scholarly journals Alcoholic-Hepatitis, Links to Brain and Microbiome: Mechanisms, Clinical and Experimental Research

Biomedicines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 63
Author(s):  
Manuela G. Neuman ◽  
Helmut Karl Seitz ◽  
Samuel W. French ◽  
Stephen Malnick ◽  
Heidekazu Tsukamoto ◽  
...  
Keyword(s):  
Liver Disease ◽  
Alcohol Consumption ◽  
Immune Responses ◽  
Alcoholic Hepatitis ◽  
Liver Steatosis ◽  
Hepatocellular Cancer ◽  
Organ Damage ◽  
Experimental Models ◽  
T Helper 17

The following review article presents clinical and experimental features of alcohol-induced liver disease (ALD). Basic aspects of alcohol metabolism leading to the development of liver hepatotoxicity are discussed. ALD includes fatty liver, acute alcoholic hepatitis with or without liver failure, alcoholic steatohepatitis (ASH) leading to fibrosis and cirrhosis, and hepatocellular cancer (HCC). ALD is fully attributable to alcohol consumption. However, only 10–20% of heavy drinkers (persons consuming more than 40 g of ethanol/day) develop clinical ALD. Moreover, there is a link between behaviour and environmental factors that determine the amount of alcohol misuse and their liver disease. The range of clinical presentation varies from reversible alcoholic hepatic steatosis to cirrhosis, hepatic failure, and hepatocellular carcinoma. We aimed to (1) describe the clinico-pathology of ALD, (2) examine the role of immune responses in the development of alcoholic hepatitis (ASH), (3) propose diagnostic markers of ASH, (4) analyze the experimental models of ALD, (5) study the role of alcohol in changing the microbiota, and (6) articulate how findings in the liver and/or intestine influence the brain (and/or vice versa) on ASH; (7) identify pathways in alcohol-induced organ damage and (8) to target new innovative experimental concepts modeling the experimental approaches. The present review includes evidence recognizing the key toxic role of alcohol in ALD severity. Cytochrome p450 CYP2E1 activation may change the severity of ASH. The microbiota is a key element in immune responses, being an inducer of proinflammatory T helper 17 cells and regulatory T cells in the intestine. Alcohol consumption changes the intestinal microbiota and influences liver steatosis and liver inflammation. Knowing how to exploit the microbiome to modulate the immune system might lead to a new form of personalized medicine in ALF and ASH.

Impact of PPAR-α induction on glucose homoeostasis in alcohol-fed mice

2013 ◽  
Vol 125 (11) ◽  
pp. 501-511 ◽  
Author(s):  
Valérie Lebrun ◽  
Olivier Molendi-Coste ◽  
Nicolas Lanthier ◽  
Christine Sempoux ◽  
Patrice D. Cani ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Liver Disease ◽  
Insulin Sensitivity ◽  
Alcohol Consumption ◽  
Insulin Signalling ◽  
Liver Steatosis ◽  
Hepatic Insulin Resistance ◽  
Alcoholic Fatty Liver ◽  
Glucose Homoeostasis

Alcohol consumption is a major cause of liver disease. It also associates with increased cardiovascular risk and Type 2 diabetes. ALD (alcoholic liver disease) and NAFLD (non-alcoholic fatty liver disease) share pathological features, pathogenic mechanisms and pattern of disease progression. In NAFLD, steatosis, lipotoxicity and liver inflammation participate to hepatic insulin resistance. The aim of the present study was to verify the effect of alcohol on hepatic insulin sensitivity and to evaluate the role of alcohol-induced steatosis and inflammation on glucose homoeostasis. C57BL/6J mice were fed for 20 days a modified Lieber–DeCarli diet in which the alcohol concentration was gradually increased up to 35% of daily caloric intake. OH (alcohol liquid diet)-fed mice had liver steatosis and inflammatory infiltration. In addition, these mice developed insulin resistance in the liver, but not in muscles, as demonstrated by euglycaemic–hyperinsulinaemic clamp and analysis of the insulin signalling cascade. Treatment with the PPAR-α (peroxisome-proliferator-activated receptor-α) agonist Wy14,643 protected against OH-induced steatosis and KC (Kupffer cell) activation and almost abolished OH-induced insulin resistance. As KC activation may modulate insulin sensitivity, we repeated the clamp studies in mice depleted in KC to decipher the role of macrophages. Depletion of KC using liposomes-encapsuled clodronate in OH-fed mice failed both to improve hepatic steatosis and to restore insulin sensitivity as assessed by clamp. Our study shows that chronic alcohol consumption induces steatosis, KC activation and hepatic insulin resistance in mice. PPAR-α agonist treatment that prevents steatosis and dampens hepatic inflammation also prevents alcohol-induced hepatic insulin resistance. However, KC depletion has little impact on OH-induced metabolic disturbances.

scholarly journals Role of hepatic macrophages in alcoholic liver disease

2016 ◽  
Vol 64 (6) ◽  
pp. 1075-1077 ◽  
Author(s):  
Cynthia Ju ◽  
Suthat Liangpunsakul
Keyword(s):  
Liver Disease ◽  
Alcohol Consumption ◽  
Immune Responses ◽  
Alcoholic Liver Disease ◽  
Phenotypic Diversity ◽  
Critical Role ◽  
Gut Permeability ◽  
Hepatic Macrophages ◽  
Translocation Of Bacteria

Alcohol consumption can lead to the increase in gut permeability and cause the translocation of bacteria-derived lipopolysaccharides from the gut to the liver, which subsequently activates immune responses. In this process, macrophages play a critical role and involve in the pathogenesis of alcoholic liver disease (ALD). To define the mechanism underpinning the function of macrophages, it is important to conduct extensive studies to further explicate the phenotypic diversity of macrophages in the context of ALD. In this review, the role of hepatic macrophages in the pathogenesis of ALD is discussed.

scholarly journals Role of autophagy in the pathogenesis of liver diseases

2011 ◽  
Vol 152 (49) ◽  
pp. 1955-1961 ◽  
Author(s):  
Klára Werling
Keyword(s):  
Endoplasmic Reticulum ◽  
Liver Disease ◽  
Liver Diseases ◽  
Liver Tumors ◽  
Liver Steatosis ◽  
Prognostic Significance ◽  
Adenosine Monophosphate ◽  
Mutant Proteins ◽  
Alpha 1 Antitrypsin Deficiency

Autophagy is a self-digestion process that plays an important role in the development, differentiation and homeostasis of cells, helping their survival during starvation and hypoxia. Accumulated mutant proteins in the endoplasmic reticulum can be degraded by autophagy in alpha-1 antitrypsin deficiency. Hepatitis C and B virus may exploit the autophagy pathway to escape the innate immune response and to promote their own replication. Autophagy is decreased in response to chronic alcohol consumption, likely due to a decrease in 5’-adenosine monophosphate-activated protein kinase, increase in mTOR activity and due to an alteration in vesicle transport in hepatocytes. In obesity and alcoholic liver disease the decreased function of autophagy causes formation of Mallory-Denk bodies and cell death. The deficient autophagy can contribute to liver steatosis, to endoplasmic reticulum stress, and to progression of liver disease. Autophagy defect in hepatocellular carcinoma suggests that it can serve a tumor-suppressor function. The autophagy protein Beclin-1 levels have prognostic significance in liver tumors. Understanding of the molecular mechanism and the role of autophagy may lead to more effective therapeutic strategies in liver diseases in the future. Orv. Hetil., 2011, 152, 1955–1961.

Liver disease: changing epidemiology

2020 ◽  
Vol 26 (3) ◽  
pp. 84-86
Author(s):  
George Winter
Keyword(s):  
Liver Disease ◽  
Alcohol Consumption ◽  
Viral Hepatitis ◽  
Significant Progress ◽  
Prevention And Treatment ◽  
The Uk

The UK has made significant progress in the prevention and treatment of viral hepatitis, yet the prevalence of severity of liver disease continues to rise. George Winter discusses the role of alcohol consumption and obesity in this changing epidemiology.

scholarly journals Adipokines in Nonalcoholic Steatohepatitis: From Pathogenesis to Implications in Diagnosis and Therapy

2009 ◽  
Vol 2009 ◽  
pp. 1-8 ◽  
Author(s):  
Emmanuel A. Tsochatzis ◽  
George V. Papatheodoridis ◽  
Athanasios J. Archimandritis
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Experimental Models ◽  
Liver Fat ◽  
Nonalcoholic Fatty Liver ◽  
The Metabolic Syndrome ◽  
Noninvasive Markers ◽  
End Stage ◽  
Multiple Hit

Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome and can vary from benign steatosis to end-stage liver disease. The pathogenesis of non-alcoholic steatohepatitis (NASH) is currently thought to involve a multiple-hit process with the first hit being the accumulation of liver fat which is followed by the development of necroinflammation and fibrosis. There is mounting evidence that cytokines secreted from adipose tissue, namely, adipokines, are implicated in the pathogenesis and progression of NAFLD. In the current review, we explore the role of these adipokines, particularly leptin, adiponectin, resistin, tumor necrosis factor-a, and interleukin-6 in NASH, as elucidated in experimental models and clinical practice. We also comment on their potential use as noninvasive markers for differentiating simple fatty liver from NASH as well as on their potential future therapeutic role in patients with NASH.

scholarly journals Urinary acrolein metabolite levels in severe acute alcoholic hepatitis patients

2019 ◽  
Vol 316 (1) ◽  
pp. G115-G122 ◽  
Author(s):  
Vatsalya Vatsalya ◽  
Maiying Kong ◽  
Leila Gobejishvili ◽  
Wei-Yang Chen ◽  
Sanjay Srivastava ◽  
...  
Keyword(s):  
Cell Death ◽  
Liver Disease ◽  
Proinflammatory Cytokines ◽  
Alcoholic Hepatitis ◽  
Pathogenic Role ◽  
Cytokeratin 18 ◽  
Acute Alcoholic Hepatitis ◽  
Noninvasive Biomarker ◽  
Liver Cell Death

Alcohol-associated liver disease (ALD) remains a major health concern worldwide. Alcohol consumption gives rise to reactive/toxic acrolein, a pathogenic mediator of liver injury in experimental ALD. Elevated acrolein adducts and metabolites are detectable in blood and urine. This study evaluates the major urinary acrolein metabolite, 3-hydroxypropylmercapturic acid (HPMA), in patients with acute alcoholic hepatitis (AAH) and examines its association with disease severity and markers of hepatic inflammation and injury. Urine HPMA was significantly higher in patients with severe [model for end-stage liver disease (MELD) ≥ 20] AAH compared with nonsevere AAH (MELD ≤ 19) or non-alcohol-consuming controls, suggesting that urine HPMA is a novel noninvasive biomarker in severe AAH. The association between HPMA and MELD in patients with AAH was nonlinear. In patients with nonsevere AAH, there was a positive trend, although not significant, whereas in severe AAH the association was negative, indicative of extensive injury and glutathione depletion. Consistent with the multifactorial etiology of ALD, our data identified strong combined effects of HPMA and proinflammatory cytokines on hepatocyte cell death, thereby supporting the pathogenic role of acrolein in liver injury. HPMA, together with IL-1β, showed robust associations with cytokeratin 18 caspase-cleaved fragment (CK18-M30; adjusted R2 = 0.812, P = 0.016) and cytokeratin 18 full-length protein (CK18-M65; adjusted R2 = 0.670, P = 0.048); similarly, HPMA, with IL-8, correlated with CK18-M30 (adjusted R2 = 0.875, P = 0.007) and CK18-M65 (adjusted R2 = 0.831, P = 0.013). The apoptosis index (CK18-M30:CK18-M65 ratio) strongly correlated with HPMA, together with IL-1β (adjusted R2 = 0.777, P = 0.022) or tumor necrosis factor-α (TNFα; adjusted R2 = 0.677, P = 0.046). In patients with severe AAH, IL-1β, IL-8, and TNFα are the predominant proinflammatory cytokines that interact with HPMA and play important mediating roles in influencing the extent/pattern of liver cell death. NEW & NOTEWORTHY This is the first study to examine the urinary acrolein metabolite 3-hydroxypropylmercapturic acid (HPMA) in alcoholic liver disease. HPMA was higher in patients with severe acute alcoholic hepatitis (AAH) compared with controls or nonsevere AAH and may be a novel selective, noninvasive biomarker for severe AAH. Consistent with the multifactorial etiology of alcohol-associated liver disease, we identified strong combined effects of HPMA and proinflammatory cytokines (IL-1β, IL-8, and TNFα) on the extent/pattern of liver cell death, thereby supporting the pathogenic role of acrolein.

Fatty liver disease in children

2011 ◽  
Author(s):  
R. Mark Beattie ◽  
Anil Dhawan ◽  
John W.L. Puntis
Keyword(s):  
Liver Disease ◽  
Alcohol Consumption ◽  
Liver Injury ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Alcoholic Hepatitis ◽  
Alcoholic Fatty Liver ◽  
End Stage Liver Disease ◽  
End Stage ◽  
Alcoholic Fatty Liver Disease

Demographics 406Pathophysiology 406Differential diagnoses 407Presenting features 407Investigation 408Management 409Fatty liver disease is now increasingly recognized in children, particularly in the setting of obesity.The term non-alcoholic steatohepatitis (NASH) was first coined in 1980 by Ludwig to describe a pattern of liver injury in adults in which the liver histology was consistent with alcoholic hepatitis, but in whom significant alcohol consumption was denied. NASH can be considered as part of a broader spectrum of non-alcoholic fatty liver disease that extends from simple steatosis through steatohepatitis that is characterized by the potential to progress to fibrosis, cirrhosis and subsequent end stage liver disease....

scholarly journals C57BL/6 and A/J Mice Have Different Inflammatory Response and Liver Lipid Profile in Experimental Alcoholic Liver Disease

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Lorena Bavia ◽  
Íris Arantes de Castro ◽  
Lourdes Isaac
Keyword(s):  
Liver Disease ◽  
Alcoholic Liver Disease ◽  
Genetic Background ◽  
Inflammatory Responses ◽  
Liver Lipid ◽  
Liver Steatosis ◽  
Public Health Issue ◽  
Mouse Strains ◽  
Mice Liver

Alcoholic liver disease (ALD) is an important worldwide public health issue characterized by liver steatosis, inflammation, necrosis, and apoptosis of hepatocytes with eventual development of fibrosis and cirrhosis. Comparison of murine models with different inflammatory responses for ALD is important for an evaluation of the importance of genetic background in the interpretation of ethanol-induced phenotypes. Here, we investigated the role of inflammation and genetic background for the establishment of ALD using two different mouse strains: C57BL/6 (B6) and A/J. B6 and A/J mice were treated with a high fat diet containing ethanol (HFDE) and compared to the controls for 10 weeks. Hepatomegaly and steatohepatitis were similar in B6 and A/J mice, but only A/J mice were resistant to weight gain. On the other hand, HFDE-fed B6 accumulated more triglycerides (TG) and cholesterol and presented more intense cellular infiltrate in the liver when compared to HFDM-fed mice. Liver inflammatory environment was distinct in these two mouse strains. While HFDE-fed B6 produced more liver IL-12, A/J mice increased the TNF-αproduction. We concluded that mouse genetic background could dictate the intensity of the HFDE-induced liver injury.

scholarly journals S0965 Role of Metadoxine in Alcoholic Fatty Liver Disease and Alcoholic Hepatitis

2020 ◽  
Vol 115 (1) ◽  
pp. S493-S493
Author(s):  
Zaid Ansari ◽  
Mays Almohammedawi ◽  
Ali Alshati ◽  
Shehroz Aslam ◽  
Dimas Kosa ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Alcoholic Hepatitis ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

scholarly journals NLRP6 Inflammasome Modulates Disease Progression in a Chronic-Plus-Binge Mouse Model of Alcoholic Liver Disease

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 182
Author(s):  
Rebecca Elena Mainz ◽  
Stefanie Albers ◽  
Madhuri Haque ◽  
Roland Sonntag ◽  
Nicole Simone Treichel ◽  
...  
Keyword(s):  
Liver Disease ◽  
Mouse Model ◽  
Alcoholic Liver Disease ◽  
Immune Cell ◽  
Liver Steatosis ◽  
Neutrophil Infiltration ◽  
Ethanol Administration ◽  
Intestinal Homeostasis ◽  
Binge Ethanol

A considerable percentage of the population is affected by alcoholic liver disease (ALD). It is characterized by inflammatory signals from the liver and other organs, such as the intestine. The NLR family pyrin domain containing 6 (NLRP6) inflammasome complex is one of the most important inflammatory mediators. The aim of this study was to evaluate a novel mouse model for ALD characterized by 8-week chronic-plus-binge ethanol administration and to investigate the role of NLRP6 inflammasome for intestinal homeostasis and ALD progression using Nlrp6-/- mice. We showed that chronic-plus-binge ethanol administration triggers hepatic steatosis, injury, and neutrophil infiltration. Furthermore, we discovered significant changes of intestinal microbial communities, including increased relative abundances of bacteria within the phyla Bacteroidota and Campilobacterota, as well as reduced Firmicutes. In this ALD model, inhibiting NLRP6 signaling had no effect on liver steatosis or damage, but had a minor impact on intestinal homeostasis via affecting intestinal epithelium function and gut microbiota. Surprisingly, Nlrp6 loss resulted in significantly decreased hepatic immune cell infiltration. As a result, our novel mouse model encompasses several aspects of human ALD, such as intestinal dysbiosis. Interfering with NLRP6 inflammasome activity reduced hepatic immune cell recruitment, indicating a disease-aggravating role of NLRP6 during ALD.

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