High resolution metabolomics technology reveals widespread pathway changes of alcoholic liver disease

Globally, alcohol consumption contributes to more than 3 million deaths each year. While much of its ramifications is preventable, a coherent public health discourse on how to limit alcohol-related harm has been overdue. By synthesizing information from national and global databases, we show in this analysis that alcohol consumption level and alcohol-attributable burden of diseases, particularly alcoholic liver disease (ALD), are intimately linked to national income distribution, cultural norms, religion, sex, age, and health status. Prevalence and burden of ALD are positively associated with economic standing in most countries, which necessitate active governmental control via cost-effective policies, such as the best buys proposed by the World Health Organization. To date, a number of critical questions remain unanswered over the molecular mechanisms underlying ALD pathophysiology; the insights gained thereof should provide new opportunities for the advancement of novel diagnostic and management strategies. In comparison with other prevailing liver diseases (e.g., viral hepatitis and nonalcoholic fatty liver disease), governmental support to ALD investigation has been sluggish in most Western countries and China, resulting in a dearth of breakthroughs on both the basic and clinical research fronts in the past decades. Emerging foci of clinical trials for ALD therapy include empirical use of probiotics, antioxidants, growth factors, monoclonal antibodies against key inflammatory mediators, and technology-enhanced behavioral interventions. In this article, we seek to provide a comprehensive analysis on the progress and challenges in tackling ALD as a global health problem, with particular emphasis on global disease burden, socioeconomic influences, research trends, government roles, and future therapies.

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Amino Acid Metabolism is Altered in Adolescents with Nonalcoholic Fatty Liver Disease—An Untargeted, High Resolution Metabolomics Study

The Journal of Pediatrics ◽

10.1016/j.jpeds.2016.01.026 ◽

2016 ◽

Vol 172 ◽

pp. 14-19.e5 ◽

Cited By ~ 37

Author(s):

Ran Jin ◽

Sophia Banton ◽

ViLinh T. Tran ◽

Juna V. Konomi ◽

Shuzhao Li ◽

...

Keyword(s):

Liver Disease ◽

Amino Acid ◽

High Resolution ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Nonalcoholic Fatty Liver ◽

Metabolomics Study ◽

High Resolution Metabolomics

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Alcoholic Liver Disease: Alcohol Metabolism, Cascade of Molecular Mechanisms, Cellular Targets, and Clinical Aspects

Biomedicines ◽

10.3390/biomedicines6040106 ◽

2018 ◽

Vol 6 (4) ◽

pp. 106 ◽

Cited By ~ 28

Author(s):

Rolf Teschke

Keyword(s):

Liver Disease ◽

Liver Injury ◽

Alcoholic Liver Disease ◽

Molecular Mechanisms ◽

Lipid Peroxides ◽

Sirtuin 1 ◽

Clinical Aspects ◽

Alkoxyl Radical ◽

Alcoholic Fatty Liver ◽

Cyp 2E1

Alcoholic liver disease is the result of cascade events, which clinically first lead to alcoholic fatty liver, and then mostly via alcoholic steatohepatitis or alcoholic hepatitis potentially to cirrhosis and hepatocellular carcinoma. Pathogenetic events are linked to the metabolism of ethanol and acetaldehyde as its first oxidation product generated via hepatic alcohol dehydrogenase (ADH) and the microsomal ethanol-oxidizing system (MEOS), which depends on cytochrome P450 2E1 (CYP 2E1), and is inducible by chronic alcohol use. MEOS induction accelerates the metabolism of ethanol to acetaldehyde that facilitates organ injury including the liver, and it produces via CYP 2E1 many reactive oxygen species (ROS) such as ethoxy radical, hydroxyethyl radical, acetyl radical, singlet radical, superoxide radical, hydrogen peroxide, hydroxyl radical, alkoxyl radical, and peroxyl radical. These attack hepatocytes, Kupffer cells, stellate cells, and liver sinusoidal endothelial cells, and their signaling mediators such as interleukins, interferons, and growth factors, help to initiate liver injury including fibrosis and cirrhosis in susceptible individuals with specific risk factors. Through CYP 2E1-dependent ROS, more evidence is emerging that alcohol generates lipid peroxides and modifies the intestinal microbiome, thereby stimulating actions of endotoxins produced by intestinal bacteria; lipid peroxides and endotoxins are potential causes that are involved in alcoholic liver injury. Alcohol modifies SIRT1 (Sirtuin-1; derived from Silent mating type Information Regulation) and SIRT2, and most importantly, the innate and adapted immune systems, which may explain the individual differences of injury susceptibility. Metabolic pathways are also influenced by circadian rhythms, specific conditions known from living organisms including plants. Open for discussion is a 5-hit working hypothesis, attempting to define key elements involved in injury progression. In essence, although abundant biochemical mechanisms are proposed for the initiation and perpetuation of liver injury, patients with an alcohol problem benefit from permanent alcohol abstinence alone.

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Molecular Mechanisms of Alcoholic Liver Disease: Innate Immunity and Cytokines

Alcoholism Clinical and Experimental Research ◽

10.1111/j.1530-0277.2010.01399.x ◽

2011 ◽

Vol 35 (5) ◽

pp. 787-793 ◽

Cited By ~ 94

Author(s):

Andrew M. Miller ◽

Norio Horiguchi ◽

Won-IL Jeong ◽

Svetlana Radaeva ◽

Bin Gao

Keyword(s):

Innate Immunity ◽

Liver Disease ◽

Alcoholic Liver Disease ◽

Molecular Mechanisms

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Comparative Transcriptome Analyses Provide Potential Insights into the Molecular Mechanisms of Astaxanthin in the Protection against Alcoholic Liver Disease in Mice

Marine Drugs ◽

10.3390/md17030181 ◽

2019 ◽

Vol 17 (3) ◽

pp. 181 ◽

Cited By ~ 4

Author(s):

Huilin Liu ◽

Huimin Liu ◽

Lingyu Zhu ◽

Ziqi Zhang ◽

Xin Zheng ◽

...

Keyword(s):

Liver Disease ◽

Differentially Expressed Genes ◽

Alcoholic Liver Disease ◽

Antigen Processing ◽

Molecular Mechanisms ◽

Enrichment Analysis ◽

Liquid Diet ◽

Differentially Expressed ◽

Ethanol Administration ◽

Receptor Signaling

Alcoholic liver disease (ALD) is a major cause of chronic liver disease worldwide. It is a complex process, including a broad spectrum of hepatic lesions from fibrosis to cirrhosis. Our previous study suggested that astaxanthin (AST) could alleviate the hepatic inflammation and lipid dysmetabolism induced by ethanol administration. In this study, a total of 48 male C57BL/6J mice were divided into 4 groups: a Con group (fed with a Lieber–DeCarli liquid diet), an AST group (fed with a Lieber–DeCarli liquid diet and AST), an Et group (fed with an ethanol-containing Lieber–DeCarli liquid diet), and a EtAST group (fed with an ethanol-containing Lieber–DeCarli liquid diet and AST). Then, comparative hepatic transcriptome analysis among the groups was performed by Illumina RNA sequencing. Gene enrichment analysis was conducted to identify pathways affected by the differentially expressed genes. Changes of the top genes were verified by quantitative real-time PCR (qRT-PCR) and Western blot. A total of 514.95 ± 6.89, 546.02 ± 15.93, 576.06 ± 21.01, and 690.85 ± 54.14 million clean reads were obtained for the Con, AST, Et, and EtAST groups, respectively. Compared with the Et group, 1892 differentially expressed genes (DEGs) (including 351 upregulated and 1541 downregulated genes) were identified in the AST group, 1724 differentially expressed genes (including 233 upregulated and 1491 downregulated genes) were identified in the Con group, and 1718 DEGs (including 1380 upregulated and 338 downregulated genes) were identified in the EtAST group. The enrichment analyses revealed that the chemokine signaling, the antigen processing and presentation, the nucleotide-binding and oligomerization domain (NOD)-like receptor signaling, and the Toll-like receptor signaling pathways enriched the most differentially expressed genes. The findings of this study provide insights for the development of nutrition-related therapeutics for ALD.

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Analysis of the liver mitochondrial proteome in response to ethanol and S-adenosylmethionine treatments: novel molecular targets of disease and hepatoprotection

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00332.2009 ◽

2010 ◽

Vol 298 (5) ◽

pp. G732-G745 ◽

Cited By ~ 33

Author(s):

Kelly K. Andringa ◽

Adrienne L. King ◽

Heather B. Eccleston ◽

Sudheer K. Mantena ◽

Aimee Landar ◽

...

Keyword(s):

Liver Disease ◽

Alcoholic Liver Disease ◽

Molecular Mechanisms ◽

Early Stage ◽

Sulfur Metabolism ◽

Liver Mitochondria ◽

Male Rats ◽

Protective Effects ◽

Mitochondrial Proteome ◽

Sds Page

S-adenosylmethionine (SAM) minimizes alcohol hepatotoxicity; however, the molecular mechanisms responsible for SAM hepatoprotection remain unknown. Herein, we use proteomics to determine whether the hepatoprotective action of SAM against early-stage alcoholic liver disease is linked to alterations in the mitochondrial proteome. For this, male rats were fed control or ethanol-containing liquid diets ± SAM and liver mitochondria were prepared for proteomic analysis. Two-dimensional isoelectric focusing (2D IEF/SDS-PAGE) and blue native gel electrophoresis (BN-PAGE) were used to determine changes in matrix and oxidative phosphorylation (OxPhos) proteins, respectively. SAM coadministration minimized alcohol-dependent inflammation and preserved mitochondrial respiration. SAM supplementation preserved liver SAM levels in ethanol-fed rats; however, mitochondrial SAM levels were increased by ethanol and SAM treatments. With use of 2D IEF/SDS-PAGE, 30 proteins showed significant changes in abundance in response to ethanol, SAM, or both. Classes of proteins affected by ethanol and SAM treatments were chaperones, beta oxidation proteins, sulfur metabolism proteins, and dehydrogenase enzymes involved in methionine, glycine, and choline metabolism. BN-PAGE revealed novel changes in the levels of 19 OxPhos proteins in response to ethanol, SAM, or both. Ethanol- and SAM-dependent alterations in the proteome were not linked to corresponding changes in gene expression. In conclusion, ethanol and SAM treatment led to multiple changes in the liver mitochondrial proteome. The protective effects of SAM against alcohol toxicity are mediated, in part, through maintenance of proteins involved in key mitochondrial energy conserving and biosynthetic pathways. This study demonstrates that SAM may be a promising candidate for treatment of alcoholic liver disease.

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Peroxisome Proliferator-Activated Receptor and Retinoic X Receptor in Alcoholic Liver Disease

PPAR Research ◽

10.1155/2009/748174 ◽

2009 ◽

Vol 2009 ◽

pp. 1-11 ◽

Cited By ~ 18

Author(s):

Tommaso Mello ◽

Simone Polvani ◽

Andrea Galli

Keyword(s):

Liver Disease ◽

Alcoholic Liver Disease ◽

Molecular Mechanisms ◽

Redox Balance ◽

Ethanol Metabolism ◽

Peroxisome Proliferator ◽

Clinical Progression ◽

Metabolizing Enzymes ◽

Peroxisome Proliferator Activated Receptor ◽

Reciprocal Interactions

A growing number of new studies demonstrate that nuclear receptors are involved in the development of alcoholic liver disease (ALD). Ethanol metabolism and RXR/PPAR functions are tightly interconnected in the liver. Several ethanol metabolizing enzymes are potently regulated by RXR and PPARαafter alcohol consumption. The increased ethanol metabolism, in turn, leads to alteration of the redox balance of the cells and impairment of RXR/PPAR functions by direct and indirect effects of acetaldehyde, resulting in deranged lipid metabolism, oxidative stress, and release of proinflammatory cytokines. The use of animal models played a crucial role in understanding the molecular mechanisms of ALD. In this paper we summarize the reciprocal interactions between ethanol metabolism and RXR/PPAR functions. In conclusion, RXR and PPAR play a central role in the onset and perpetuation of the mechanisms underling all steps of the clinical progression in ALD.

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Crystalloid Inclusions in Hepatocyte Mitochondria and Their Similarity to Cytoplasmic Crystalloids

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100051001 ◽

1974 ◽

Vol 32 ◽

pp. 198-199

Author(s):

Odell T. Minick ◽

Hidejiro Yokoo

Keyword(s):

Liver Disease ◽

Alcoholic Liver Disease ◽

Special Interest ◽

Structural Variations ◽

Mitochondrial Alterations ◽

The Matrix ◽

Crystalloid Inclusions ◽

Liver Biopsies

Mitochondrial alterations were studied in 25 liver biopsies from patients with alcoholic liver disease. Of special interest were the morphologic resemblance of certain fine structural variations in mitochondria and crystalloid inclusions. Four types of alterations within mitochondria were found that seemed to relate to cytoplasmic crystalloids.Type 1 alteration consisted of localized groups of cristae, usually oriented in the long direction of the organelle (Fig. 1A). In this plane they appeared serrated at the periphery with blind endings in the matrix. Other sections revealed a system of equally-spaced diagonal lines lengthwise in the mitochondrion with cristae protruding from both ends (Fig. 1B). Profiles of this inclusion were not unlike tangential cuts of a crystalloid structure frequently seen in enlarged mitochondria described below.

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