metabolism of alcohol in liver

Xiang X., Hwang S., Feng D., Shah V.H., Gao B. Interleukin-22 in alcoholic hepatitis and beyond. Jeon S., Carr R. Alcohol effects on hepatic lipid metabolism. Alcoholic hepatitis. The amounts of circulating antibodies against hydroxyethyl radicals (HER)-protein adducts and lipid peroxidation-derived aldehydes, such as malondialdehyde (MDA), are elevated in patients with alcoholic hepatitis [74]. Alcoholic Liver Disease: Alcohol Metabolism, Cascade of Molecular Mechanisms of alcohol-induced hepatic fibrosis: A summary of the Ron Thurman Symposium. Liver Physiol. The Role of Nrf2 in Liver Disease: Novel Molecular Mechanisms and Therapeutic Approaches. Notably, it is known that the alcohol-catabolizing rate is much faster in rodents than humans. Brenner D.A. Metabolic pathways of alcohol in the liver - PubMed Takase S., Yasuhara M., Takada A., Ueshima Y. Exploring Alcohol's Effects on Liver Function - PMC The Defective Allele of Aldehyde Dehydrogenase 2 Gene is Associated with Favorable Postoperative Prognosis in Hepatocellular Carcinoma. Ethanol metabolism, cirrhosis and alcoholism. Heavy long-term alcohol consumption accelerates the transition of alcoholic fatty liver into alcoholic hepatitis, which is characterized by steatosis, ballooning hepatocytes, and infiltration of neutrophils with or without fibrosis [11,12,13,14,15,16]. Osna N.A., Donohue T.M., Jr., Kharbanda K.K. Why do some people drink more than others? First, ADH metabolizes alcohol toacetaldehyde, a highly toxic substance and known carcinogen.1 Then, acetaldehyde is further metabolized down to another, less active byproduct calledacetate,1 which then is broken down into water and carbon dioxide for easy elimination.2, The enzymes cytochrome P450 2E1 (CYP2E1) and catalase also break down alcohol to acetaldehyde. In 2018, the World Health Organization (WHO) estimated that alcohol consumption is responsible for three million deaths worldwide annually, accounting for nearly 14% of the total mortality in people aged 20 to 40 years old [5]. Alcohol consumption alters the metabolism of the most common type of cell found in the liver, the hepatocyte. ALT, alanine aminotransferase; BAL, blood alcohol level; CCl4, carbon tetrachloride; DEN, diethylnitrosamine; LPS, lipopolysaccharide. Li S., Tan H.Y., Wang N., Zhang Z.J., Lao L., Wong C.W., Feng Y. The oxidative pathway is the major pathway for alcohol metabolism and is composed of two steps. The relation between different dimensions of alcohol consumption and burden of disease: An overview. This occurs for the processing of ethanol in the human body. Overview: how is alcohol metabolized by the body? As mentioned above, ALDH2-KO mice have higher levels of acetaldehyde and acetaldehyde adducts in blood and/or liver than wild-type mice when exposed to ethanol [145]. 1). Metabolism of Alcohol - Clinics in Liver Disease LPS from the gastrointestinal tract also contributes to HSC activation by increasing the susceptibility of HSCs to acetaldehyde and TGF [88,89,90]. Alcohol, oxidative stress, and free radical damage. The detrimental effects of acetaldehyde contribute to this via upregulation of microRNA-212 in enterocytes and downregulation of zonula occludens 1 (ZO-1), a tight junction component [64]. Some tests can detect alcohol in the body for . Alcohol Metabolism in the Progression of Human Nonalcoholic Alcoholic liver disease (ALD) is a globally prevalent chronic liver disease caused by chronic or binge consumption of alcohol. In addition to social and psychiatric problems, more than 200 diseases that affect several organs, such as the brain, heart, gastrointestinal tract, and liver, are related to habitual alcohol consumption [6,7,8]. Although various animal models such as primates and micropigs have been proposed for ALD study, rodent models are commonly used because of better handiness in experiments and efficiency in terms of cost and time [124]. Pathophysiological Aspects of Alcohol Metabolism in the Liver Influence of alcohol consumption and gene polymorphisms of ADH2 and ALDH2 on hepatocellular carcinoma in a Japanese population. The increased levels of anti-HER and anti-MDA antibodies are associated with the presence of activated CD4+ T cells in peripheral blood. Genetic variations in the alcohol-metabolizing enzymes, such as acetaldehyde dehydrogenase (ALDH)2*2 and alcohol dehydrogenase (ADH)1C*1 alleles, suppress the activity of the enzymes, enhancing the amount of acetaldehyde. Israel Y., Hurwitz E., Niemel O., Arnon R. Monoclonal and polyclonal antibodies against acetaldehyde-containing epitopes in acetaldehyde-protein adducts. Alcohol is also produced minimally by several metabolic pathways, including: Fatty acid synthesis Glycerolipid metabolism Bile acid biosynthesis pathways Also enters the body via alcohol consumption: Alcohol is consumed enters the stomach and small intestine absorbed into the bloodstream (due to solubility in water) Sergent O., Pereira M., Belhomme C., Chevanne M., Huc L., Lagadic-Gossmann D. Role for membrane fluidity in ethanol-induced oxidative stress of primary rat hepatocytes. Characterisation of the DNA repair enzyme for O(6)-methylguanine in cirrhosis. Yin H., Hu M., Liang X., Ajmo J.M., Li X., Bataller R., Odena G., Stevens S.M., Jr., You M. Deletion of SIRT1 from hepatocytes in mice disrupts lipin-1 signaling and aggravates alcoholic fatty liver. Lee J.Y., Ye J., Gao Z., Youn H.S., Lee W.H., Zhao L., Sizemore N., Hwang D.H. The levels of pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF), interleukin (IL)-1, and IL-8, are upregulated in patients with ALD [70]. Targeted deletion of FATP5 reveals multiple functions in liver metabolism: Alterations in hepatic lipid homeostasis. The gut-liver axis and gut microbiota in health and liver disease Social and Cultural Contexts of Alcohol Use: Influences in a Social-Ecological Framework. Alcohol metabolism: reactions, metabolites, and byproducts. In addition, secretome analysis for inflammatory mediators showed that a number of pro-inflammatory cytokines were upregulated in this model after alcohol treatment. ROS also upregulate angiogenesis and the metastatic process [109,123]. Therefore, further studies are necessary to elucidate the detailed mechanisms of ALD and to discover potential therapeutic targets for treating ALD. Cellular interactions during the pathogenesis of ALD. These findings suggest that the suppression of oxidative stress, potentially by antioxidants, could attenuate ALD-related fibrosis. ADH has a high affinity (low Km: 0.2-2 mM) for alcohol and accounts for essentially all alcohol metabolism when blood and tissue concentrations are low. Pathogenesis of Alcohol-Associated Liver Disease - ScienceDirect ; Pirola, R.C. Furthermore, the sex, age, and genetic background of the animal, and even the animal facility environment, impact susceptibility to alcohol-induced liver damage, and bring to the high inter-variability in each experimental animal, hindering the generation of rodent models of ALD [127]. The second step in the oxidative pathway involves the rapid conversion of acetaldehyde to acetate by aldehyde dehydrogenase (ALDH). LIPIN1 plays a role in lipid homeostasis. The most common of these pathways involves two enzymesalcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). High blood acetaldehyde levels after ethanol administration. An official website of the United States government. Kong X., Feng D., Wang H., Hong F., Bertola A., Wang F.S., Gao B. Interleukin-22 induces hepatic stellate cell senescence and restricts liver fibrosis in mice. A healthy lifestyle reduces risk of developing severe liver disease Metabolites and byproducts generated during alcohol metabolism cause liver damage, leading to ALD via several mechanisms, such as impairing lipid metabolism, intensifying inflammatory reactions, and inducing fibrosis. PMID: 17718404, 8 Aragon, C.M. Rodent models of alcoholic liver disease: Of mice and men. Schwartz J.M., Reinus J.F. The ROS also stimulate intracellular pro-fibrogenic pathways in HSCs, including the ERK, protein kinase B (PKB/Akt), c-Jun N-terminal kinase (JNK), and tissue inhibitor of metalloproteinase 1 (TIMP1) pathways. Fischer M., You M., Matsumoto M., Crabb D.W. Peroxisome proliferator-activated receptor alpha (PPARalpha) agonist treatment reverses PPARalpha dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice. Addolorato G., Mirijello A., Leggio L., Ferrulli A., Landolfi R. Management of alcohol dependence in patients with liver disease. Lamas-Paz A., Hao F., Nelson L.J., Vzquez M.T., Canals S., Gmez Del Moral M., Martnez-Naves E., Nevzorova Y.A., Cubero F.J. Alcoholic liver disease: Utility of animal models. In addition, there is no effective Food and Drug Administration (FDA)-approved drug for treating patients with ALD [24]. Influence of some aliphatic alcohols on the metabolism of rat liver slices. PMID: 17718394. Chen M., Liu J., Yang W., Ling W. Lipopolysaccharide mediates hepatic stellate cell activation by regulating autophagy and retinoic acid signaling. Effect of endotoxin pretreatment on hepatic stellate cell response to ethanol and acetaldehyde. The PubMed database was used to identify publications for the following terms: Alcoholic liver disease, alcoholic fatty liver disease, alcoholic steatohepatitis, alcoholic hepatitis, alcoholic cirrhosis, alcohol metabolism, alcohol dehydrogenase, microsomal ethanol-oxidizing system, cytochrome P450 2E1 (CYP 2E1), catalase, and mitochondrial acetaldehyde dehydrogenase. Kwon H.J., Won Y.S., Park O., Chang B., Duryee M.J., Thiele G.E., Matsumoto A., Singh S., Abdelmegeed M.A., Song B.J., et al. Chronic alcohol ingestion decreases the number of F4/80+ cells expressing major histocompatibility complex (MHC)-I and MHC-II [77]. Three pathways for alcohol metabolism exist in the liver. Activated CYP2E1 promotes the production of acetaldehyde through the formation of reactive oxygen species (ROS) [29,30]. Chen X., Ying X., Sun W., Zhu H., Jiang X., Chen B. Variations in genes influence alcohol metabolism and drinking behavior. The findings reveal that local clock function in each tissue is not enough for whole-body glucose metabolism but also requires signals from feeding and fasting cycles to properly maintain glucose . Lieber C.S. In addition, neutrophil infiltration is hardly detected in rodents during ALD pathogenesis, whereas it is one of the key features of alcoholic steatohepatitis in humans [73]. Sims O.T., Pollio D.E., Hong B.A., Jain M.K., Brown G.R., North C.S. Nuutinen H., Lindros K.O., Salaspuro M. Determinants of blood acetaldehyde level during ethanol oxidation in chronic alcoholics. These enzymes help break apart the alcohol molecule, making it possible to eliminate it from the body. DNA binding affinity and activity of CCAT/enhanced binding protein beta (C/EBP) that promotes the transcription of collagen I 1 (COLI 1) are increased by acetaldehyde, and the actions of C/EBP are mediated by H2O2 [93]. When the liver metabolizes alcohol, it can lead to the build-up of lipids, or fats, in the liver. Nuclear erythroid 2-related factor 2 (NRF2), a transcription factor activated by oxidative stress, is presented to upregulate antioxidant gene expression [96]. This is primarily because the liver is the first to see alcohol absorbed from the gastrointestinal tract via the portal circulation and second, because the liver is the principal site of ethanol metabolism. National Library of Medicine In addition, acetaldehyde binds to glutathione (GSH) and weakens its antioxidant activity [95]. 1960 Feb 22; 318:1-5. It has also been reported that N2-propano-2-deoxyguanosine (N2-Et-dGTP), another DNA adduct, changes DNA integrity [114]. Massive hepatocyte death provokes the fibrotic repair process in the liver [81]. Alcohol Metabolism Drinking heavily puts people at risk for many adverse health consequences, including alcohol use disorder, liver damage, and various cancers. Anti-fibrotic effect of natural killer (NK) cells that are cytotoxic to activated HSCs is inhibited by chronic alcohol consumption. There is a particular focus on the occurrence of ALD caused by hepatotoxicity originating from alcohol metabolism. Holford N.H. Clinical pharmacokinetics of ethanol. Much of the research on alcohol metabolism has focused on an intermediate byproduct that occurs early in the breakdown processacetaldehyde. Furthermore, it has been demonstrated in in vivo experiments; TLR4 knockout (KO) mice were found to be resistant to alcohol-induced hepatic steatosis [68,69]. A national survey in the September 2020 issue of JAMA revealed that people 18 and older were consuming alcohol more often. But some people appear to be at greater risk than others for developing these problems. The major pathway for alcohol metabolism involves the enzyme alcohol dehydrogenase (ADH). A Systematic Review and Meta-Analysis of Alcohol Consumption and All-Cause Mortality. Rao R.K. Acetaldehyde-induced increase in paracellular permeability in Caco-2 cell monolayer. These findings might explain why the prevalence of ALD-associated liver cancer is high in the Asian population, among whom 3040% have an ALDH2 deficiency. Xu D., Xu M., Jeong S., Qian Y., Wu H., Xia Q., Kong X. Received 2021 May 10; Accepted 2021 May 24. In addition, the homozygous ADH1C*1 allele has been discovered to be a predictor of an increased risk of HCC in ALD patients, since the ADH1C*1 allele encodes a 2.5-fold higher ethanol oxidizing capacity to generate more acetaldehyde than the ADH1C*2 allele [122]. Tsukamoto H., Reidelberger R.D., French S.W., Largman C. Long-term cannulation model for blood sampling and intragastric infusion in the rat. Wilson C.G., Tran J.L., Erion D.M., Vera N.B., Febbraio M., Weiss E.J. They weaken DNA integrity and interfere with DNA repair system, increasing carcinogenic DNA mutation. Korsten M.A., Matsuzaki S., Feinman L., Lieber C.S. PMID:17718399, 6 Deitrich, R.; Zimatkin, S.;and Pronko S. Oxidation of ethanol in the brain and its consequences. It also binds to a variety of proteins to form acetaldehyde adducts, which distorts liver function and structure [37,38]. Jia L., Chang X., Qian S., Liu C., Lord C.C., Ahmed N., Lee C.E., Lee S., Gautron L., Mitchell M.C., et al. Pathophysiological Aspects of Alcohol Metabolism in the Liver - MDPI Acetate is metabolized into carbon dioxide (CO2), fatty acids (FAs), and water (H2O) in peripheral tissues, not the liver [10,27]. Effects of alcohol on health and liver - Mayo Clinic Health System Seo W., Gao Y., He Y., Sun J., Xu H., Feng D., Park S.H., Cho Y.E., Guillot A., Ren T., et al. ALDH2 deficiency promotes alcohol-associated liver cancer by activating oncogenic pathways via oxidized DNA-enriched extracellular vesicles. ROS released from Kupffer cells mediates the activation of the toll-like receptor 4 (TLR4)/mitogen-activated protein kinase (MAPK)/nuclear factor (NF)-B axis [66]. Hepatic and metabolic effects of ethanol: Pathogenesis and prevention. Kersten S. Integrated physiology and systems biology of PPAR. Although public awareness of the hepatotoxicity caused by alcohol is rising, the trend of alcohol consumption is steadily increasing [4,17]. Among them, the carcinogenic effect of ethanol-derived acetaldehyde forming protein and DNA adducts may be specific to ALD-associated HCC [111,112]. [149] developed a three-dimensional in vitro model of ALD by co-culturing rat primary hepatocytes and HSCs in a microfluidic chip where the cells were exposed to ethanol via the flow. Souza-Mello V. Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease. Eken A., Ortiz V., Wands J.R. Ethanol inhibits antigen presentation by dendritic cells. Sakamoto T., Hara M., Higaki Y., Ichiba M., Horita M., Mizuta T., Eguchi Y., Yasutake T., Ozaki I., Yamamoto K., et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Go to: Reciprocal modulation of Toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acids. Lieber C.S. Biomarkers for monitoring alcohol sobriety after liver transplantation According to the periods of ethanol feeding, high BALs, elevated level of serum alanine aminotransferase hepatic neutrophil infiltration, and even severe liver damage can be generated. Lipid clearance in the liver is mediated by mitochondrial -oxidation and secretion of excessive stored triglycerides that are packed into very-low density lipoprotein (VLDL) [53]. Most of the alcohol that people drink is metabolized in the liver. Transcriptional Regulation by Nrf2. Although acetaldehyde is short-lived, usually existing in the body only for a brief time before it is further broken down into acetate, it has the potential to cause significant damage. Ingested alcohol is absorbed through the stomach and intestines. Bile acid metabolism is also dysregulated in patients with alcohol-associated liver disease. As the consumption of alcoholic beverages increases, it contributes to the significant elevation of morbidity and mortality worldwide [3,4]. Acetaldehyde interacts directly with DNA and causes point mutations and chromosomal damage. Thus, whereas FPM is SAMIRZAKHARI, PH.D., is director, sharing sensitive information, make sure youre on a federal Ethanol inhibits antigen presentation in macrophages and dendritic cells [76]. Alcohol Metabolism - an overview | ScienceDirect Topics The ethanol-derived toxic metabolites dysregulate multiple aspects of hepatic lipid metabolismthey increase hepatic FA uptake and de novo lipid synthesis and decrease FA oxidation and lipid export. Alcohol Metabolism Although the liver is the main organ responsible for metabolizing ingested alcohol, stomach (i.e., gastric) ADHhas been reported to contribute to FPM. Limited understanding of ALD hampers the development of novel therapies for ALD. Rehm J., Baliunas D., Borges G.L., Graham K., Irving H., Kehoe T., Parry C.D., Patra J., Popova S., Poznyak V., et al. DeCarli L.M., Lieber C.S. 1976;2:150-93. doi: 10.1159/000398596. Alcohol circulating in the blood is transported to the liver, where it is broken down by several enzymes, the most important of which are ADH and cytochrome P450 (figure 2). We focused on the hepatotoxicity of ethanol-derived metabolites produced by oxidative alcohol metabolism (acetaldehyde and ROS) during excessive exposure to alcohol. Excess alcohol consumption increases the expression and activity of cytochrome P450 2E1 (CYP2E1), not ADH. Many of the metabolic and toxic effects of alcohol in the liver have been linked to its metabolism in that organ ( Fig. Aldehyde-Induced DNA and Protein Adducts as Biomarker Tools for Alcohol Use Disorder. It has been shown that the ALDH2-KO mouse having highly accumulated acetaldehyde in the liver is more susceptible to alcohol-induced liver inflammation and fibrosis compared to wide-type mice because of the higher level of MDA-acetaldehyde adducts [82]. Alcohol Research & Health29(4):266273, 2006. Herein, the metabolic processes of alcohol are summarized, and ALD pathogenesis is reviewed, providing knowledge into the underlying mechanism of ALD. Before Ceni E., Mello T., Galli A. Pathogenesis of alcoholic liver disease: Role of oxidative metabolism. Ethanol is readily absorbed from the gastrointestinal tract. Authors G Ugarte, H Iturriaga. Fibrogenic actions of acetaldehyde are -catenin dependent but Wingless independent: A critical role of nucleoredoxin and reactive oxygen species in human hepatic stellate cells. Research-based information on drinking and its impact. Lindros K.O., Stowell A., Pikkarainen P., Salaspuro M. Elevated blood acetaldehyde in alcoholics with accelerated ethanol elimination. This is because alcohol causes many types of cancers, including hepatocellular carcinoma (HCC) in humans [109]. Dangerous byproducts of alcohol breakdown--focus on adducts. First, alcohol is oxidized to acetaldehyde by alcohol dehydrogenase (ADH), a primary enzyme that converts alcohol to acetaldehyde [28]. The fibrogenic mechanisms are initiated and perpetuated by alcohol metabolism (Figure 3) [11]. Askgaard G., Grnbk M., Kjr M.S., Tjnneland A., Tolstrup J.S. Alcohol Metabolism - an overview | ScienceDirect Topics Lieber C.S. Alcoholic Liver Disease | Johns Hopkins Medicine The liver plays a key role in the body's metabolic regulation and is a "frontline" organ that rapidly metabolizes (i.e., chemically converts or oxidizes) alcohol to less harmful substances. [150] generated the expandable hepatic organoids derived from human embryonic stem cells. Although the acetaldehyde level also increases in rodents after ethanol treatment, its amount varies depending on the dose of alcohol and duration of alcohol feeding. In particular, much higher concentrations of such enzymes are found in the liver, which is the primary site for alcohol catabolism.

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