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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 -
Nutrients Mar 2023Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease associated with the pathological accumulation of lipids inside hepatocytes. Untreated NAFL can... (Review)
Review
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease associated with the pathological accumulation of lipids inside hepatocytes. Untreated NAFL can progress to non-alcoholic hepatitis (NASH), followed by fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). The common denominator of the above-mentioned metabolic disorders seems to be insulin resistance, which occurs in NAFLD patients. Obesity is the greatest risk factor for lipid accumulation inside hepatocytes, but a part of the NAFLD patient population has a normal body weight according to the BMI index. Obese people with or without NAFLD have a higher incidence of small intestinal bacterial overgrowth (SIBO), and those suffering from NAFLD show increased intestinal permeability, including a more frequent presence of bacterial overgrowth in the small intestine (SIBO). The health consequences of SIBO are primarily malabsorption disorders (vitamin B12, iron, choline, fats, carbohydrates and proteins) and bile salt deconjugation. Undetected and untreated SIBO may lead to nutrient and/or energy malnutrition, thus directly impairing liver function (e.g., folic acid and choline deficiency). However, whether SIBO contributes to liver dysfunction, decreased intestinal barrier integrity, increased inflammation, endotoxemia and bacterial translocation is not yet clear. In this review, we focus on gut-liver axis and discuss critical points, novel insights and the role of nutrition, lifestyle, pre- and probiotics, medication and supplements in the therapy and prevention of both SIBO and NAFLD.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Carcinoma, Hepatocellular; Liver Neoplasms; Liver; Risk Factors; Obesity; Fibrosis
PubMed: 36986052
DOI: 10.3390/nu15061323 -
Nature Communications Jul 2021Alcoholic hepatitis (AH) is associated with liver neutrophil infiltration through activated cytokine pathways leading to elevated chemokine expression. Super-enhancers...
Alcoholic hepatitis (AH) is associated with liver neutrophil infiltration through activated cytokine pathways leading to elevated chemokine expression. Super-enhancers are expansive regulatory elements driving augmented gene expression. Here, we explore the mechanistic role of super-enhancers linking cytokine TNFα with chemokine amplification in AH. RNA-seq and histone modification ChIP-seq of human liver explants show upregulation of multiple CXCL chemokines in AH. Liver sinusoidal endothelial cells (LSEC) are identified as an important source of CXCL expression in human liver, regulated by TNFα/NF-κB signaling. A super-enhancer is identified for multiple CXCL genes by multiple approaches. dCas9-KRAB-mediated epigenome editing or pharmacologic inhibition of Bromodomain and Extraterminal (BET) proteins, transcriptional regulators vital to super-enhancer function, decreases chemokine expression in vitro and decreases neutrophil infiltration in murine models of AH. Our findings highlight the role of super-enhancer in propagating inflammatory signaling by inducing chemokine expression and the therapeutic potential of BET inhibition in AH treatment.
Topics: Animals; Chemokines; Cytokines; Disease Models, Animal; Endothelial Cells; Enhancer Elements, Genetic; Epigenesis, Genetic; Gene Expression Regulation; Hepatitis, Alcoholic; Histones; Humans; Lipopolysaccharides; Liver; Mice, Inbred C57BL; NF-kappa B; Neutrophils; Promoter Regions, Genetic; RNA-Seq; Signal Transduction; Transcription Factors; Tumor Necrosis Factor-alpha; Mice
PubMed: 34315876
DOI: 10.1038/s41467-021-24843-w -
Clinical Liver Disease Aug 2021
Review
PubMed: 34584675
DOI: 10.1002/cld.1092 -
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 -
Gut Oct 2021Mitochondrial dysfunction plays a dominant role in the pathogenesis of alcoholic liver disease (ALD); however, the underlying mechanisms remain to be fully understood....
OBJECTIVE
Mitochondrial dysfunction plays a dominant role in the pathogenesis of alcoholic liver disease (ALD); however, the underlying mechanisms remain to be fully understood. We previously found that hepatic activating transcription factor 4 (ATF4) activation was associated with mitochondrial dysfunction in ALD. This study aimed to investigate the function and mechanism of ATF4 in alcohol-induced hepatic mitochondrial dysfunction.
DESIGN
ATF4 activation was detected in the livers of patients with severe alcoholic hepatitis (AH). The role of ATF4 and mitochondrial transcription factor A (TFAM) in alcohol-induced liver damage was determined in hepatocyte-specific knockout mice and liver-specific overexpression mice, respectively.
RESULTS
Hepatic PERK-eIF2α-ATF4 ER stress signalling was upregulated in patients with AH. Hepatocyte-specific ablation of in mice ameliorated alcohol-induced steatohepatitis. ablation also attenuated alcohol-impaired mitochondrial biogenesis and respiratory function along with the restoration of TFAM. Cell studies confirmed that TFAM expression was negatively regulated by ATF4. silencing in hepatoma cells abrogated the protective effects of knockdown on ethanol-mediated mitochondrial dysfunction and cell death. Moreover, hepatocyte-specific overexpression in mice attenuated alcohol-induced mitochondrial dysfunction and liver damage. Mechanistic studies revealed that ATF4 repressed the transcription activity of nuclear respiratory factor 1 (NRF1), a key regulator of TFAM, through binding to its promoter region. Clinical relevance among ATF4 activation, NRF1-TFAM pathway disruption and mitochondrial dysfunction was validated in the livers of patients with AH.
CONCLUSION
This study demonstrates that hepatic ATF4 plays a pathological role in alcohol-induced mitochondrial dysfunction and liver injury by disrupting the NRF1-TFAM pathway.
Topics: Activating Transcription Factor 4; Animals; DNA-Binding Proteins; Fatty Liver, Alcoholic; Humans; Mice, Knockout; Mitochondria, Liver; Mitochondrial Proteins; Signal Transduction; Transcription Factors; Up-Regulation; eIF-2 Kinase; Mice
PubMed: 33177163
DOI: 10.1136/gutjnl-2020-321548 -
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