Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 224
Filtrar
1.
BMC Med ; 19(1): 39, 2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33593348

RESUMO

BACKGROUND: Serum transferrin levels represent an independent predictor of mortality in patients with liver failure. Hepatocyte nuclear factor 4 alpha (HNF4α) is a master regulator of hepatocyte functions. The aim of this study was to explore whether serum transferrin reflects HNF4α activity. METHODS: Factors regulating transferrin expression in alcoholic hepatitis (AH) were assessed via transcriptomic/methylomic analysis as well as chromatin immunoprecipitation coupled to DNA sequencing. The findings were corroborated in primary hepatocytes. Serum and liver samples from 40 patients with advanced liver disease of multiple etiologies were also studied. RESULTS: In patients with advanced liver disease, serum transferrin levels correlated with hepatic transferrin expression (r = 0.51, p = 0.01). Immunohistochemical and biochemical tests confirmed reduced HNF4α and transferrin protein levels in individuals with cirrhosis. In AH, hepatic gene-gene correlation analysis in liver transcriptome revealed an enrichment of HNF4α signature in transferrin-correlated transcriptome while transforming growth factor beta 1 (TGFß1), tumor necrosis factor α (TNFα), interleukin 1 beta (IL-1ß), and interleukin 6 (IL-6) negatively associated with transferrin signature. A key regulatory region in transferrin promoter was hypermethylated in patients with AH. In primary hepatocytes, treatment with TGFß1 or the HNF4α inhibitor BI6015 suppressed transferrin production, while exposure to TNFα, IL-1ß, and IL-6 had no effect. The correlation between hepatic HNF4A and transferrin mRNA levels was also seen in advanced liver disease. CONCLUSIONS: Serum transferrin levels constitute a prognostic and mechanistic biomarker. Consequently, they may serve as a surrogate of impaired hepatic HNF4α signaling and liver failure.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33516950

RESUMO

BACKGROUND AND AIMS: Alcoholic hepatitis (AH) is a severe condition with poor short-term prognosis. Specific treatment with corticosteroids slightly improves short-term survival but is associated with infection and is not used in many centers. A reliable method to identify patients who will recover spontaneously will minimise the numbers of patients who experience side effects of available treatments. METHODS: We analysed the trajectory of serum bilirubin concentration over the course of hospital admissions in patients with AH to predict spontaneous survival and the need for treatment. RESULTS: data from 426 patients were analysed. Based on bilirubin trajectory, patients were categorized into three groups: 'fast fallers' (bilirubin <0.8 x admission value at day 7), 'static' (bilirubin of >0.9 - <1.2 x admission value) and 'rapid risers' (bilirubin of ≥1.2 x admission bilirubin). Fast fallers had significantly better 90-day survival compared to other groups (log rank p < .001), and showed no benefit of corticosteroid therapy (OR for survival at 28 days of treatment, 0.94, 95% CI 0.06 - 8.41). These findings remained even amongst patients with severe disease based on initial DF, GAHS or MELD scores. CONCLUSIONS: We present an intuitive method of classifying patients with AH based on the trajectory of bilirubin over the first week of admission. It is complimentary to existing scores that identify candidates for corticosteroid treatment or assess response to treatment. This method identifies a group of patients with AH who recover spontaneously and can avoid corticosteroid therapy.

3.
Gastroenterology ; 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33309778

RESUMO

BACKGROUND & AIMS: We recently showed that alcoholic hepatitis (AH) is characterized by dedifferentiation of hepatocytes and loss of mature functions. Glucose metabolism is tightly regulated in healthy hepatocytes. We hypothesize that AH may lead to metabolic reprogramming of the liver, including dysregulation of glucose metabolism. METHODS: We performed integrated metabolomic and transcriptomic analyses of liver tissue from patients with AH or alcoholic cirrhosis or normal liver tissue from hepatic resection. Focused analyses of chromatin immunoprecipitation coupled to DNA sequencing was performed. Functional in vitro studies were performed in primary rat and human hepatocytes and HepG2 cells. RESULTS: Patients with AH exhibited specific changes in the levels of intermediates of glycolysis/gluconeogenesis, the tricarboxylic acid cycle, and monosaccharide and disaccharide metabolism. Integrated analysis of the transcriptome and metabolome showed the used of alternate energetic pathways, metabolite sinks and bottlenecks, and dysregulated glucose storage in patients with AH. Among genes involved in glucose metabolism, hexokinase domain containing 1 (HKDC1) was identified as the most up-regulated kinase in patients with AH. Histone active promoter and enhancer markers were increased in the HKDC1 genomic region. High HKDC1 levels were associated with the development of acute kidney injury and decreased survival. Increased HKDC1 activity contributed to the accumulation of glucose-6-P and glycogen in primary rat hepatocytes. CONCLUSIONS: Altered metabolite levels and messenger RNA expression of metabolic enzymes suggest the existence of extensive reprogramming of glucose metabolism in AH. Increased HKDC1 expression may contribute to dysregulated glucose metabolism and represents a novel biomarker and therapeutic target for AH.

4.
Liver Transpl ; 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33232547

RESUMO

Preserved physical function is key for successful liver transplantation (LT), however, prehabilitation strategies are underdeveloped. We created a smartphone app, EL-FIT (Exercise & Liver FITness), to facilitate exercise training in end-stage liver disease (ESLD). In this feasibility study, we tested EL-FIT app usage, accuracy of physical activity data transfer, and obtained feedback from initial users. Twenty-eight subjects used EL-FIT and wore a physical activity tracker for 38±12 days (age 60±8 years, 57% males, MELDNa 19±5). There was fidelity in data transfer from tracker to EL-FIT. Participants were sedentary (1957 [IQR: 873-4643] steps/day) at baseline. Level of training assigned by EL-FIT agreed with that from a physical therapist in 93% of cases. Participants interacted with all app features (videos, perceived exertion, and gamification/motivational features). We rearranged training data to generate heart rate-validated steps as a marker of performance and showed that 35% of subjects had a significant increase in their physical performance. Participants emphasized their interest in having choices to better engage in exercise and they appreciated the sense of community EL-FIT generated. Conclusion: We showed that ESLD patients are able to use and interact with EL-FIT. This novel smartphone app has the potential of becoming an invaluable tool for home-based prehabilitation in LT candidates.

5.
Rev. esp. enferm. dig ; 112(11): 869-878, nov. 2020. ilus, tab
Artigo em Inglês | IBECS-Express | IBECS | ID: ibc-ET6-1524

RESUMO

Alcohol-related liver disease (ALD) is the most frequent cause of advanced chronic liver disease worldwide. Excessive and prolonged alcohol use leads to ALD, which ranges from early forms such as alcoholic fatty liver (AFL) and alcoholic steatohepatitis (ASH), through progressive fibrosis to cirrhosis and the development of hepatocellular cancer (HCC). In addition, patients with underlying ALD and continuous alcohol use can develop alcoholic hepatitis (AH), which presents a rapid progression of liver failure and has a high short-term mortality. Genetic, environmental and epigenetic factors influence the progression of ALD to more severe forms. The pathogenesis of ALD is complex and involves multiple pathways. Recent translational studies have demonstrated a key role of the gut-liver axis and innate immunity in hepatocellular damage and fibrosis. In severe forms, hepatocellular de-differentiation and systemic inflammation contribute to liver failure and multiorgan failure. Alcohol abstinence is the cornerstone of therapy for ALD and the prevention of its complications, but the efficacy and accessibility of psycho-familial-social interventions is still poor and effective public health policies to limit problematic alcohol use need to be implemented. Prednisolone is the only current option for AH, with a transient beneficial effect over placebo. For patients with decompensated ALD-cirrhosis and/or development of HCC, liver transplantation (LT) may be required. In recent years, early LT is being increasingly offered to carefully selected AH patients, with excellent long-term survival. New trials of AH treatments are currently ongoing, and translational studies in human samples are paving the way to new promising targeted therapies


No disponible

6.
Rev Esp Enferm Dig ; 112(11): 869-878, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33054302

RESUMO

Alcohol-related liver disease (ALD) is the most frequent cause of advanced chronic liver disease worldwide. Excessive and prolonged alcohol use leads to ALD, which ranges from early forms such as alcoholic fatty liver (AFL) and alcoholic steatohepatitis (ASH), through progressive fibrosis to cirrhosis and the development of hepatocellular cancer (HCC). In addition, patients with underlying ALD and continuous alcohol use can develop alcoholic hepatitis (AH), which presents a rapid progression of liver failure and has a high short-term mortality. Genetic, environmental and epigenetic factors influence the progression of ALD to more severe forms. The pathogenesis of ALD is complex and involves multiple pathways. Recent translational studies have demonstrated a key role of the gut-liver axis and innate immunity in hepatocellular damage and fibrosis. In severe forms, hepatocellular de-differentiation and systemic inflammation contribute to liver failure and multiorgan failure. Alcohol abstinence is the cornerstone of therapy for ALD and the prevention of its complications, but the efficacy and accessibility of psycho-familial-social interventions is still poor and effective public health policies to limit problematic alcohol use need to be implemented. Prednisolone is the only current option for AH, with a transient beneficial effect over placebo. For patients with decompensated ALD-cirrhosis and/or development of HCC, liver transplantation (LT) may be required. In recent years, early LT is being increasingly offered to carefully selected AH patients, with excellent long-term survival. New trials of AH treatments are currently ongoing, and translational studies in human samples are paving the way to new promising targeted therapies.

8.
Sci Rep ; 10(1): 15558, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968110

RESUMO

Advanced fibrosis and portal hypertension influence short-term mortality. Lipocalin 2 (LCN2) regulates infection response and increases in liver injury. We explored the role of intrahepatic LCN2 in human alcoholic hepatitis (AH) with advanced fibrosis and portal hypertension and in experimental mouse fibrosis. We found hepatic LCN2 expression and serum LCN2 level markedly increased and correlated with disease severity and portal hypertension in patients with AH. In control human livers, LCN2 expressed exclusively in mononuclear cells, while its expression was markedly induced in AH livers, not only in mononuclear cells but also notably in hepatocytes. Lcn2-/- mice were protected from liver fibrosis caused by either ethanol or CCl4 exposure. Microarray analysis revealed downregulation of matrisome, cell cycle and immune related gene sets in Lcn2-/- mice exposed to CCl4, along with decrease in Timp1 and Edn1 expression. Hepatic expression of COL1A1, TIMP1 and key EDN1 system components were elevated in AH patients and correlated with hepatic LCN2 expression. In vitro, recombinant LCN2 induced COL1A1 expression. Overexpression of LCN2 increased HIF1A that in turn mediated EDN1 upregulation. LCN2 contributes to liver fibrosis and portal hypertension in AH and could represent a new therapeutic target.

9.
Pancreatology ; 20(6): 1069-1077, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32800649

RESUMO

BACKGROUND: Available estimates of coexistent alcohol-related pancreatitis (ALP) and alcohol-related liver disease (ALD) vary widely, and factors that determine coexistent disease are largely unknown. We performed a systematic review of published literature with the primary aim to generate robust estimates for coexistent alcohol-related chronic pancreatitis (ACP) and alcohol-related cirrhosis (ALC). METHODS: We searched PubMed, EMBASE, and Web of Science databases from inception until February 2018. Studies included were those in English-language, sample size ≥25 and allowed calculation of the coexistent disease. Pooled estimates were calculated using a random-effects model approach. RESULTS: Twenty-nine (including 5 autopsy studies) of 2000 eligible studies met inclusion criteria. Only 6.9% included patients were female. Fifteen studies enabled calculation of ACP in ALC, and 11 for ALC in ACP. Pooled prevalence of ACP in ALC was 16.2% (95% CI 10.4-24.5) overall, and 15.5% (95% CI 8.0-27.7) when data were limited to clinical studies. Corresponding prevalence for ALC in ACP was 21.5% (95% CI 12.0-35.6) and 16.9% (95% CI 11.5-24.3), respectively. There was significant heterogeneity among studies (I2 - 65-92%). Pooled prevalence for ALP in ALD or ALD in ALP in clinical studies were 15.2% and 39%, respectively. None of the studies reported outcomes in patients with coexistent disease. CONCLUSION: A sizeable fraction of patients with ACP or ALC have coexistent disease. Future studies should define the prevalence of coexistent disease in women and minority populations, and the consequences of coexistent disease on clinical presentation and short- and long-term outcomes.

10.
Hepatol Commun ; 4(8): 1168-1182, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32766476

RESUMO

Alcohol-related liver disease is a major public health burden, and the gut microbiota is an important contributor to disease pathogenesis. The aim of the present study is to characterize functional alterations of the gut microbiota and test their performance for short-term mortality prediction in patients with alcoholic hepatitis. We integrated shotgun metagenomics with untargeted metabolomics to investigate functional alterations of the gut microbiota and host co-metabolism in a multicenter cohort of patients with alcoholic hepatitis. Profound changes were found in the gut microbial composition, functional metagenome, serum, and fecal metabolomes in patients with alcoholic hepatitis compared with nonalcoholic controls. We demonstrate that in comparison with single omics alone, the performance to predict 30-day mortality was improved when combining microbial pathways with respective serum metabolites in patients with alcoholic hepatitis. The area under the receiver operating curve was higher than 0.85 for the tryptophan, isoleucine, and methionine pathways as predictors for 30-day mortality, but achieved 0.989 for using the urea cycle pathway in combination with serum urea, with a bias-corrected prediction error of 0.083 when using leave-one-out cross validation. Conclusion: Our study reveals changes in key microbial metabolic pathways associated with disease severity that predict short-term mortality in our cohort of patients with alcoholic hepatitis.

11.
Hepatology ; 2020 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-32654263

RESUMO

BACKGROUND AND AIMS: Alcoholic hepatitis (AH) is a severe manifestation of alcohol-associated liver disease (ALD) with high mortality. Although gut bacteria and fungi modulate disease severity, little is known about the effects of the viral microbiome (virome) in patients with ALD. APPROACH AND RESULTS: We extracted virus-like particles from 89 patients with AH who were enrolled in a multicenter observational study, 36 with alcohol use disorder (AUD), and 17 persons without AUD (controls). Virus-like particles from fecal samples were fractionated using differential filtration techniques, and metagenomic sequencing was performed to characterize intestinal viromes. We observed an increased viral diversity in fecal samples from patients with ALD, with the most significant changes in samples from patients with AH. Escherichia-, Enterobacteria-, and Enterococcus phages were over-represented in fecal samples from patients with AH, along with significant increases in mammalian viruses such as Parvoviridae and Herpesviridae. Antibiotic treatment was associated with higher viral diversity. Specific viral taxa, such as Staphylococcus phages and Herpesviridae, were associated with increased disease severity, indicated by a higher median Model for End-Stage Liver Disease score, and associated with increased 90-day mortality. CONCLUSIONS: In conclusion, intestinal viral taxa are altered in fecal samples from patients with AH and associated with disease severity and mortality. Our study describes an intestinal virome signature associated with AH.

12.
Hepatology ; 2020 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-32418225
13.
Proc Natl Acad Sci U S A ; 117(21): 11667-11673, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32393626

RESUMO

Alcohol-related liver disease (ALD) accounts for the majority of cirrhosis and liver-related deaths worldwide. Activation of IFN-regulatory factor (IRF3) initiates alcohol-induced hepatocyte apoptosis, which fuels a robust secondary inflammatory response that drives ALD. The dominant molecular mechanism by which alcohol activates IRF3 and the pathways that amplify inflammatory signals in ALD remains unknown. Here we show that cytoplasmic sensor cyclic guanosine monophosphate-adenosine monophosphate (AMP) synthase (cGAS) drives IRF3 activation in both alcohol-injured hepatocytes and the neighboring parenchyma via a gap junction intercellular communication pathway. Hepatic RNA-seq analysis of patients with a wide spectrum of ALD revealed that expression of the cGAS-IRF3 pathway correlated positively with disease severity. Alcohol-fed mice demonstrated increased hepatic expression of the cGAS-IRF3 pathway. Mice genetically deficient in cGAS and IRF3 were protected against ALD. Ablation of cGAS in hepatocytes only phenocopied this hepatoprotection, highlighting the critical role of hepatocytes in fueling the cGAS-IRF3 response to alcohol. We identified connexin 32 (Cx32), the predominant hepatic gap junction, as a critical regulator of spreading cGAS-driven IRF3 activation through the liver parenchyma. Disruption of Cx32 in ALD impaired IRF3-stimulated gene expression, resulting in decreased hepatic injury despite an increase in hepatic steatosis. Taken together, these results identify cGAS and Cx32 as key factors in ALD pathogenesis and as potential therapeutic targets for hepatoprotection.


Assuntos
Junções Comunicantes/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Hepatopatias Alcoólicas/metabolismo , Nucleotidiltransferases/metabolismo , Adulto , Animais , Apoptose , Feminino , Hepatócitos/metabolismo , Humanos , Fígado/citologia , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Nucleotidiltransferases/genética , Transdução de Sinais
14.
Cells ; 9(5)2020 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-32429478

RESUMO

In non-alcoholic steatohepatitis (NASH), many lines of investigation have reported a dysregulation in lipid homeostasis, leading to intrahepatic lipid accumulation. Recently, the role of dysfunctional sphingolipid metabolism has also been proposed. Human and animal models of NASH have been associated with elevated levels of long chain ceramides and pro-apoptotic sphingolipid metabolites, implicated in regulating fatty acid oxidation and inflammation. Importantly, inhibition of de novo ceramide biosynthesis or knock-down of ceramide synthases reverse some of the pathology of NASH. In contrast, cell permeable, short chain ceramides have shown anti-inflammatory actions in multiple models of inflammatory disease. Here, we investigated non-apoptotic doses of a liposome containing short chain C6-Ceramide (Lip-C6) administered to human hepatic stellate cells (hHSC), a key effector of hepatic fibrogenesis, and an animal model characterized by inflammation and elevated liver fat content. On the basis of the results from unbiased liver transcriptomic studies from non-alcoholic fatty liver disease patients, we chose to focus on adenosine monophosphate activated kinase (AMPK) and nuclear factor-erythroid 2-related factor (Nrf2) signaling pathways, which showed an abnormal profile. Lip-C6 administration inhibited hHSC proliferation while improving anti-oxidant protection and energy homeostasis, as indicated by upregulation of Nrf2, activation of AMPK and an increase in ATP. To confirm these in vitro data, we investigated the effect of a single tail-vein injection of Lip-C6 in the methionine-choline deficient (MCD) diet mouse model. Lip-C6, but not control liposomes, upregulated phospho-AMPK, without inducing liver toxicity, apoptosis, or exacerbating inflammatory signaling pathways. Alluding to mechanism, mass spectrometry lipidomics showed that Lip-C6-treatment reversed the imbalance in hepatic phosphatidylcholines and diacylglycerides species induced by the MCD-fed diet. These results reveal that short-term Lip-C6 administration reverses energy/metabolic depletion and increases protective anti-oxidant signaling pathways, possibly by restoring homeostatic lipid function in a model of liver inflammation with fat accumulation.

15.
J Lipid Res ; 61(7): 983-994, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32398264

RESUMO

Alcohol's impairment of both hepatic lipid metabolism and insulin resistance (IR) are key drivers of alcoholic steatosis, the initial stage of alcoholic liver disease (ALD). Pharmacologic reduction of lipotoxic ceramide prevents alcoholic steatosis and glucose intolerance in mice, but potential off-target effects limit its strategic utility. Here, we employed a hepatic-specific acid ceramidase (ASAH) overexpression model to reduce hepatic ceramides in a Lieber-DeCarli model of experimental alcoholic steatosis. We examined effects of alcohol on hepatic lipid metabolism, body composition, energy homeostasis, and insulin sensitivity as measured by hyperinsulinemic-euglycemic clamp. Our results demonstrate that hepatic ceramide reduction ameliorates the effects of alcohol on hepatic lipid droplet (LD) accumulation by promoting VLDL secretion and lipophagy, the latter of which involves ceramide cross-talk between the lysosomal and LD compartments. We additionally demonstrate that hepatic ceramide reduction prevents alcohol's inhibition of hepatic insulin signaling. These effects on the liver are associated with a reduction in oxidative stress markers and are relevant to humans, as we observe peri- LD ASAH expression in human ALD. Together, our results suggest a potential role for hepatic ceramide inhibition in preventing ALD.

16.
Hepatology ; 2020 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-32246544

RESUMO

BACKGROUND 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.

17.
Alcohol Clin Exp Res ; 44(6): 1300-1311, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32282939

RESUMO

BACKGROUND: Activation of NLRP3 in liver macrophages contributes to alcohol-associated liver disease (ALD). Molecular chaperone heat shock protein (HSP) 90 facilitates NLRP3 inflammasome activity during infections and inflammatory diseases. We previously reported that HSP90 is induced in ALD and regulates proinflammatory cytokines, tumor necrosis factor alpha, and IL-6. Whether HSP90 affects IL-1ß and IL-18 regulated by NLRP3 inflammasome in ALD is unknown. Here, we hypothesize that HSP90 modulated NLRP3 inflammasome activity and affects IL-1ß and IL-18 secretion in ALD. METHODS: The expression of HSP90AA1 and NLRP3 inflammasome genes was evaluated in human alcoholic livers and in mouse model of ALD. The importance of HSP90 on NLRP3 inflammasome activation in ALD was evaluated by administering HSP90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) to mice subjected to ALD, and in vitro to bone marrow-derived macrophages (BMDM) stimulated with LPS and ATP. The effect of activation of HSF1/HSPA1A axis during HSP90 inhibition or direct activation during heat shock of BMDMs on NLRP3 activity and secretion of downstream cytokines was evaluated. RESULTS: We found positive correlation between induction of HSP90 and NLRP3 inflammasome genes in human alcoholic cirrhotic livers. Administration of 17-DMAG in mouse model of ALD significantly down-regulated NLRP3 inflammasome-mediated caspase-1 (CASP-1) activity and cytokine secretion, with reduction in ALD. 17-DMAG-mediated decrease in NLRP3 was restricted to liver macrophages. Using BMDMs, we show that inhibition of HSP90 prevented CASP-1 activity, and Gasdermin D (GSDMD) cleavage, important in release of active IL-1ß and IL-18. Interestingly, activation of the heat shock factor 1 (HSF1)/HSPA1A axis, either during HSP90 inhibition or by heat shock, decreased NLRP3 inflammasome activity and reduced secretion of cytokines. CONCLUSION: Our studies indicate that inhibition of HSP90 and activation of HSF1/HSPA1A reduce IL-1ß and IL-18 via decrease in NLRP3/CASP-1 and GSDMD activity in ALD.

18.
Artigo em Inglês | MEDLINE | ID: mdl-32258535

RESUMO

Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are becoming the leading causes of chronic liver disease worldwide, significantly impacting public health and healthcare cost. The development of fibrosis is the main factor leading to early mortality and morbidity in NAFLD and ALD. Thus, it is important to timely and reliably evaluate these diseases at early stages, when fibrosis is not advanced or when steatosis predominates. Liver biopsy has been the standard of reference for fibrosis and steatosis, however, its invasiveness precludes its widespread use. There is growing research on non-invasive methods for diagnosing and stratifying fibrosis and steatosis in NAFLD and ALD. This review presents clinical evidence on the use of non-invasive assessment of liver disease (blood-based and imaging-based) in patients with NALFD and ALD, and proposes algorithms incorporating these tests into their management.

19.
Alcohol Clin Exp Res ; 44(4): 856-865, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32020641

RESUMO

BACKGROUND: Mitochondria play a fundamental role in the pathogenesis of alcoholic liver disease (ALD). The preservation of functional mitochondria during toxic alcohol insults is essential for cell survival and is maintained by key processes known as mitochondrial dynamics, including fragmentation and fusion, which are regulated by mitochondria-shaping proteins (MSP). We have shown mitochondrial dynamics to be distorted by alcohol in cellular and animal models, but the effect in humans remains unknown. METHODS: Hepatic gene expression of the main MSP involved in the mitochondrial fusion and fragmentation pathways was evaluated in patients with alcoholic hepatitis (AH) by DNA microarray (n = 15) and Reverse Transcription Polymerase Chain Reaction (n = 32). The activation of dynamin-1-like protein (Drp1) was also investigated in mitochondria isolated from liver biopsies of ALD patients (n = 8). The effects of alcohol on mitochondrial dynamics and on MSP protein expression were studied in human precision-cut liver slices (PCLS) exposed for 24 hours to increasing doses of ethanol (EtOH; 50 to 250 mM). RESULTS: A profound hyperactivation of the fragmentation pathway was observed in AH patients, with a significant increase in the expression of Drp1 and its adapters/receptors. The translocation of Drp1 to the mitochondria was also induced in patients with severe ALD and was affected in the PCLS with short-term exposure to EtOH but only mildly. The fusion pathway was not altered in ALD, and this was confirmed in the PCLS model. CONCLUSIONS: The present study reveals the role of mitochondrial dynamics in human ALD, confirming our previous observations in animal and cell culture models of ALD. Taken together, we show that alcohol has a significant impact on the fragmentation pathway, and we confirm Drp1 as a potential therapeutic target in severe ALD.

20.
F1000Res ; 92020.
Artigo em Inglês | MEDLINE | ID: mdl-32089834

RESUMO

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.


Assuntos
Hepatite Alcoólica , Hepatopatias Alcoólicas , Transplante de Fígado , Hepatite Alcoólica/diagnóstico , Hepatite Alcoólica/terapia , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...