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

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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