver tissue, and noteworthy, the combination of both alcohol and HF diet led to a further marked induction of hepatic fibrosis. Moreover, endotoxin levels in the portal circulation were significantly elevated in mice that received alcohol or HF diet and were further significantly increased in those receiving both. Furthermore and surprisingly, HF diet alone and in combination with alcohol led to a markedly increased hepatic expression of the endotoxin receptor Toll-like receptor 4 (TLR4), which is known to play a crucial role in hepatic fibrosis. In summary, this new model allows the investigation of isolated or joint effects of alcohol and HF diet on hepatic injury, where alcohol and HF diet appear to act synergistically on the development of hepatic fibrosis, potentially via enhanced TLR4 signaling.
    Keywords: Disease Models, Animal ; Dietary Fats -- Toxicity ; Ethanol -- Toxicity ; Liver Cirrhosis -- Chemically Induced
    ISSN: 01456008
    E-ISSN: 1530-0277
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  • 6
    Language: English
    In: Biochemical and Biophysical Research Communications, 28 September 2012, Vol.426(3), pp.404-408
    Description: ► The expression of the atypical cadherin FAT1 is increased in chronic liver disease. ► FAT1 expression goes up during the activation of hepatic stellate cells (HSCs). ► Activated HSCs are the cellular source of enhanced FAT1 expression in diseased livers. ► FAT1 enhanced NFkB activity and resistance to apoptosis in activated HSCs. ► FAT1 is a new therapeutic target for prevention and treatment of hepatic fibrosis. Hepatic fibrosis can be considered as wound healing process in response to hepatocellular injury. Activation of hepatic stellate cells (HSCs) is a key event of hepatic fibrosis since activated HSCs are the cellular source of enhanced extracellular matrix deposition, and reversion of liver fibrosis is accompanied by clearance of activated HSCs by apoptosis. The atypical cadherin FAT1 has been shown to regulate diverse biological functions as cell proliferation and planar cell polarity, and also to affect wound healing. Here, we found increased FAT1 expression in different murine models of chronic liver injury and in cirrhotic livers of patients with different liver disease. Also in hepatic tissue of patients with non-alcoholic steatohepatitis FAT1 expression was significantly enhanced and correlated with collagen alpha I(1) expression. Immunohistochemistry revealed no significant differences in staining intensity between hepatocytes in normal and cirrhotic liver tissue but myofibroblast like cells in fibrotic septa of cirrhotic livers showed a prominent immunosignal. Furthermore, FAT1 mRNA and protein expression markedly increased during activation of primary human and murine HSCs. Together, these data indicated activated HSCs as cellular source of enhanced FAT1 expression in diseased livers. To gain insight into the functional role of FAT1 in activated HSCs we suppressed FAT1 in these cells by siRNA. We newly found that FAT1 suppression in activated HSCs caused a downregulation of NFκB activity. This transcription factor is critical for apoptosis resistance of HSCs, and consequently, we detected a higher apoptosis rate in FAT1 suppressed HSCs compared to control cells. Our findings suggest FAT1 as new therapeutic target for the prevention and treatment of hepatic fibrosis in chronic liver disease.
    Keywords: Fat1 ; Cadherin ; Hepatic Fibrosis ; Apoptosis ; Hepatic Stellate Cells ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0006-291X
    E-ISSN: 1090-2104
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  • 7
    In: Alcohol and Alcoholism, 2017, Vol. 52(suppl1), pp.i4-i30
    ISSN: 0735-0414
    E-ISSN: 1464-3502
    Source: Oxford University Press
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  • 8
    Article
    Article
    BMJ Publishing Group Ltd and British Society of Gastroenterology
    Language: English
    In: Gut, 15 March 2019, Vol.68(3), p.382
    Description: Lipolytic enzymes have received huge attention due to their crucial role in lipid metabolism and as potential pharmacological targets against obesity and its related disorders. Non-alcoholic fatty liver disease (NAFLD) is highly associated with obesity and today, NAFLD is considered to be the most common chronic liver disorders worldwide.1 The NAFLD pathology covers a wide spectrum of changes, ranging from simple steatosis to non-alcoholic steatohepatitis, progressive fibrosis/cirrhosis and hepatocellular carcinoma (HCC). The underlying mechanisms, particularly those that drive disease progression, are only incompletely understood.1 Central drivers appear to be quantitative and qualitative alterations in lipid metabolic pathways in hepatocytes.1 2 In addition, the impact of altered lipid metabolism in non-parenchymal liver cells and immune cells is increasingly recognised.1 3 Importantly, lipids are stored within the cells and act as signalling molecules or precursors thereof, which further enhances the level of complexity how alterations in the lipid metabolism affect the course of obesity-related diseases.
    Keywords: Lipids ; Liver Metabolism ; Macrophages
    ISSN: 0017-5749
    ISSN: 00175749
    E-ISSN: 1468-3288
    E-ISSN: 14683288
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  • 9
    Language: English
    In: Digestive Diseases, April 2011, Vol.28(6), pp.783-791
    Description: Chronic alcohol consumption is one of the main etiological factors for liver disease worldwide, however only a fraction of drinkers develop significant hepatic inflammation (alcoholic steatohepatitis), and even less progress to significant hepatic fibrosis and cirrhosis. The pathophysiological significance of hepatic lipid accumulation in the absence of significant alcohol consumption is also increasingly recognized. Non-alcoholic fatty liver disease (NAFLD) is regarded as the hepatic manifestation of the metabolic syndrome, and it is the most common cause of liver enzyme elevations in Western countries. Similarly to alcoholic liver disease, NAFLD encompasses mild hepatic steatosis to non-alcoholic steatohepatitis with significant necroinflammation and progressive fibrosis. Several clinical studies suggest a strong causative link between the consumption of alcohol and progressive liver disease in individuals with high fat intake and/or diabetes. However, it is incompletely understood how alcohol and obesity interact and whether the combined effects on the progression of liver injury are additive or synergistic. This review describes single as well as combined effects of alcohol and (components of) the metabolic syndrome on hepatic steatosis, inflammation and fibrosis. In addition to direct effects on the liver, the view is expanded to other organs affected by chronic alcohol consumption or the metabolic syndrome, to understand also extrahepatic pathophysiological mechanisms involved in hepatocellular injury. Undoubtedly, alcohol and the metabolic syndrome appear as a dangerous mix, and there are important synergistic effects of either condition with regard to crucial triggers of liver injury.
    Keywords: Pathomechanisms of Alcohol-Induced Damage ; Alcoholic Liver Disease ; Alcoholic Steatohepatitis ; Non-Alcoholic Fatty Liver Disease ; Non-Alcoholic Steatohepatitis ; Metabolic Syndrome ; Medicine
    ISBN: 9783805597326
    ISBN: 3805597320
    ISSN: 0257-2753
    E-ISSN: 1421-9875
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  • 10
    Language: English
    In: Gastroenterology, 2010, Vol.138(1), pp.372-382
    Description: Recent studies identified bone morphogenic protein 6 (BMP6) as a key regulator of hepatic hepcidin expression and iron metabolism, but the cellular source of BMP6 and the reason for its specific effect on hepatocytes are unknown. BMP and hepcidin expression upon iron sensing were analyzed in vivo in BMP6 and BMP6 mice and ex vivo in tissue and in vitro in cells of the liver and the small intestine. BMP6 mice developed severe hepatic iron accumulation and reduced hepcidin expression with increasing age. This phenotype could be triggered in younger BMP6 mice by dietary or parenteral iron application. Furthermore, both treatments induced a marked up-regulation of BMP6 expression in the small intestine of BMP6 mice. Ex vivo treatment of intestinal tissue of BMP6 mice with iron sulfate or holo-transferrin confirmed epithelial cells as an inducible source of BMP6. In contrast, iron overload did not promote a striking induction of BMP6 expression in hepatocytes or macrophages. Furthermore, iron-supplemented diet induced a compensatory up-regulation of BMP2, BMP4, and BMP9 in the small intestine of BMP6 mice that was apparently not sufficient to assure iron homeostasis. As a potential explanation, analysis of hepatocytes revealed an expression pattern of BMP receptor subunits preferentially used by BMP6, and treatment of hepatocytes with different recombinant BMPs identified BMP6 as the most potent stimulator of hepcidin expression. Epithelial cells of the small intestine are the predominant cellular source of BMP6 upon iron sensing. Our findings reveal a previously unknown mechanism in which the small intestine controls iron homeostasis.
    Keywords: Medicine
    ISSN: 0016-5085
    E-ISSN: 1528-0012
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