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Browsing by Subject "Alcohol-associated liver disease"
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Item Alcohol Metabolizing Enzymes, Microsomal Ethanol Oxidizing System, Cytochrome P450 2E1, Catalase, and Aldehyde Dehydrogenase in Alcohol-Associated Liver Disease(MDPI, 2020-03) Jiang, Yanchao; Zhang, Ting; Kusumanchi, Praveen; Han, Sen; Yang, Zhihong; Liangpunsakul, Suthat; Medicine, School of MedicineOnce 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.Item Circulating Extracellular Vesicles Carrying Sphingolipid Cargo for the Diagnosis and Dynamic Risk Profiling of Alcoholic Hepatitis(Wolters Kluwer, 2021) Sehrawat, Tejasav S.; Arab, Juan P.; Liu, Mengfei; Amrollahi, Pouya; Wan, Meihua; Fan, Jia; Nakao, Yasuhiko; Pose, Elisa; Navarro-Corcuera, Amaia; Dasgupta, Debanjali; Liao, Chieh-Yu; He, Li; Mauer, Amy S.; Avitabile, Emma; Ventura-Cots, Meritxell; Bataller, Ramon A.; Sanyal, Arun J.; Chalasani, Naga P.; Heimbach, Julie K.; Watt, Kymberly D.; Gores, Gregory J.; Gines, Pere; Kamath, Patrick S.; Simonetto, Douglas A.; Hu, Tony Y.; Shah, Vijay H.; Malhi, Harmeet; Medicine, School of MedicineBackground and aims: Alcoholic hepatitis (AH) is diagnosed by clinical criteria, although several objective scores facilitate risk stratification. Extracellular vesicles (EVs) have emerged as biomarkers for many diseases and are also implicated in the pathogenesis of AH. Therefore, we investigated whether plasma EV concentration and sphingolipid cargo could serve as diagnostic biomarkers for AH and inform prognosis to permit dynamic risk profiling of AH subjects. Approach and results: EVs were isolated and quantified from plasma samples from healthy controls, heavy drinkers, and subjects with end-stage liver disease (ESLD) attributed to cholestatic liver diseases and nonalcoholic steatohepatitis, decompensated alcohol-associated cirrhosis (AC), and AH. Sphingolipids were quantified by tandem mass spectroscopy. The median plasma EV concentration was significantly higher in AH subjects (5.38 × 1011 /mL) compared to healthy controls (4.38 × 1010 /mL; P < 0.0001), heavy drinkers (1.28 × 1011 /mL; P < 0.0001), ESLD (5.35 × 1010 /mL; P < 0.0001), and decompensated AC (9.2 × 1010 /mL; P < 0.0001) disease controls. Among AH subjects, EV concentration correlated with Model for End-Stage Liver Disease score. When EV counts were dichotomized at the median, survival probability for AH subjects at 90 days was 63.0% in the high-EV group and 90.0% in the low-EV group (log-rank P value = 0.015). Interestingly, EV sphingolipid cargo was significantly enriched in AH when compared to healthy controls, heavy drinkers, ESLD, and decompensated AC (P = 0.0001). Multiple sphingolipids demonstrated good diagnostic and prognostic performance as biomarkers for AH. Conclusions: Circulating EV concentration and sphingolipid cargo signature can be used in the diagnosis and differentiation of AH from heavy drinkers, decompensated AC, and other etiologies of ESLD and predict 90-day survival permitting dynamic risk profiling.Item Ethanol and its Nonoxidative Metabolites Promote Acute Liver Injury by Inducing ER Stress, Adipocyte Death, and Lipolysis(Elsevier, 2023) Park, Seol Hee; Seo, Wonhyo; Xu, Ming-Jiang; Mackowiak, Bryan; Lin, Yuhong; He, Yong; Fu, Yaojie; Hwang, Seonghwan; Kim, Seung-Jin; Guan, Yukun; Feng, Dechun; Yu, Liqing; Lehner, Richard; Liangpunsakul, Suthat; Gao, Bin; Medicine, School of MedicineBackground & aims: Binge drinking in patients with metabolic syndrome accelerates the development of alcohol-associated liver disease. However, the underlying mechanisms remain elusive. We investigated if oxidative and nonoxidative alcohol metabolism pathways, diet-induced obesity, and adipose tissues influenced the development of acute liver injury in a single ethanol binge model. Methods: A single ethanol binge was administered to chow-fed or high-fat diet (HFD)-fed wild-type and genetically modified mice. Results: Oral administration of a single dose of ethanol induced acute liver injury and hepatic endoplasmic reticulum (ER) stress in chow- or HFD-fed mice. Disruption of the Adh1 gene increased blood ethanol concentration and exacerbated acute ethanol-induced ER stress and liver injury in both chow-fed and HFD-fed mice, while disruption of the Aldh2 gene did not affect such hepatic injury despite high blood acetaldehyde levels. Mechanistic studies showed that alcohol, not acetaldehyde, promoted hepatic ER stress, fatty acid synthesis, and increased adipocyte death and lipolysis, contributing to acute liver injury. Increased serum fatty acid ethyl esters (FAEEs), which are formed by an enzyme-mediated esterification of ethanol with fatty acids, were detected in mice after ethanol gavage, with higher levels in Adh1 knockout mice than in wild-type mice. Deletion of the Ces1d gene in mice markedly reduced the acute ethanol-induced increase of blood FAEE levels with a slight but significant reduction of serum aminotransferase levels. Conclusions: Ethanol and its nonoxidative metabolites, FAEEs, not acetaldehyde, promoted acute alcohol-induced liver injury by inducing ER stress, adipocyte death, and lipolysis.Item Management of alcohol use disorder in alcohol-associated liver disease for nonaddiction specialists(Wolters Kluwer, 2023-07-11) Lee, Brian P.; Liangpunsakul, Suthat; Medicine, School of MedicineItem Reporting the cases of alcohol-associated hepatitis using the National Inpatient Sample data(Baishideng, 2023) Marlowe, Natalie; Lin, Wei-Qi; Liangpunsakul, Suthat; Medicine, School of MedicineThe letter is to respond to the recent publication "Trends in hospitalization for alcoholic hepatitis from 2011 to 2017: A USA nationwide study" (World J Gastroenterol 2022; 28: 5036-5046). We noticed a significant difference in the total numbers of reported hospitalized alcohol-associated hepatitis (AH) patients between this publication and our publication on Alcohol Clin Exp Res (2022; 46: 1472-1481). We believe the number of "AH-related hospitalizations" inflated by the inclusion of patients with non-AH forms of alcohol-associated liver disease.Item S-Adenosylmethionine Negatively Regulates the Mitochondrial Respiratory Chain Repressor MCJ in the Liver(Ivyspring, 2024-01-27) Barbier-Torres, Lucía; Chhimwal, Jyoti; Kim, So Yeon; Ramani, Komal; Robinson, Aaron; Yang, Heping; Van Eyk, Jenny; Liangpunsakul, Suthat; Seki, Ekihiro; Mato, José M.; Lu, Shelly C.; Biochemistry and Molecular Biology, School of MedicineMCJ (Methylation-Controlled J protein), an endogenous repressor of the mitochondrial respiratory chain, is upregulated in multiple liver diseases but little is known about how it is regulated. S-adenosylmethionine (SAMe), the biological methyl donor, is frequently depleted in chronic liver diseases. Here, we show that SAMe negatively regulates MCJ in the liver. While deficiency in methionine adenosyltransferase alpha 1 (MATα1), enzyme that catalyzes SAMe biosynthesis, leads to hepatic MCJ upregulation, MAT1A overexpression and SAMe treatment reduced MCJ expression. We found that MCJ is methylated at lysine residues and that it interacts with MATα1 in liver mitochondria, likely to facilitate its methylation. Lastly, we observed that MCJ is upregulated in alcohol-associated liver disease, a condition characterized by reduced MAT1A expression and SAMe levels along with mitochondrial injury. MCJ silencing protected against alcohol-induced mitochondrial dysfunction and lipid accumulation. Our study demonstrates a new role of MATα1 and SAMe in reducing hepatic MCJ expression.Item Stress-Responsive Gene FK506-Binding Protein 51 Mediates Alcohol-Induced Liver Injury Through the Hippo Pathway and Chemokine (C-X-C Motif) Ligand 1 Signaling(Wolters Kluwer, 2021) Kusumanchi, Praveen; Liang, Tiebing; Zhang, Ting; Ross, Ruth Ann; Han, Sen; Chandler, Kristina; Oshodi, Adepeju; Jiang, Yanchao; Dent, Alexander L.; Skill, Nicholas J.; Huda, Nazmul; Ma, Jing; Yang, Zhihong; Liangpunsakul, Suthat; Medicine, School of MedicineBackground and aims: Chronic alcohol drinking is a major risk factor for alcohol-associated liver disease (ALD). FK506-binding protein 51 (FKBP5), a cochaperone protein, is involved in many key regulatory pathways. It is known to be involved in stress-related disorders, but there are no reports regarding its role in ALD. This present study aimed to examine the molecular mechanism of FKBP5 in ALD. Approach and results: We found a significant increase in hepatic FKBP5 transcripts and protein expression in patients with ALD and mice fed with chronic-plus-single binge ethanol. Loss of Fkbp5 in mice protected against alcohol-induced hepatic steatosis and inflammation. Transcriptomic analysis revealed a significant reduction of Transcriptional enhancer factor TEF-1 (TEA) domain transcription factor 1 (Tead1) and chemokine (C-X-C motif) ligand 1 (Cxcl1) mRNA in ethanol-fed Fkbp5-/- mice. Ethanol-induced Fkbp5 expression was secondary to down-regulation of methylation level at its 5' untranslated promoter region. The increase in Fkbp5 expression led to induction in transcription factor TEAD1 through Hippo signaling pathway. Fkbp5 can interact with yes-associated protein (YAP) upstream kinase, mammalian Ste20-like kinase 1 (MST1), affecting its ability to phosphorylate YAP and the inhibitory effect of hepatic YAP phosphorylation by ethanol leading to YAP nuclear translocation and TEAD1 activation. Activation of TEAD1 led to increased expression of its target, CXCL1, a chemokine-mediated neutrophil recruitment, causing hepatic inflammation and neutrophil infiltration in our mouse model. Conclusions: We identified an FKBP5-YAP-TEAD1-CXCL1 axis in the pathogenesis of ALD. Loss of FKBP5 ameliorates alcohol-induced liver injury through the Hippo pathway and CXCL1 signaling, suggesting its potential role as a target for the treatment of ALD.