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Frontiers in Immunology 2023Alcoholic hepatitis (AH) is a major health problem worldwide. There is increasing evidence that immune cells, iron metabolism and copper metabolism play important roles...
BACKGROUNDS
Alcoholic hepatitis (AH) is a major health problem worldwide. There is increasing evidence that immune cells, iron metabolism and copper metabolism play important roles in the development of AH. We aimed to explore biomarkers that are co-associated with M1 macrophages, ferroptosis and cuproptosis in AH patients.
METHODS
GSE28619 and GSE103580 datasets were integrated, CIBERSORT algorithm was used to analyze the infiltration of 22 types of immune cells and GSVA algorithm was used to calculate ferroptosis and cuproptosis scores. Using the "WGCNA" R package, we established a gene co-expression network and analyzed the correlation between M1 macrophages, ferroptosis and cuproptosis scores and module characteristic genes. Subsequently, candidate genes were screened by WGCNA and differential expression gene analysis. The LASSO-SVM analysis was used to identify biomarkers co-associated with M1 macrophages, ferroptosis and cuproptosis. Finally, we validated these potential biomarkers using GEO datasets (GSE155907, GSE142530 and GSE97234) and a mouse model of AH.
RESULTS
The infiltration level of M1 macrophages was significantly increased in AH patients. Ferroptosis and cuproptosis scores were also increased in AH patients. In addition, M1 macrophages, ferroptosis and cuproptosis were positively correlated with each other. Combining bioinformatics analysis with a mouse model of AH, we found that ALDOA, COL3A1, LUM, THBS2 and TIMP1 may be potential biomarkers co-associated with M1 macrophages, ferroptosis and cuproptosis in AH patients.
CONCLUSION
We identified 5 potential biomarkers that are promising new targets for the treatment and diagnosis of AH patients.
Topics: Animals; Mice; Biomarkers; Computational Biology; Disease Models, Animal; Ferroptosis; Hepatitis, Alcoholic; Macrophages; Copper; Apoptosis
PubMed: 37090703
DOI: 10.3389/fimmu.2023.1146693 -
Clinics in Liver Disease Aug 2021The natural history of moderate alcoholic hepatitis (AH) is not well known. It is a frequent disease with a probable underestimated incidence compared with its severe... (Review)
Review
The natural history of moderate alcoholic hepatitis (AH) is not well known. It is a frequent disease with a probable underestimated incidence compared with its severe form. Among the different prognostic scores predicting short-term mortality in AH, MELD seems to be the most accurate. The mortality of moderate AH is 3% to 7% in the short to medium term and 13% to 20% at 1 year, mainly because of liver-related complications, including severe infections. Long-term abstinence is the main goal of the treatment. There is still need for the development of new therapies for AH, including the less severe forms.
Topics: Hepatitis, Alcoholic; Humans; Incidence
PubMed: 34229838
DOI: 10.1016/j.cld.2021.03.001 -
Hepatology (Baltimore, Md.) Jan 2020
Topics: Acute-On-Chronic Liver Failure; Adult; Alcoholism; Behavior Therapy; Biomarkers; Body Mass Index; Fatty Liver, Alcoholic; Female; Hepatitis, Alcoholic; Humans; Liver Cirrhosis, Alcoholic; Liver Diseases, Alcoholic; Liver Transplantation; Male; Nutrition Therapy; Prognosis; Recurrence; Risk Factors; United States
PubMed: 31314133
DOI: 10.1002/hep.30866 -
Journal of Hepatology Oct 2021Alcoholic hepatitis (AH) is a life-threatening disease with limited therapeutic options, as the molecular mechanisms leading to death are not well understood. This study...
BACKGROUND & AIMS
Alcoholic hepatitis (AH) is a life-threatening disease with limited therapeutic options, as the molecular mechanisms leading to death are not well understood. This study evaluates the Hippo/Yes-associated protein (YAP) pathway which has been shown to play a role in liver regeneration.
METHOD
The Hippo/YAP pathway was dissected in explants of patients transplanted for AH or alcohol-related cirrhosis and in control livers, using RNA-seq, real-time PCR, western blot, immunohistochemistry and transcriptome analysis after laser microdissection. We transfected primary human hepatocytes with constitutively active YAP (YAPS127A) and treated HepaRG cells and primary hepatocytes isolated from AH livers with a YAP inhibitor. We also used mouse models of ethanol exposure (Lieber de Carli) and liver regeneration (carbon tetrachloride) after hepatocyte transduction of YAPS127A.
RESULTS
In AH samples, RNA-seq analysis and immunohistochemistry of total liver and microdissected hepatocytes revealed marked downregulation of the Hippo pathway, demonstrated by lower levels of active MST1 kinase and abnormal activation of YAP in hepatocytes. Overactivation of YAP in hepatocytes in vitro and in vivo led to biliary differentiation and loss of key biological functions such as regeneration capacity. Conversely, a YAP inhibitor restored the mature hepatocyte phenotype in abnormal hepatocytes taken from patients with AH. In ethanol-fed mice, YAP activation using YAPS127A resulted in a loss of hepatocyte differentiation. Hepatocyte proliferation was hampered by YAPS127A after carbon tetrachloride intoxication.
CONCLUSION
Aberrant activation of YAP plays an important role in hepatocyte transdifferentiation in AH, through a loss of hepatocyte identity and impaired regeneration. Thus, targeting YAP is a promising strategy for the treatment of patients with AH.
LAY SUMMARY
Alcoholic hepatitis is characterized by inflammation and a life-threatening alteration of liver regeneration, although the mechanisms behind this have not been identified. Herein, we show that liver samples from patients with alcoholic hepatitis are characterized by profound deregulation of the Hippo/YAP pathway with uncontrolled activation of YAP in hepatocytes. We used human cell and mouse models to show that inhibition of YAP reverts this hepatocyte defect and could be a novel therapeutic strategy for alcoholic hepatitis.
Topics: Animals; Disease Models, Animal; Female; France; Hepatitis, Alcoholic; Hepatocytes; Mice; YAP-Signaling Proteins
PubMed: 34129887
DOI: 10.1016/j.jhep.2021.05.041 -
Cancer Science Nov 2021Gut microbiota and the mammalian host share a symbiotic relationship, in which the host provides a suitable ecosystem for the gut bacteria to digest indigestible... (Review)
Review
Gut microbiota and the mammalian host share a symbiotic relationship, in which the host provides a suitable ecosystem for the gut bacteria to digest indigestible nutrients and produce useful metabolites. Although gut microbiota primarily reside in and influence the intestine, they also regulate liver function via absorption and subsequent transfer of microbial components and metabolites through the portal vein to the liver. Due to this transfer, the liver may be continuously exposed to gut-derived metabolites and components. For example, short-chain fatty acids (SCFA) produced by gut microbiota, through the fermentation of dietary fiber, can suppress inflammation via regulatory T cell induction through SCFA-induced epigenetic mechanisms. Additionally, secondary bile acids (BA), such as deoxycholic acid, produced by gut bacteria through the 7α-dehydroxylation of primary BAs, are thought to induce DNA damage and contribute to the remodeling of tumor microenvironments. Other substances that are also thought to influence liver function include lipopolysaccharides (components of the outer membrane of gram-negative bacteria) and lipoteichoic acid (cell wall component of Gram-positive bacteria), which are ligands of innate immune receptors, Toll-like receptor-4, and Toll-like receptor-2, respectively, through which inflammatory signaling is elicited. In this review, we focus on the role of gut microbiota in the liver microenvironment, describing the anatomy of the gut-liver axis, the role of gut microbial metabolites, and the relationships that exist between gut microbiota and liver diseases, including liver cancer.
Topics: Bile Acids and Salts; Carcinoma, Hepatocellular; Cellular Senescence; Choline; DNA Damage; Ethanol; Fatty Acids, Volatile; Gastrointestinal Microbiome; Gram-Positive Bacteria; Hepatitis, Alcoholic; Humans; Lipopolysaccharides; Liver; Liver Diseases; Liver Neoplasms; Non-alcoholic Fatty Liver Disease; Symbiosis; Teichoic Acids; Tumor Microenvironment
PubMed: 34533882
DOI: 10.1111/cas.15142 -
Hepatology (Baltimore, Md.) Mar 2023Mixed lineage kinase domain-like pseudokinase (MLKL), a key terminal effector of necroptosis, also plays a role in intracellular vesicle trafficking that is critical for...
BACKGROUND AND AIMS
Mixed lineage kinase domain-like pseudokinase (MLKL), a key terminal effector of necroptosis, also plays a role in intracellular vesicle trafficking that is critical for regulating liver inflammation and injury in alcohol-associated liver disease (ALD). Although receptor interacting protein kinase 3 (Rip3)-/- mice are completely protected from ethanol-induced liver injury, Mlkl-/- mice are only partially protected. Therefore, we hypothesized that cell-specific functions of MLKL may contribute to ethanol-induced injury.
APPROACH AND RESULTS
Bone marrow transplants between Mlkl-/- mice and littermates were conducted to distinguish the role of myeloid versus nonmyeloid Mlkl in the Gao-binge model of ALD. Ethanol-induced hepatic injury, steatosis, and inflammation were exacerbated in Mlkl-/- →wild-type (WT) mice, whereas Mlkl deficiency in nonmyeloid cells (WT→ Mlkl-/- ) had no effect on Gao-binge ethanol-induced injury. Importantly, Mlkl deficiency in myeloid cells exacerbated ethanol-mediated bacterial burden and accumulation of immune cells in livers. Mechanistically, challenging macrophages with lipopolysaccharide (LPS) induced signal transducer and activator of transcription 1-mediated expression and phosphorylation of MLKL, as well as translocation and oligomerization of MLKL to intracellular compartments, including phagosomes and lysosomes but not plasma membrane. Importantly, pharmacological or genetic inhibition of MLKL suppressed the phagocytic capability of primary mouse Kupffer cells (KCs) at baseline and in response to LPS with/without ethanol as well as peripheral monocytes isolated from both healthy controls and patients with alcohol-associated hepatitis. Further, in vivo studies revealed that KCs of Mlkl-/- mice phagocytosed fewer bioparticles than KCs of WT mice.
CONCLUSION
Together, these data indicate that myeloid MLKL restricts ethanol-induced liver inflammation and injury by regulating hepatic immune cell homeostasis and macrophage phagocytosis.
Topics: Mice; Animals; Lipopolysaccharides; Liver Diseases, Alcoholic; Liver; Ethanol; Hepatitis, Alcoholic; Inflammation; Macrophages; Phagocytosis; Receptor-Interacting Protein Serine-Threonine Kinases; Mice, Inbred C57BL; Protein Kinases
PubMed: 35689613
DOI: 10.1002/hep.32612 -
Revue Medicale de Liege May 2019Alcoholic hepatitis is a syndrome defined primarily by the clinical onset of jaundice in patients with a concomitant heavy consumption of alcoholic beverages. This...
Alcoholic hepatitis is a syndrome defined primarily by the clinical onset of jaundice in patients with a concomitant heavy consumption of alcoholic beverages. This pathology is managed by alcohol withdrawal with a 30-day survival rate of 90 %. For patients with severe alcoholic hepatitis, with a Maddrey score greater than 32 (taking into account bilirubin and prothrombin time), treatment with corticosteroids is discussed provided that a possible infection can be sufficiently excluded or adequately managed. The administration of corticosteroids is continued for 28 days if the Lille score, calculated after 7 days of treatment, is favourable (inferior to 0.45), leading to a survival rate of 80-90 %. However, if the Lille score is unfavourable (superior to 0.45), the prognosis is bad, with a survival of only 25-30 % at 6 months. Special attention needs to be paid to assure a sufficient caloric intake during the treatment period for a successful management. Liver transplantation, previously prohibited for this indication, can be discussed under certain circumstances. However, the success of treatment is contingent upon the alcohol withdrawal. Innovative drugs are currently under investigation to improve the prognosis of this condition.
Topics: Adrenal Cortex Hormones; Bilirubin; Hepatitis, Alcoholic; Humans; Liver Transplantation; Prognosis
PubMed: 31206275
DOI: No ID Found -
Journal of Clinical and Translational... Aug 2022Severe alcoholic hepatitis (sAH) is defined by a modified discriminant function ≥32 or model for end-stage liver disease (MELD) >20. Patients with sAH are in an... (Review)
Review
Severe alcoholic hepatitis (sAH) is defined by a modified discriminant function ≥32 or model for end-stage liver disease (MELD) >20. Patients with sAH are in an immunocompromised state attributed to cirrhosis-related immunoparesis and corticosteroid use. Individuals with sAH often develop severe infections that adversely impact short-term prognosis. Currently, the corticosteroid prednisolone is the only treatment with proven efficacy in sAH; however, the combination of corticosteroid treatment and altered host defense in sAH has been thought to increase the risk of acquiring of bacterial, opportunistic fungal, and viral infections. Newer studies have shown that corticosteroids do not increase occurrence of infections in those with sAH; unfortunately, the lack of response to corticosteroids may instead predispose to infection development. Prompt and appropriate antibiotic treatment is therefore essential to improving patient outcomes. This review highlights common infections and risk factors in patients with sAH. Additionally, current diagnostic, therapeutic, and prophylactic strategies in these patients are discussed.
PubMed: 36062291
DOI: 10.14218/JCTH.2022.00024 -
Gut Apr 2019Alcoholic liver disease (ALD) is a leading cause of death among chronic liver diseases. However, its pathogenesis has not been completely established. MicroRNAs (miRNAs)...
OBJECTIVE
Alcoholic liver disease (ALD) is a leading cause of death among chronic liver diseases. However, its pathogenesis has not been completely established. MicroRNAs (miRNAs) are key contributors to liver diseases progression. This study investigated hepatocyte-abundant miRNAs dysregulated by ALD, its impact on hepatocyte injury and the underlying basis.
DESIGN
Alcoholic hepatitis (AH) human and animal liver samples and hepatocytes were used to assess miR-148a levels. Pre-miR-148a was delivered specifically to hepatocytes in vivo using lentivirus. Immunoblottings, luciferase reporter assays, chromatin immunoprecipitation and immunofluorescence assays were carried out in cell models.
RESULTS
The miRNA profile and PCR analyses enabled us to find substantial decrease of miR-148a in the liver of patients with AH. In mice subjected to Lieber-DeCarli alcohol diet or binge alcohol drinking, miR-148a levels were also markedly reduced. In cultured hepatocytes and mouse livers, alcohol exposure inhibited forkhead box protein O1 (FoxO1) expression, which correlated with miR-148a levels and significantly decreased in human AH specimens. FoxO1 was identified as a transcription factor for transactivation. MiR-148a directly inhibited thioredoxin-interacting protein (TXNIP) expression. Consequently, treatment of hepatocytes with ethanol resulted in TXNIP overexpression, activating NLRP3 inflammasome and caspase-1-mediated pyroptosis. These events were reversed by miR-148a mimic or TXNIP small-interfering RNA transfection. Hepatocyte-specific delivery of miR-148a to mice abrogated alcohol-induced TXNIP overexpression and inflammasome activation, attenuating liver injury.
CONCLUSION
Alcohol decreases miR-148a expression in hepatocytes through FoxO1, facilitating TXNIP overexpression and NLRP3 inflammasome activation, which induces hepatocyte pyroptosis. Our findings provide information on novel targets for reducing incidence and progression of ALD.
Topics: Animals; Carrier Proteins; Cells, Cultured; Disease Progression; Fluorescent Antibody Technique; Hepatitis, Alcoholic; Hepatocytes; Humans; Immunoblotting; Inflammasomes; Mice; MicroRNAs; Polymerase Chain Reaction; Pyroptosis; Thioredoxins; Transcription Factors
PubMed: 29475852
DOI: 10.1136/gutjnl-2017-315123 -
American Family Physician Apr 2022Alcoholic hepatitis is a clinical syndrome characterized by acute-onset jaundice and liver enzyme abnormalities in the setting of long-term heavy alcohol use. High rates...
Alcoholic hepatitis is a clinical syndrome characterized by acute-onset jaundice and liver enzyme abnormalities in the setting of long-term heavy alcohol use. High rates of concomitant infections, systemic inflammation, and multiorgan failure lead to significant morbidity and mortality. Diagnosis of alcoholic hepatitis is primarily clinical, based on a consensus definition from the National Institute on Alcohol Abuse and Alcoholism. Initial workup should include chest radiography and cultures of peritoneal fluid, blood, and urine. Close monitoring for inflammation and organ failure is crucial throughout hospitalization. Laboratory-based prognostic scores, including Maddrey Discriminant Function and the Model for End-Stage Liver Disease, help determine disease severity and treatment options. Treatment for moderate disease primarily consists of supportive care, including alcohol cessation and nutritional support. Corticosteroids are recommended for severe alcoholic hepatitis. Responsiveness to corticosteroid therapy should be evaluated using the Lille score on day 7 of treatment. Hospital physicians should involve a multidisciplinary team, including substance abuse specialists, gastroenterologists or hepatologists, nephrologists, dietitians, and intensivists, as appropriate. Long-term follow-up should focus on abstinence from alcohol, management of underlying cirrhosis, and evaluation for liver transplantation if indicated. Pharmacologic treatment of alcohol use disorder can aid patients in maintaining abstinence from alcohol. The presence of underlying cirrhosis and continued alcohol use negatively impact long-term prognosis.
Topics: End Stage Liver Disease; Hepatitis, Alcoholic; Humans; Inflammation; Liver Cirrhosis; Severity of Illness Index
PubMed: 35426628
DOI: No ID Found