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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 -
Journal of Hepatology Nov 2019As a nicotinamide adenine dinucleotide-dependent deacetylase and a key epigenetic regulator, sirtuin 6 (SIRT6) has been implicated in the regulation of metabolism, DNA...
BACKGROUND & AIMS
As a nicotinamide adenine dinucleotide-dependent deacetylase and a key epigenetic regulator, sirtuin 6 (SIRT6) has been implicated in the regulation of metabolism, DNA repair, and inflammation. However, the role of SIRT6 in alcohol-related liver disease (ALD) remains unclear. The aim of this study was to investigate the function and mechanism of SIRT6 in ALD pathogenesis.
METHODS
We developed and characterized Sirt6 knockout (KO) and transgenic mouse models that were treated with either control or ethanol diet. Hepatic steatosis, inflammation, and oxidative stress were analyzed using biochemical and histological methods. Gene regulation was analyzed by luciferase reporter and chromatin immunoprecipitation assays.
RESULTS
The Sirt6 KO mice developed severe liver injury characterized by a remarkable increase of oxidative stress and inflammation, whereas the Sirt6 transgenic mice were protected from ALD via normalization of hepatic lipids, inflammatory response, and oxidative stress. Our molecular analysis has identified a number of novel Sirt6-regulated genes that are involved in antioxidative stress, including metallothionein 1 and 2 (Mt1 and Mt2). Mt1/2 genes were downregulated in the livers of Sirt6 KO mice and patients with alcoholic hepatitis. Overexpression of Mt1 in the liver of Sirt6 KO mice improved ALD by reducing hepatic oxidative stress and inflammation. We also identified a critical link between SIRT6 and metal regulatory transcription factor 1 (Mtf1) via a physical interaction and functional coactivation. Mt1/2 promoter reporter assays showed a strong synergistic effect of SIRT6 on the transcriptional activity of Mtf1.
CONCLUSIONS
Our data suggest that SIRT6 plays a critical protective role against ALD and it may serve as a potential therapeutic target for ALD.
LAY SUMMARY
The liver, the primary organ for ethanol metabolism, can be damaged by the byproducts of ethanol metabolism, including reactive oxygen species. In this study, we have identified a key epigenetic regulator SIRT6 that plays a critical role in protecting the liver from oxidative stress-induced liver injury. Thus, our data suggest that SIRT6 may be a potential therapeutic target for alcohol-related liver disease.
Topics: Adult; Animals; Disease Models, Animal; Down-Regulation; Epigenesis, Genetic; Ethanol; Fatty Liver; Female; Gene Expression Regulation; Hepatocytes; Humans; Liver; Liver Diseases, Alcoholic; Male; Mice; Mice, Knockout; Middle Aged; Oxidative Stress; Reactive Oxygen Species; Sirtuins
PubMed: 31295533
DOI: 10.1016/j.jhep.2019.06.019 -
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 -
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 -
Journal of Clinical and Experimental... 2022Acute-on-chronic liver failure (ACLF) is a clinical syndrome that occurs in patients with cirrhosis and is characterised by acute deterioration, organ failure and high... (Review)
Review
Acute-on-chronic liver failure (ACLF) is a clinical syndrome that occurs in patients with cirrhosis and is characterised by acute deterioration, organ failure and high short-term mortality. Alcohol is one of the leading causes of ACLF and the most frequently reported aetiology of underlying chronic liver disease. Among patients with alcoholic hepatitis (AH), ACLF is a frequent and severe complication. It is characterised by both immune dysfunction associated to an increased risk of infection and high-grade systemic inflammation that ultimately induce organ failure. Diagnosis and severity of ACLF determine AH prognosis, and therefore, ACLF prognostic scores should be used in severe AH with organ failure. Corticosteroids remain the first-line treatment for severe AH but they seem insufficient when ACLF is associated. Novel therapeutic targets to contain the excessive inflammatory response and reduce infection have been identified and are under investigation. With liver transplantation remaining one of the most effective therapies for severe AH and ACLF, adequate organ allocation represents a growing challenge. Hence, a clear understanding of the pathophysiology, clinical implications and management strategies of ACLF in AH is essential for hepatologists, which is narrated briefly in this review.
PubMed: 36157143
DOI: 10.1016/j.jceh.2021.12.010 -
The Lancet. Gastroenterology &... May 2022Early liver transplantation for severe alcohol-related hepatitis is an emerging treatment option. We aimed to assess the risk of alcohol relapse 2 years after early...
BACKGROUND
Early liver transplantation for severe alcohol-related hepatitis is an emerging treatment option. We aimed to assess the risk of alcohol relapse 2 years after early liver transplantation for alcohol-related hepatitis compared with liver transplantation for alcohol-related cirrhosis after at least 6 months of abstinence.
METHODS
We conducted a multicentre, non-randomised, non-inferiority, controlled study in 19 French and Belgian hospitals. All participants were aged 18 years or older. There were three groups of patients recruited prospectively: patients with severe alcohol-related hepatitis who did not respond to medical treatment and were eligible for early liver transplantation according to a new selection scoring system based on social and addiction items that can be quantified in points (early transplantation group); patients with alcohol-related cirrhosis listed for liver transplantation after at least 6 months of abstinence (standard transplantation group); patients with severe alcohol-related hepatitis not responding to medical treatment not eligible for early liver transplantation according to the selection score (not eligible for early transplantation group), this group did not enter any further liver transplantation processes. We also defined a historical control group of patients with severe alcohol-related hepatitis unresponsive to medical therapy and non-transplanted. The primary outcome was the non-inferiority of 2-year rate of alcohol relapse after transplantation in the early transplantation group compared with the standard transplantation group using the alcohol timeline follow back (TLFB) method and a prespecified non-inferiority margin of 10%. Secondary outcomes were the pattern of alcohol relapse, 2-year survival rate post-transplant in the early transplantation group compared with the standard transplantation group, and 2-year overall survival in the early transplantation group compared with patients in the not eligible for early transplantation group and historical controls. This trial is registered with ClinicalTrials.gov, NCT01756794.
FINDINGS
Between Dec 5, 2012, and June 30, 2016, we included 149 patients with severe alcohol-related hepatitis: 102 in the early transplantation group and 47 in the not eligible for early transplantation group. 129 patients were included in the standard transplantation group. 68 patients in the early transplantation group and 93 patients in the standard transplantation group received a liver transplant. 23 (34%) patients relapsed in the early transplantation group, and 23 (25%) patients relapsed in the standard transplantation group; therefore, the non-inferiority of early transplantation versus standard transplantation was not demonstrated (absolute difference 9·1% [95% CI -∞ to 21·1]; p=0·45). The 2-year rate of high alcohol intake was greater in the early transplantation group than the standard transplantation group (absolute difference 16·7% [95% CI 5·8-27·6]) The time spent drinking alcohol was not different between the two groups (standardised difference 0·24 [95% CI -0·07 to 0·55]), but the time spent drinking a large quantity of alcohol was higher in the early transplantation group than the standard transplantation group (standardised difference 0·50 [95% CI 0·17-0·82]). 2-year post-transplant survival was similar between the early transplantation group and the standard transplantation group (hazard ratio [HR] 0·87 [95% CI 0·33-2·26]); 2-year overall survival was higher in the early transplantation group than the not eligible for early transplantation group and historical controls (HR 0·27 [95% CI 0·16-0·47] and 0·21 [0·13-0·32]).
INTERPRETATION
We cannot conclude non-inferiority in terms of rate of alcohol relapse post-transplant between early liver transplantation and standard transplantation. High alcohol intake is more frequent after early liver transplantation. This prospective controlled study confirms the important survival benefit related to early liver transplantation for severe alcohol-related hepatitis; and this study provides objective data on survival and alcohol relapse to tailor the management of patients with severe alcohol-related hepatitis.
FUNDING
The present study has been granted by the French Ministry of Health-Programme Hospitalier de Recherche Clinique 2010.
Topics: Hepatitis, Alcoholic; Humans; Liver Cirrhosis, Alcoholic; Liver Transplantation; Neoplasm Recurrence, Local; Prospective Studies
PubMed: 35202597
DOI: 10.1016/S2468-1253(21)00430-1 -
Nutrients Dec 2022Alterations in the composition of the gut microbiota (dysbiosis) are observed in nutritional liver diseases, including non-alcoholic fatty liver disease (NAFLD) and... (Review)
Review
Alterations in the composition of the gut microbiota (dysbiosis) are observed in nutritional liver diseases, including non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) and have been shown to be associated with the severity of both. Editing the composition of the microbiota by fecal microbiota transfer or by application of probiotics or prebiotics/fiber in rodent models and human proof-of-concept trials of NAFLD and ALD have demonstrated its possible contribution to reducing the progression of liver damage. In this review, we address the role of a soluble fiber, pectin, in reducing the development of liver injury in NAFLD and ALD through its impact on gut bacteria.
Topics: Humans; Non-alcoholic Fatty Liver Disease; Pectins; Liver; Prebiotics; Probiotics; Liver Diseases, Alcoholic; Dysbiosis
PubMed: 36615814
DOI: 10.3390/nu15010157 -
Hepatology Communications Sep 2023Patients with liver diseases, including decompensated cirrhosis, alcohol-associated hepatitis, and liver transplant recipients are at increased risk of acquiring...
Patients with liver diseases, including decompensated cirrhosis, alcohol-associated hepatitis, and liver transplant recipients are at increased risk of acquiring invasive fungal infections (IFIs). These infections carry high morbidity and mortality. Multiple factors, including host immune dysfunction, barrier failures, malnutrition, and microbiome alterations, increase the risk of developing IFI. Candida remains the most common fungal pathogen causing IFI. However, other pathogens, including Aspergillus, Cryptococcus, Pneumocystis, and endemic mycoses, are being increasingly recognized. The diagnosis of IFIs can be ascertained by the direct observation or isolation of the pathogen (culture, histopathology, and cytopathology) or by detecting antigens, antibodies, or nucleic acid. Here, we provide an update on the epidemiology, pathogenesis, diagnosis, and management of IFI in patients with liver disease and liver transplantation.
Topics: Humans; Liver Diseases; Invasive Fungal Infections; Liver Transplantation; Cytology; Hepatitis, Alcoholic
PubMed: 37639701
DOI: 10.1097/HC9.0000000000000216 -
F1000Research 2020Alcoholic hepatitis is the severest clinical presentation of alcoholic liver disease. Lacking an effective pharmacologic treatment, alcoholic hepatitis is associated... (Review)
Review
Alcoholic hepatitis is the severest clinical presentation of alcoholic liver disease. Lacking an effective pharmacologic treatment, alcoholic hepatitis is associated with a poor prognosis and its recovery relies mostly on abstinence. With alcohol use disorder being universally on the rise, the impact of alcoholic hepatitis on society and health-care costs is expected to increase significantly. Prognostic factors and liver biopsy can help with timely diagnosis, to determine eligibility and response to corticosteroids, and for prognostication and transplant referral. Although recent discoveries in the pathophysiology of alcoholic hepatitis are encouraging and could pave the way for novel treatment modalities, a multidisciplinary approach considering timely identification and treatment of liver-related complications, infectious and metabolic disease, malnutrition, and addiction counseling should be emphasized. Apart from proper selection of candidates, transplant programs should provide adequate post-transplant addiction support in order to make of early liver transplantation for alcoholic hepatitis the ultimate sobering experience in the next decade.
Topics: Hepatitis, Alcoholic; Humans; Liver Diseases, Alcoholic; Liver Transplantation
PubMed: 32089834
DOI: 10.12688/f1000research.20394.1