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Alcoholic Liver Injury: Metabolism, Molecular Mechanisms, and Cascade of Events
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Alcoholic Liver Injury: Metabolism, Molecular Mechanisms, and Cascade of Events

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 5599

Special Issue Editor

Prof. Dr. Rolf Teschke

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Guest Editor
Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Goethe University, 999035 Frankfurt, Germany
Interests: Heavy metals; Heavy metal uptake; Heavy metal disposition, Heavy metal homeostasis; Haber Weiss reaction; Fenton reaction; Benefits and risks for human health; Environmental pollution
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The focus of this Special Issue is an update on alcoholic liver injury, including its molecular background and the molecular events leading to injury, excluding clinical aspects of diagnosis and therapy related to alcoholic liver disease (ALD). Alcoholic liver injury is closely related to the metabolic events and molecular mechanisms that emerge following the acute ingestion of alcohol or prolonged alcohol abuse. In both conditions, the hepatic alcohol dehydrogenase (ADH) and the hepatic microsomal ethanol-oxidizing system (MEOS) metabolize alcohol to the toxic acetaldehyde, which is further metabolized by mitochondrial aldehyde dehydrogenase (ALDH). Chronic alcohol abuse decreases mitochrondrial ALDH activity and contributes to increased acetaldehyde levels. In addition, the genetic polymorphic ALDH III has an important modulatory role on acetaldehyde levels and the extent of liver injury. Prolonged alcohol consumption induces the activity of MEOS by upregulating the expression of cytochrome P450 (CYP) 2E1, a major constituent of MEOS. CYP 2E1 by itself produces a lot of reactive oxygen species due to lack of efficient electron coupling, leading to hepatic oxidative stress and the activation of non-parenchymal liver cells. In addition, ethanol metabolism mediated by CYP 2E1 causes the formation of ethoxy radicals, hydroxyethyl radicals, acetyl radicals, singlet radicals, superoxide radicals and many other reactive species. These intermediates activate Kupffer cells and Stellate cells, which in turn cause hepatocyte stress, resulting in apoptosis and cell necrosis, leading to severe stages of alcoholic liver disease. The ethanol-mediated induction of CYP 2E1 also potentiates the liver toxicity of chemicals such as carbon tetrachloride and of drugs like paracetamol. For many questions, animal models are available, including genetic animal models for studying the alcohol metabolizing enzymes ADH, MEOS, and catalase, the genetic CYP 2E1 knockout mice model, transgenic knockin CYP 2E1 mice model CYP 2E1, overexpressing transgenic mice model, and a forced ethanol delivery animal model for studying the mechanisms of liver injury. Other topics of interest focus on molecular circadian rhythms, metabolomics, proteomics, transcriptomics, and genetic factors including genetic polymorphism and their importance for the development of alcoholic liver injury. In addition, many other molecular mechanisms and risk factors will be discussed. Finally, much experimental and clinical research has been devoted to the intestinal microbiomes and endotoxins modulating the risk for injury, which is an important topic in ALD research.

Overall, the spectrum covered in this Special Issue is broad, and we hope to receive many contributions on the specific topics that may enlarge our molecular and metabolic knowledge and also stimulate discussion on controversial issues.

Prof. Dr. Rolf Teschke
Prof. Dr. Arthur I. Cederbaum
Guest Editors

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Keywords

  • alcoholic liver injury
  • alcohol
  • acetaldehyde
  • alcohol metabolism
  • alcohol dehydrogenase
  • microsomal ethanol-oxidizing system
  • cytochrome P450 2E1
  • endotoxins
  • intestinal microbiome
  • circadian rhythms
  • metabolomics
  • proteomics
  • transcriptomics reactive oxygen radicals
  • oxidative stress
  • mitochondrial damage
  • autophagy

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Related Special Issue

Published Papers (5 papers)

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Research

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10 pages, 1517 KiB  
Article
Global Burden of Alcohol Use Disorders and Alcohol Liver Disease
by Jürgen Rehm and Kevin D. Shield
Biomedicines 2019, 7(4), 99; https://doi.org/10.3390/biomedicines7040099 - 13 Dec 2019
Cited by 119 | Viewed by 13299
Abstract
Alcohol use is a major risk factor for burden of mortality and morbidity. Alcoholic liver disease (ALD) and alcohol use disorders (AUDs) are important disease outcomes caused by alcohol use. We will describe the global mortality and burden of disease in disability-adjusted life [...] Read more.
Alcohol use is a major risk factor for burden of mortality and morbidity. Alcoholic liver disease (ALD) and alcohol use disorders (AUDs) are important disease outcomes caused by alcohol use. We will describe the global mortality and burden of disease in disability-adjusted life years for ALD and AUDs, based on data from the comparative risk assessment of the World Health Organization for 2016. AUDs have a limited impact on mortality in this assessment, since alcohol poisonings are almost the only disease category directly attributable to AUDs; most other alcohol-related deaths are indirect, and the cause which directly led to the death, such as liver cirrhosis, is the one recorded on the death certificate. Burden of disease for AUDs is thus mainly due to disability resulting from alcohol use. In contrast to AUDs, ALD is one of the major lethal outcomes of alcohol use, and burden of disease is mainly due to (premature) years of life lost. Many of the negative outcomes attributable to both AUDs and ALD are due to their interactions with other factors, most notably economic wealth. To avoid alcohol-attributable morbidity and mortality, measures should be taken to reduce the AUDs and ALD burden globally, especially among the poor. Full article
(This article belongs to the Special Issue Alcoholic Liver Disease: Diagnostics and Therapeutics)
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Review

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28 pages, 10030 KiB  
Review
Alcoholic-Hepatitis, Links to Brain and Microbiome: Mechanisms, Clinical and Experimental Research
by Manuela G. Neuman, Helmut Karl Seitz, Samuel W. French, Stephen Malnick, Heidekazu Tsukamoto, Lawrence B. Cohen, Paula Hoffman, Boris Tabakoff, Michael Fasullo, Laura E. Nagy, Pamela L. Tuma, Bernd Schnabl, Sebastian Mueller, Jennifer L. Groebner, French A. Barbara, Jia Yue, Afifiyan Nikko, Mendoza Alejandro, Tillman Brittany, Vitocruz Edward, Kylie Harrall, Laura Saba and Opris Mihaiadd Show full author list remove Hide full author list
Biomedicines 2020, 8(3), 63; https://doi.org/10.3390/biomedicines8030063 - 18 Mar 2020
Cited by 17 | Viewed by 5774
Abstract
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) [...] Read more.
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. Full article
(This article belongs to the Special Issue Alcoholic Liver Disease: Diagnostics and Therapeutics)
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16 pages, 500 KiB  
Review
Alcohol Metabolizing Enzymes, Microsomal Ethanol Oxidizing System, Cytochrome P450 2E1, Catalase, and Aldehyde Dehydrogenase in Alcohol-Associated Liver Disease
by Yanchao Jiang, Ting Zhang, Praveen Kusumanchi, Sen Han, Zhihong Yang and Suthat Liangpunsakul
Biomedicines 2020, 8(3), 50; https://doi.org/10.3390/biomedicines8030050 - 4 Mar 2020
Cited by 124 | Viewed by 23523
Abstract
Once ingested, most of the alcohol is metabolized in the liver by alcohol dehydrogenase to acetaldehyde. Two additional pathways of acetaldehyde generation are by microsomal ethanol oxidizing system (cytochrome P450 2E1) and catalase. Acetaldehyde can form adducts which can interfere with cellular function, [...] Read more.
Once ingested, most of the alcohol is metabolized in the liver by alcohol dehydrogenase to acetaldehyde. Two additional pathways of acetaldehyde generation are by microsomal ethanol oxidizing system (cytochrome P450 2E1) and catalase. Acetaldehyde can form adducts which can interfere with cellular function, leading to alcohol-induced liver injury. The variants of alcohol metabolizing genes encode enzymes with varied kinetic properties and result in the different rate of alcohol elimination and acetaldehyde generation. Allelic variants of these genes with higher enzymatic activity are believed to be able to modify susceptibility to alcohol-induced liver injury; however, the human studies on the association of these variants and alcohol-associated liver disease are inconclusive. In addition to acetaldehyde, the shift in the redox state during alcohol elimination may also link to other pathways resulting in activation of downstream signaling leading to liver injury. Full article
(This article belongs to the Special Issue Alcoholic Liver Disease: Diagnostics and Therapeutics)
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19 pages, 1012 KiB  
Review
Autophagy, Metabolism, and Alcohol-Related Liver Disease: Novel Modulators and Functions
by Shengmin Yan, Bilon Khambu, Honghai Hong, Gang Liu, Nazmul Huda and Xiao-Ming Yin
Int. J. Mol. Sci. 2019, 20(20), 5029; https://doi.org/10.3390/ijms20205029 - 11 Oct 2019
Cited by 15 | Viewed by 5096
Abstract
Alcohol-related liver disease (ALD) is caused by over-consumption of alcohol. ALD can develop a spectrum of pathological changes in the liver, including steatosis, inflammation, cirrhosis, and complications. Autophagy is critical to maintain liver homeostasis, but dysfunction of autophagy has been observed in ALD. [...] Read more.
Alcohol-related liver disease (ALD) is caused by over-consumption of alcohol. ALD can develop a spectrum of pathological changes in the liver, including steatosis, inflammation, cirrhosis, and complications. Autophagy is critical to maintain liver homeostasis, but dysfunction of autophagy has been observed in ALD. Generally, autophagy is considered to protect the liver from alcohol-induced injury and steatosis. In this review, we will summarize novel modulators of autophagy in hepatic metabolism and ALD, including autophagy-mediating non-coding RNAs (ncRNAs), and crosstalk of autophagy machinery and nuclear factors. We will also discuss novel functions of autophagy in hepatocytes and non-parenchymal hepatic cells during the pathogenesis of ALD and other liver diseases. Full article
(This article belongs to the Special Issue Alcoholic Liver Injury: Metabolism, Molecular Mechanisms, and Cascade of Events)
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12 pages, 540 KiB  
Review
Alcoholic Liver Disease: Current Mechanistic Aspects with Focus on Their Clinical Relevance
by Rolf Teschke
Biomedicines 2019, 7(3), 68; https://doi.org/10.3390/biomedicines7030068 - 5 Sep 2019
Cited by 47 | Viewed by 6206
Abstract
The spectrum of alcoholic liver disease (ALD) is broad and includes alcoholic fatty liver, alcoholic steatohepatitis, alcoholic hepatitis, alcoholic fibrosis, alcoholic cirrhosis, and alcoholic hepatocellular carcinoma, best explained as a five-hit sequelae of injurious steps. ALD is not primarily the result of malnutrition [...] Read more.
The spectrum of alcoholic liver disease (ALD) is broad and includes alcoholic fatty liver, alcoholic steatohepatitis, alcoholic hepatitis, alcoholic fibrosis, alcoholic cirrhosis, and alcoholic hepatocellular carcinoma, best explained as a five-hit sequelae of injurious steps. ALD is not primarily the result of malnutrition as assumed for many decades but due to the ingested alcohol and its metabolic consequences although malnutrition may marginally contribute to disease aggravation. Ethanol is metabolized in the liver to the heavily reactive acetaldehyde via the alcohol dehydrogenase (ADH) and the cytochrome P450 isoform 2E1 of the microsomal ethanol-oxidizing system (MEOS). The resulting disturbances modify not only the liver parenchymal cells but also non-parenchymal cells such as Kupffer cells (KCs), hepatic stellate cells (HSCs), and liver sinusoidal endothelial cells (LSECs). These are activated by acetaldehyde, reactive oxygen species (ROS), and endotoxins, which are produced from bacteria in the gut and reach the liver due to gut leakage. A variety of intrahepatic signaling pathways and innate or acquired immune reactions are under discussion contributing to the pathogenesis of ALD via the five injurious hits responsible for disease aggravation. As some of the mechanistic steps are based on studies with in vitro cell systems or animal models, respective proposals for humans may be considered as tentative. However, sufficient evidence is provided for clinical risk factors that include the amount of alcohol used daily for more than a decade, gender differences with higher susceptibility of women, genetic predisposition, and preexisting liver disease. In essence, efforts within the last years were devoted to shed more light in the pathogenesis of ALD, much has been achieved but issues remain to what extent results obtained from experimental studies can be transferred to humans. Full article
(This article belongs to the Special Issue Alcoholic Liver Disease: Diagnostics and Therapeutics)
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