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

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.

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Effect of Chronic Alcohol Consumption and Moderate Fat Diet on Vitamin A Status in Rats Fed either Vitamin A or β-Carotene

Journal of Nutrition ◽

10.1093/jn/113.2.350 ◽

1983 ◽

Vol 113 (2) ◽

pp. 350-364 ◽

Cited By ~ 29

Author(s):

Mary A. Grummer ◽

John W. Erdman

Keyword(s):

Alcohol Consumption ◽

Vitamin A ◽

Chronic Alcohol ◽

Chronic Alcohol Consumption ◽

Vitamin A Status ◽

Β Carotene

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Alcohol and cancer: genetic and nutritional aspects

Proceedings of The Nutrition Society ◽

10.1079/pns2003323 ◽

2004 ◽

Vol 63 (1) ◽

pp. 65-71 ◽

Cited By ~ 71

Author(s):

Gudrun Pöschl ◽

Felix Stickel ◽

Xiang D. Wang ◽

Helmut K. Seitz

Keyword(s):

Cytochrome P450 ◽

Alcohol Consumption ◽

Bacterial Flora ◽

Oral Bacteria ◽

Alcoholic Beverages ◽

Cytochrome P450 2E1 ◽

Chronic Alcohol ◽

Environmental Carcinogens ◽

Dna Hypomethylation ◽

Chronic Alcohol Consumption

Chronic alcohol consumption is a major risk factor for cancer of upper aero-digestive tract (oro-pharynx, hypopharynx, larynx and oesophagus), the liver, the colo-rectum and the breast. Evidence has accumulated that acetaldehyde is predominantly responsible for alcohol-associated carcinogenesis. Acetaldehyde is carcinogenic and mutagenic, binds to DNA and protein, destroys the folate molecule and results in secondary cellular hyper-regeneration. Acetaldehyde is produced by mucosal and cellular alcohol dehydrogenase, cytochrome P450 2E1 and through bacterial oxidation. Its generation and/or its metabolism is modulated as a result of polymorphisms or mutations of the genes responsible for these enzymes. Acetaldehyde can also be produced by oral bacteria. Smoking, which changes the oral bacterial flora, also increases salivary acetaldehyde. Cigarette smoke and some alcoholic beverages, such as Calvados, contain acetaldehyde. In addition, chronic alcohol consumption induces cytochrome P450 2E1 enxyme activity in mucosal cells, resulting in an increased generation of reactive oxygen species and in an increased activation of various dietary and environmental carcinogens. Deficiencies of riboflavin, Zn, folate and possibly retinoic acid may further enhance alcohol-associated carcinogenesis. Finally, methyl deficiency as a result of multiple alcohol-induced changes leads to DNA hypomethylation. A depletion of lipotropes, including methionine, choline, betaine and S-adenosylmethionine, as well as folate, results in the hypomethylation of oncogenes and may lead to DNA strand breaks, all of which are associated with increased carcinogenesis.

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Hepatic SIRT3 Upregulation in Response to Chronic Alcohol Consumption Contributes to Alcoholic Liver Disease in Mice

Frontiers in Physiology ◽

10.3389/fphys.2019.01042 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 5

Author(s):

Yue Ma ◽

Hui Chai ◽

Qinchao Ding ◽

Qianyu Qian ◽

Zhaoyuan Yan ◽

...

Keyword(s):

Liver Disease ◽

Alcohol Consumption ◽

Alcoholic Liver Disease ◽

Chronic Alcohol ◽

Chronic Alcohol Consumption

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Regulatory T cells suppress excessive lipid accumulation in alcoholic liver disease

The Journal of Lipid Research ◽

10.1194/jlr.m083568 ◽

2019 ◽

Vol 60 (5) ◽

pp. 922-936 ◽

Cited By ~ 3

Author(s):

Hongwu Wang ◽

Ting Wu ◽

Yaqi Wang ◽

Xiaoyang Wan ◽

Junying Qi ◽

...

Keyword(s):

Oxidative Stress ◽

T Cells ◽

Liver Disease ◽

Alcohol Consumption ◽

Regulatory T Cells ◽

Alcoholic Liver Disease ◽

Lipid Accumulation ◽

Chronic Alcohol ◽

Chronic Alcohol Consumption ◽

Alcoholic Fatty Liver

Sensitization of hepatic immune cells from chronic alcohol consumption gives rise to inflammatory accumulation, which is considered a leading cause of liver damage. Regulatory T cells (Tregs) are an immunosuppressive cell subset that plays an important role in a variety of liver diseases; however, data about pathological involvement of Tregs in liver steatosis of alcoholic liver disease (ALD) is insufficient. In mouse models of ALD, we found that increased lipid accumulation by chronic alcohol intake was accompanied by oxidative stress, inflammatory accumulation, and Treg decline in the liver. Adoptive transfer of Tregs relieved lipid metabolic disorder, oxidative stress, inflammation, and, consequently, ameliorated the alcoholic fatty liver. Macrophages are a dominant source of inflammation in ALD. Aberrant macrophage activation and cytokine production were activated during chronic alcohol consumption, but were significantly inhibited after Treg transfer. In vitro, macrophages were co-activated by alcohol and lipopolysaccharide to mimic a condition for alcoholic liver microenvironment. Tregs suppressed monocyte chemoattractant protein-1 and TNF-α production from these macrophages. However, such effects of Tregs were remarkably neutralized when interleukin (IL)-10 was blocked. Altogether, our data uncover a novel role of Tregs in restoring liver lipid metabolism in ALD, which partially relies on IL-10-mediated suppression of hepatic pro-inflammatory macrophages.

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Study of clinical and biochemical profile of acute alcoholic liver disease in a teaching hospital in Telangana

International Journal of Advances in Medicine ◽

10.18203/2349-3933.ijam20182389 ◽

2018 ◽

Vol 5 (4) ◽

pp. 804

Author(s):

Shamsunder Khatroth

Keyword(s):

Liver Disease ◽

Alcohol Consumption ◽

Alcoholic Liver Disease ◽

Biochemical Parameters ◽

Clinical Manifestations ◽

Age Group ◽

Biochemical Profile ◽

Chronic Alcohol ◽

Chronic Alcohol Consumption ◽

Female Ratio

Background: Chronic alcohol consumption gives rise to various health risks that include liver disease, heart disease, pancreatitis, central nervous system disorders and certain forms of cancer. Alcoholic liver disease (ALD) is a spectrum of clinicopathological abnormalities, reflecting an acute or chronic inflammation of the liver parenchyma induced by alcohol use. It is associated with changes in various biochemical parameters and also various clinical manifestations in the patients. The objective of the present study to evaluate clinical and biochemical profile of acute alcoholic liver disease.Methods: The prospective hospital-based case control study was done at MNR Medical College, in the department of General Medicine for duration of one year from March 2017 to April 2018. A total of 120 cases diagnosed clinically and biochemically as Acute alcoholic liver disease were included in the study.Results: The age group ranged from 20 to 60 years and the male to female ratio was 2.42. Majority of the patients were in the age group of 30-40 years (54.1%). Majority of the patients (66.6%) consumed >60 grams/24hours of alcohol. Jaundice, nausea and vomiting were seen in 83.3% cases followed by hepatomegaly in 66.6% cases. Majority of them had been consuming alcohol for more than 5 years.Conclusions: Chronic alcohol consumption is more common in adult males. Chronic alcoholics consume more amount of alcohol. Alcoholic liver disease has a varied clinical presentation and is associated with deranged biochemical parameters.

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Chronic Alcohol Exposure Alters Gene Expression and Neurodegeneration Pathways in the Brain of Adult Mice

Journal of Alzheimer s Disease ◽

10.3233/jad-215508 ◽

2022 ◽

pp. 1-17

Author(s):

Mingjing Liu ◽

Shipeng Guo ◽

Daochao Huang ◽

Dongjie Hu ◽

Yili Wu ◽

...

Keyword(s):

Energy Metabolism ◽

Alcohol Consumption ◽

Alcohol Exposure ◽

Chronic Alcohol ◽

Rna Seq ◽

Chronic Alcohol Consumption ◽

Mitochondrial Energy Metabolism ◽

Brain Transcriptome ◽

Chronic Alcohol Exposure ◽

The Brain

Background: Chronic alcohol consumption can alter the structure of the central nervous system and disrupt cognitive function. Alcoholics are more likely to develop neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). However, the role of alcohol in promoting neurotoxicity and neurodegeneration remains unclear. Objective: In this study, we aimed at estimating the effects of chronic binge alcohol exposure on brain transcriptome and behavior changes in a chronic “Drinking in the Dark” (DID) mouse model. Methods: The adult C57BL/6J male mice were exposed to alcohol for 4 weeks. RNA-seq was applied to assess the effects of chronic alcohol exposure on transcriptome in brain. The open field test and novel object recognition test were used to assess the changes of anxiety level, locomotive function, and short-term memory induced by alcohol. RNA-seq analysis revealed that chronic alcohol exposure caused significant change in the brain transcriptome, especially in prefrontal cortex. Results: The gene dysregulation caused by chronic alcohol exposure includes pathways related to mitochondrial energy metabolism (such as oxidative phosphorylation) and multiple neurodegenerative diseases (such as AD and PD). Furthermore, the pathway and network analyses suggest that the genes involved in mitochondrial energy metabolism, ubiquitin-proteasome system, Wnt signaling pathway, and microtubules may attribute to the neurotoxicity and neurodegeneration caused by chronic alcohol consumption. Additionally, locomotive function was also significantly impaired. Conclusion: This work provides gene transcriptional profile data for future research on alcohol-induced neurodegenerative diseases, especially AD and PD.

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A Pilot Metabolomic Study on Myocardial Injury Caused by Chronic Alcohol Consumption—Alcoholic Cardiomyopathy

Molecules ◽

10.3390/molecules26082177 ◽

2021 ◽

Vol 26 (8) ◽

pp. 2177

Author(s):

Zhipeng Cao ◽

Tianqi Wang ◽

Wei Xia ◽

Baoli Zhu ◽

Meihui Tian ◽

...

Keyword(s):

Alcohol Consumption ◽

Left Ventricle ◽

Cardiac Function ◽

Myocardial Injury ◽

Alcohol Exposure ◽

Differentially Expressed ◽

Chronic Alcohol ◽

Metabolomic Analysis ◽

Alcoholic Cardiomyopathy ◽

Chronic Alcohol Consumption

Chronic alcohol consumption leads to myocardial injury, ventricle dilation, and cardiac dysfunction, which is defined as alcoholic cardiomyopathy (ACM). To explore the induced myocardial injury and underlying mechanism of ACM, the Liber-DeCarli liquid diet was used to establish an animal model of ACM and histopathology, echocardiography, molecular biology, and metabolomics were employed. Hematoxylin-eosin and Masson’s trichrome staining revealed disordered myocardial structure and local fibrosis in the ACM group. Echocardiography revealed thinning wall and dilation of the left ventricle and decreased cardiac function in the ACM group, with increased serum levels of brain natriuretic peptide (BNP) and expression of myocardial BNP mRNA measured through enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction (PCR), respectively. Through metabolomic analysis of myocardium specimens, 297 differentially expressed metabolites were identified which were involved in KEGG pathways related to the biosynthesis of unsaturated fatty acids, vitamin digestion and absorption, oxidative phosphorylation, pentose phosphate, and purine and pyrimidine metabolism. The present study demonstrated chronic alcohol consumption caused disordered cardiomyocyte structure, thinning and dilation of the left ventricle, and decreased cardiac function. Metabolomic analysis of myocardium specimens and KEGG enrichment analysis further demonstrated that several differentially expressed metabolites and pathways were involved in the ACM group, which suggests potential causes of myocardial injury due to chronic alcohol exposure and provides insight for further research elucidating the underlying mechanisms of ACM.

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Chronic alcohol exposure inhibits biotin uptake by pancreatic acinar cells: possible involvement of epigenetic mechanisms

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00278.2014 ◽

2014 ◽

Vol 307 (9) ◽

pp. G941-G949 ◽

Cited By ~ 8

Author(s):

Padmanabhan Srinivasan ◽

Rubina Kapadia ◽

Arundhati Biswas ◽

Hamid M. Said

Keyword(s):

Transgenic Mice ◽

Chronic Exposure ◽

Methylation Status ◽

Acinar Cells ◽

Alcohol Exposure ◽

Significant Inhibition ◽

Pancreatic Acinar Cells ◽

Chronic Alcohol ◽

Wild Type ◽

Chronic Alcohol Exposure

Chronic exposure to alcohol affects different physiological aspects of pancreatic acinar cells (PAC), but its effect on the uptake process of biotin is not known. We addressed this issue using mouse-derived pancreatic acinar 266-6 cells chronically exposed to alcohol and wild-type and transgenic mice (carrying the human SLC5A6 5′-promoter) fed alcohol chronically. First we established that biotin uptake by PAC is Na+ dependent and carrier mediated and involves sodium-dependent multivitamin transporter (SMVT). Chronic exposure of 266-6 cells to alcohol led to a significant inhibition in biotin uptake, expression of SMVT protein, and mRNA as well as in the activity of the SLC5A6 promoter. Similarly, chronic alcohol feeding of wild-type and transgenic mice carrying the SLC5A6 promoter led to a significant inhibition in biotin uptake by PAC, as well as in the expression of SMVT protein and mRNA and the activity of the SLC5A6 promoters expressed in the transgenic mice. We also found that chronic alcohol feeding of mice is associated with a significant increase in the methylation status of CpG islands predicted to be in the mouse Slc5a6 promoters and a decrease in the level of expression of transcription factor KLF-4, which plays an important role in regulating SLC5A6 promoter activity. These results demonstrate, for the first time, that chronic alcohol exposure negatively impacts biotin uptake in PAC and that this effect is exerted (at least in part) at the level of transcription of the SLC5A6 gene and may involve epigenetic/molecular mechanisms.

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