scholarly journals New Insights into the Pathogenesis of Alcohol-Induced ER Stress and Liver Diseases

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Cheng Ji
Keyword(s):  
Liver Disease ◽  
Alcohol Consumption ◽  
Er Stress ◽  
Liver Diseases ◽  
Cell Cycle Progression ◽  
Alcohol Exposure ◽  
Cellular Protein ◽  
Protein Homeostasis ◽  
Lipid Species

Alcohol-induced liver disease increasingly contributes to human mortality worldwide. Alcohol-induced endoplasmic reticulum (ER) stress and disruption of cellular protein homeostasis have recently been established as a significant mechanism contributing to liver diseases. The alcohol-induced ER stress occurs not only in cultured hepatocytes but also in vivo  in the livers of several species including mouse, rat, minipigs, zebrafish, and humans. Identified causes for the ER stress include acetaldehyde, oxidative stress, impaired one carbon metabolism, toxic lipid species, insulin resistance, disrupted calcium homeostasis, and aberrant epigenetic modifications. Importance of each of the causes in alcohol-induced liver injury depends on doses, duration and patterns of alcohol exposure, genetic disposition, environmental factors, cross-talks with other pathogenic pathways, and stages of liver disease. The ER stress may occur more or less all the time during alcohol consumption, which interferes with hepatic protein homeostasis, proliferation, and cell cycle progression promoting development of advanced liver diseases. Emerging evidence indicates that long-term alcohol consumption and ER stress may directly be involved in hepatocellular carcinogenesis (HCC). Dissecting ER stress signaling pathways leading to tumorigenesis will uncover potential therapeutic targets for intervention and treatment of human alcoholics with liver cancer.

scholarly journals ER stress causes widespread protein aggregation and prion formation

2017 ◽  
Vol 216 (8) ◽  
pp. 2295-2304 ◽  
Author(s):  
Norfadilah Hamdan ◽  
Paraskevi Kritsiligkou ◽  
Chris M. Grant
Keyword(s):  
Protein Aggregation ◽  
Er Stress ◽  
Secretory Pathway ◽  
Cellular Protein ◽  
Protein Homeostasis ◽  
Er Quality Control ◽  
Unfolded Protein ◽  
The Unfolded Protein Response ◽  
Protein Response ◽  
Er Homeostasis

Disturbances in endoplasmic reticulum (ER) homeostasis create a condition termed ER stress. This activates the unfolded protein response (UPR), which alters the expression of many genes involved in ER quality control. We show here that ER stress causes the aggregation of proteins, most of which are not ER or secretory pathway proteins. Proteomic analysis of the aggregated proteins revealed enrichment for intrinsically aggregation-prone proteins rather than proteins which are affected in a stress-specific manner. Aggregation does not arise because of overwhelming proteasome-mediated degradation but because of a general disruption of cellular protein homeostasis. We further show that overexpression of certain chaperones abrogates protein aggregation and protects a UPR mutant against ER stress conditions. The onset of ER stress is known to correlate with various disease processes, and our data indicate that widespread amorphous and amyloid protein aggregation is an unanticipated outcome of such stress.

scholarly journals A Mouse Model Of Binge Alcohol Consumption andBurkholderiaInfection

2018 ◽  
Author(s):  
Victor Jimenez ◽  
Ryan Moreno ◽  
Erik Settles ◽  
Bart J Currie ◽  
Paul Keim ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Binge Drinking ◽  
Burkholderia Pseudomallei ◽  
Alcohol Exposure ◽  
Model Systems ◽  
Phagocytic Cells ◽  
Intracellular Invasion ◽  
The Impact

AbstractBackgroundBinge drinking, a common form of alcohol consumption, is associated with increased mortality and morbidity; yet, its effects on the immune system’s ability to defend against infectious agents are poorly understood.Burkholderia pseudomallei, the causative agent of melioidosis can occur in healthy humans, yet binge alcohol use is progressively being recognized as a major risk factor. Although our previous studies demonstrated that binge alcohol exposure results in reduced alveolar macrophage function and increasedBurkholderiavirulencein vitro, no experimental studies have investigated the outcomes of binge alcohol onBurkholderiaspp. infectionin vivo.Principal FindingsWe used the close genetic relatives ofB. pseudomallei, B. thailandensisE264 andB. vietnamiensis, as useful BSL-2 model systems. Eight-week-old female C57BL/6 mice were administered alcohol comparable to human binge drinking episodes (4.4 g/kg) or PBS intraperitoneally 30 min before a non-lethal intranasal infection. In an initialB. thailandensisinfection (3 x 105), bacteria accumulated in the lungs and disseminated to the spleen in alcohol administered mice only, compared with PBS treated mice at 24 h post-infection (PI). The greatest bacterial load occurred withB. vietnamiensis(1 x 106) in lungs, spleen, and brain tissue by 72 h PI. Pulmonary cytokine expression (TNF-α, GM-CSF) decreased, while splenic cytokine (IL-10) increased in binge drunk mice. Increased lung and brain permeability was observed as early as 2 h post alcohol administrationin vivo.Trans-epithelial electrical resistance (TEER) was significantly decreased, while intracellular invasion of non-phagocytic cells increased with 0.2% v/v alcohol exposurein vitro.ConclusionsOur results indicate that a single binge alcohol dose suppressed innate immune functions and increased the ability of less virulentBurkholderiastrains to disseminate through increased barrier permeability and intracellular invasion of non-phagocytic cells.Author SummaryBurkholderia pseudomalleicauses the disease melioidosis, which occurs in most tropical regions across the globe. Exposure rarely evolves to significant disease in the absence of specific comorbidities, such as binge alcohol intoxication. In susceptible hosts, the disease is primarily manifested as pneumonic melioidosis and can be rapidly fatal if untreated. In this study, we utilizedB. thailandensis, a genetically similar strain toB. pseudomallei, and opportunisticB. vietnamiensis, a known human pathogen that utilizes similar virulence strategies asB. pseudomalleiin immunocompromised and cystic fibrosis patients. The study investigates the impact of a single binge alcohol episode on infectivity and immune responsein vivo. We show that a single binge alcohol episode prior to inhalingBurkholderiaspecies increases bacterial spread to the lungs and brain. We also identify alcohol-induced tissue permeability and epithelial cell invasion as modes of action for greater bacterial spread and survival inside the host. Our results support the public health responses being developed in melioidosis-endemic regions that emphasize the nature of binge drinking as a prime concern, especially around potential times of exposure to environmentalB. pseudomallei.

scholarly journals Alcohol drinking and risks of liver cancer and non-neoplastic chronic liver diseases in China: a 10-year prospective study of 0.5 million adults

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Pek Kei Im ◽  
Iona Y. Millwood ◽  
Christiana Kartsonaki ◽  
Yu Guo ◽  
Yiping Chen ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Liver Disease ◽  
Alcohol Consumption ◽  
Liver Cancer ◽  
Liver Diseases ◽  
Alcohol Intake ◽  
Chronic Liver ◽  
Drinking Patterns ◽  
Chronic Liver Diseases ◽  
Alcoholic Fatty Liver

Abstract Background Alcohol consumption is an important risk factor for hepatic neoplastic and non-neoplastic diseases. Questions remain, however, about the relevance to disease risk of drinking patterns and alcohol tolerability, which differ appreciably between Chinese and Western populations. Methods The prospective China Kadoorie Biobank included 512,715 adults (41% men) aged 30–79 years recruited from ten areas during 2004–2008, recording alcohol intake, drinking patterns, and other characteristics. After median 10 years’ follow-up, 2531 incident liver cancer, 2040 liver cirrhosis, 260 alcoholic liver disease (ALD), and 1262 non-alcoholic fatty liver disease (NAFLD) cases were recorded among 492,643 participants without prior cancer or chronic liver disease at baseline. Cox regression was used to estimate adjusted hazard ratios (HR) relating alcohol intake and drinking patterns to each disease. Results Overall, 33% of men and 2% of women drank alcohol regularly (i.e. at least weekly) at baseline. Among male current regular drinkers, alcohol consumption showed positive dose-response associations with risks of several major chronic liver diseases, with HRs per 280 g/week (i.e. around four drinks/day) higher usual alcohol intake of 1.44 (95% CI 1.23–1.69) for liver cancer (n = 547), 1.83 (1.60–2.09) for liver cirrhosis (n = 388), 2.01 (1.77–2.28) for ALD (n = 200), 1.71 (1.35–2.16) for NAFLD (n = 198), and 1.52 (1.40–1.64) for total liver disease (n = 1775). The association with ALD appeared stronger among men reporting flushing (i.e., with low alcohol tolerance). After adjustment for the total amount of weekly alcohol consumption, daily drinkers had significantly increased risk of ALD (2.15, 1.40–3.31) compared with non-daily drinkers, and drinking without meals was associated with significantly greater risks of liver cancer (1.32, 1.01–1.72), liver cirrhosis (1.37, 1.02–1.85), and ALD (1.60, 1.09–2.33) compared with drinking with meals. Female current regular drinkers had significantly higher risk of ALD, but not other liver diseases, than female abstainers. Conclusions In Chinese men, alcohol intake was associated with significantly increased risks of several major chronic liver diseases, and certain drinking patterns (e.g. drinking daily, drinking without meals) may further exacerbate the disease risks.

scholarly journals Alcohol induced hepatic retinoid depletion is associated with the induction of multiple retinoid catabolizing cytochrome P450 enzymes

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0261675
Author(s):  
Afroza Ferdouse ◽  
Rishi R. Agrawal ◽  
Madeleine A. Gao ◽  
Hongfeng Jiang ◽  
William S. Blaner ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Retinoic Acid ◽  
Liver Disease ◽  
Alcohol Consumption ◽  
Vitamin A ◽  
Alcohol Exposure ◽  
Chronic Alcohol ◽  
Wild Type ◽  
Chronic Alcohol Consumption ◽  
Retinyl Esters

Chronic alcohol consumption leads to a spectrum of liver disease that is associated with significant global mortality and morbidity. Alcohol is known to deplete hepatic vitamin A content, which has been linked to the pathogenesis of alcoholic liver disease. It has been suggested that induction of Cytochrome P450 2E1 (CYP2E1) contributes to alcohol-induced hepatic vitamin A depletion, but the possible contributions of other retinoid-catabolizing CYPs have not been well studied. The main objective of this study was to better understand alcohol-induced hepatic vitamin A depletion and test the hypothesis that alcohol-induced depletion of hepatic vitamin A is due to CYP-mediated oxidative catabolism. This hypothesis was tested in a mouse model of chronic alcohol consumption, including wild type and Cyp2e1 -/- mice. Our results show that chronic alcohol consumption is associated with decreased levels of hepatic retinol, retinyl esters, and retinoic acid. Moreover, the depletion of hepatic retinoid is associated with the induction of multiple retinoid catabolizing CYPs, including CYP26A1, and CYP26B1 in alcohol fed wild type mice. In Cyp2e1 -/- mice, alcohol-induced retinol decline is blunted but retinyl esters undergo a change in their acyl composition and decline upon alcohol exposure like WT mice. In conclusion, the alcohol induced decline in hepatic vitamin A content is associated with increased expression of multiple retinoid-catabolizing CYPs, including the retinoic acid specific hydroxylases CYP26A1 and CYP26B1.

scholarly journals Effects of chronic voluntary alcohol consumption on PDE10A availability: a longitudinal behavioural and [18F]JNJ42259152 PET study in rats

2021 ◽  
Author(s):  
Bart de Laat ◽  
Yvonne E. Klingl ◽  
Gwen Schroyen ◽  
Maarten Ooms ◽  
Jacob M Hooker ◽  
...  
Keyword(s):  
Decision Making ◽  
Alcohol Consumption ◽  
Alcohol Intake ◽  
Iowa Gambling Task ◽  
Alcohol Exposure ◽  
Alcohol Preference ◽  
Binding Potential ◽  
Reference Tissue ◽  
Volume Of Interest

Abstract Purpose Phosphodiesterase 10A (PDE10A) is a dual substrate enzyme highly enriched in dopamine-receptive striatal medium spiny neurons, which are involved in psychiatric disorders such as alcohol use disorders (AUD). Although preclinical studies suggest a correlation of PDE10A mRNA expression in neuronal and behavioral responses to alcohol intake, little is known about the effects of alcohol exposure on in vivo PDE10A activity in relation to apparent risk factors for AUD such as decision-making and anxiety. Methods We performed a longitudinal [18F]JNJ42259152 microPET study to evaluate PDE10A changes over a 9-week intermittent access to alcohol model, including 6 weeks of alcohol exposure, 2 weeks of abstinence followed by 1 week relapse. Parametric PDE10A binding potential (BPND) images were generated using a Logan reference tissue model with cerebellum as reference region and were analyzed using both a volume-of-interest and voxel-based approach. Moreover, individual decision-making and anxiety levels were assessed with the rat Iowa Gambling Task and open field test over the IAE model. Results We observed an increased alcohol preference especially in those animals that exhibited poor initial decision-making. The first 2-weeks of alcohol exposure resulted in an increased striatal PDE10A binding (> 10%). Comparing PDE10A binding potential after 2- versus 4-weeks of exposure, showed a significant decreased PDE10A in the caudate-putamen and nucleus accumbens (pFWEcorrected<0.05). This striatal PDE10A decrease was related to alcohol consumption and preference. Normalization of striatal PDE10A to initial levels was observed after 1 week of relapse, apart from the globus pallidus. Conclusion This study shows that chronic voluntary alcohol consumption induces a reversible increased PDE10A enzymatic availability in the striatum, which is related to the amount of alcohol preference. Thus, PDE10A-mediated signaling plays an important role in modulating the reinforcing effects of alcohol, and the data suggest that PDE10A inhibition may have beneficial behavioral effects on alcohol intake.

scholarly journals How to design an optimal sensor network for the unfolded protein response

2018 ◽  
Vol 29 (25) ◽  
pp. 3052-3062 ◽  
Author(s):  
Wylie Stroberg ◽  
Hadar Aktin ◽  
Yonatan Savir ◽  
Santiago Schnell
Keyword(s):  
Er Stress ◽  
Unfolded Protein Response ◽  
Cellular Protein ◽  
Protein Accumulation ◽  
Protein Homeostasis ◽  
Unfolded Protein ◽  
Stress Sensing ◽  
Coarse Model ◽  
The Unfolded Protein Response ◽  
Protein Response

Cellular protein homeostasis requires continuous monitoring of stress in the endoplasmic reticulum (ER). Stress-detection networks control protein homeostasis by mitigating the deleterious effects of protein accumulation, such as aggregation and misfolding, with precise modulation of chaperone production. Here, we develop a coarse model of the unfolded protein response in yeast and use multi-objective optimization to determine which sensing and activation strategies optimally balance the trade-off between unfolded protein accumulation and chaperone production. By comparing a stress-sensing mechanism that responds directly to the level of unfolded protein in the ER to a mechanism that is negatively regulated by unbound chaperones, we show that chaperone-mediated sensors are more efficient than sensors that detect unfolded proteins directly. This results from the chaperone-mediated sensor having separate thresholds for activation and deactivation. Finally, we demonstrate that a sensor responsive to both unfolded protein and unbound chaperone does not further optimize homeostatic control. Our results suggest a strategy for designing stress sensors and may explain why BiP-mitigated ER stress-sensing networks have evolved.

scholarly journals Does moderate alcohol consumption accelerate the progression of liver disease in NAFLD? A systematic review and narrative synthesis

BMJ Open ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. e049767
Author(s):  
Helen Jarvis ◽  
Hannah O'Keefe ◽  
Dawn Craig ◽  
Daniel Stow ◽  
Barbara Hanratty ◽  
...  
Keyword(s):  
Systematic Review ◽  
Liver Disease ◽  
Alcohol Consumption ◽  
Disease Progression ◽  
Meta Analysis ◽  
Alcohol Exposure ◽  
Cochrane Library ◽  
Narrative Synthesis ◽  
Moderate Alcohol Consumption ◽  
Liver Disease Progression

ObjectivesLiver disease is a leading cause of premature death, partly driven by the increasing incidence of non-alcohol-related fatty liver disease (NAFLD). Many people with a diagnosis of NAFLD drink moderate amounts of alcohol. There is limited guidance for clinicians looking to advise these patients on the effect this will have on their liver disease progression. This review synthesises the evidence on moderate alcohol consumption and its potential to predict liver disease progression in people with diagnosed NAFLD.MethodsA systematic review of longitudinal observational cohort studies was conducted. Databases (Medline, Embase, The Cochrane Library and ClinicalTrials.gov) were searched up to September 2020. Studies were included that reported progression of liver disease in adults with NAFLD, looking at moderate levels of alcohol consumption as the exposure of interest. Risk of bias was assessed using the Quality in Prognostic factor Studies tool.ResultsOf 4578 unique citations, 6 met the inclusion criteria. Pooling of data was not possible due to heterogeneity and studies were analysed using narrative synthesis. Evidence suggested that any level of alcohol consumption is associated with worsening of liver outcomes in NAFLD, even for drinking within recommended limits. Well conducted population based studies estimated up to a doubling of incident liver disease outcomes in patients with NAFLD drinking at moderate levels.ConclusionsThis review found that any level of alcohol intake in NAFLD may be harmful to liver health.Study heterogeneity in definitions of alcohol exposure as well as in outcomes limited quantitative pooling of results. Use of standardised definitions for exposure and outcomes would support future meta-analysis.Based on this synthesis of the most up to date longitudinal evidence, clinicians seeing patients with NAFLD should currently advise abstinence from alcohol.PROSPERO registration numberThe protocol was registered with PROSPERO (#CRD42020168022).

A Metabonomics Approach to Drug Toxicology in Liver Disease and its Application in Traditional Chinese Medicine

2019 ◽  
Vol 20 (4) ◽  
pp. 292-300 ◽  
Author(s):  
Guangyue Su ◽  
Haifeng Wang ◽  
Jiao Bai ◽  
Gang Chen ◽  
Yuehu Pei
Keyword(s):  
Liver Disease ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Liver Diseases ◽  
Biomarker Discovery ◽  
Protective Mechanisms ◽  
Metabolic Transformation ◽  
Drug Interventions ◽  
Endogenous Metabolites

Background: The progression of liver disease causes metabolic transformation in vivo and thus affects corresponding endogenous small molecular compounds. Metabonomics is a powerful technology which is able to assess global low-molecular-weight endogenous metabolites in a biological system. This review is intended to provide an overview of a metabonomics approach to the drug toxicology of diseases of the liver. Methods: The regulation of, and relationship between, endogenous metabolites and diseases of the liver is discussed in detail. Furthermore, the metabolic pathways involved in drug interventions of liver diseases are reviewed. Evaluation of the protective mechanisms of traditional Chinese medicine in liver diseases using metabonomics is also reviewed. Examples of applications of metabolite profiling concerning biomarker discovery are highlighted. In addition, new developments and future prospects are described. Results: Metabonomics can measure changes in metabolism relating to different stages of liver disease, so metabolic differences can provide a basis for the diagnosis, treatment and prognosis of various diseases. Conclusion: Metabonomics has great advantages in all aspects of the therapy of liver diseases, with good prospects for clinical application.

scholarly journals Etiology and Viral Genotype in Patients with End-Stage Liver Diseases admitted to a Hepatology Unit in Colombia

2011 ◽  
Vol 2011 ◽  
pp. 1-10 ◽  
Author(s):  
Fabian Cortes-Mancera ◽  
Carmen Luisa Loureiro ◽  
Sergio Hoyos ◽  
Juan-Carlos Restrepo ◽  
Gonzalo Correa ◽  
...  
Keyword(s):  
Risk Factor ◽  
Liver Disease ◽  
Alcohol Consumption ◽  
Liver Diseases ◽  
Core Promoter ◽  
Hepatic Tissue ◽  
Basal Core Promoter ◽  
Tissue Samples ◽  
Viral Aetiology ◽  
End Stage

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are the principal risk factor associated to end-stage liver diseases in the world. A study was carried out on end-stage liver disease cases admitted to an important hepatology unit in Medellin, the second largest city in Colombia. From 131 patients recruited in this prospective study, 71% of cases were diagnosed as cirrhosis, 12.2% as HCC, and 16.8% as cirrhosis and HCC. Regarding the risk factors of these patients, alcohol consumption was the most frequent (37.4%), followed by viral etiology (17.6%). Blood and/or hepatic tissue samples from patients with serological markers for HCV or HBV infection were characterized; on the basis of the phylogenetic analysis of HCV 5′ UTR and HBV S gene, isolates belonged to HCV/1 and HBV/F3, respectively. These results confirm the presence of strains associated with poor clinical outcome, in patients with liver disease in Colombia; additionally, HBV basal core promoter double mutant was identified in HCC cases. Here we show the first study of cirrhosis and/or HCC in Colombian and HBV and HCV molecular characterization of these patients. Viral aetiology was not the main risk factor in this cohort but alcohol consumption.

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