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1.
Life Sci ; 262: 118509, 2020 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-33010280

RESUMEN

Phosphoesterase complex (Pho), a major active component of barley malt, has been demonstrated to be clinically effective in relieving alcoholic fatty liver disease (AFLD), and several lines of evidence have suggested that microbial dysbiosis, caused by chronic alcohol overconsumption, plays a key role in the progression of AFLD. The current study aimed to investigate the modulatory effect of Pho on gut microflora. The microbiota diversity, determined via detection of the V4 region of 16S rDNA genes, was analyzed in rats fed the Lieber-Decarli diet. Gut permeability was evaluated via mucus layer staining. Dysbiosis-associated chronic inflammation was investigated by observing the expression of the following inflammatory molecules in the liver: tumor necrosis factor α (TNF-α), monocyte chemotactic protein 1 (MCP-1), chemokine (C-X-C motif) ligand 1 (CXCL-1) and interleukin 1 beta (IL-1ß). Pyrosequencing revealed that the gut microbiota in Pho-treated rats was different from that of AFLD rats at both the phylum and genus levels. In addition, Pho significantly alleviated dysbiosis-associated disruption of gut permeability and inflammation, increased mucus layer thickness and downregulated TNF-α, MCP-1, CXCL-1 and IL-1ß expression. In summary, the current results revealed that the microflora, gut barrier and chronic inflammation in AFLD may be modulated by Pho.


Asunto(s)
Disbiosis/tratamiento farmacológico , Hígado Graso Alcohólico/tratamiento farmacológico , Hordeum/química , Inflamación/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Disbiosis/microbiología , Disbiosis/fisiopatología , Enzimas/aislamiento & purificación , Enzimas/farmacología , Hígado Graso Alcohólico/microbiología , Hígado Graso Alcohólico/fisiopatología , Microbioma Gastrointestinal , Hordeum/enzimología , Inflamación/microbiología , Inflamación/patología , Masculino , Ratas , Ratas Wistar
2.
Curr Pharm Des ; 26(10): 1093-1109, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31969088

RESUMEN

Nonalcoholic fatty liver disease and alcohol-related liver disease together, compose the majority of cases of liver disease and cirrhosis worldwide. Although in the last years, there has been much interest in the differentiation between the two entities, it is increasingly recognized that a large overlap exists between them. The main pathophysiological aspects are very similar, with the exceptions of mechanisms directly related to alcohol, acting as an added factor in the presence of metabolic risk factors. Genetic factors so far identified are also very similar. In both cases, the disease is more prevalent in males, the difference being more significant in the ALD group, having to do with harmful alcohol consumption, which is more frequent in males. NAFLD advanced stages usually present in older age than ALD. Regarding laboratory features, the ratio AST/ALT < 1 is more frequent in NAFLD than ALD, in the absence of cirrhosis. Histological aspects of both situations are very similar, but some are specific for ALD, such as alcoholic foamy degeneration or cholestasis, or fibroobliterative venous lesions. Regarding treatment, several drugs now included in clinical trials in NAFLD, could also be assayed in ALD, since similar mechanisms of action, are potentially acting in ALD. In summary, similarities seem to outnumber differences, and since so large overlap between risk factors exist, the use of a common designation such as Fatty Liver Disease (FLD) or Metabolic Fatty Liver disease (MEFLD), could better serve the field.


Asunto(s)
Hígado Graso Alcohólico/fisiopatología , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Alcoholismo/complicaciones , Femenino , Humanos , Cirrosis Hepática , Masculino , Factores de Riesgo
3.
Hepatology ; 71(5): 1575-1591, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-31520476

RESUMEN

BACKGROUND AND AIMS: Microbial dysbiosis is associated with alcohol-related hepatitis (AH), with the mechanisms yet to be elucidated. The present study aimed to determine the effects of alcohol and zinc deficiency on Paneth cell (PC) antimicrobial peptides, α-defensins, and to define the link between PC dysfunction and AH. APPROACH AND RESULTS: Translocation of pathogen-associated molecular patterns (PAMPs) was determined in patients with severe AH and in a mouse model of alcoholic steatohepatitis. Microbial composition and PC function were examined in mice. The link between α-defensin dysfunction and AH was investigated in α-defensin-deficient mice. Synthetic human α-defensin 5 (HD5) was orally given to alcohol-fed mice to test the therapeutic potential. The role of zinc deficiency in α-defensin was evaluated in acute and chronic mouse models of zinc deprivation. Hepatic inflammation was associated with PAMP translocation and lipocalin-2 (LCN2) and chemokine (C-X-C motif) ligand 1 (CXCL1) elevation in patients with AH. Antibiotic treatment, lipopolysaccharide injection to mice, and in vitro experiments showed that PAMPs, but not alcohol, directly induced LCN2 and CXCL1. Chronic alcohol feeding caused systemic dysbiosis and PC α-defensin reduction in mice. Knockout of functional α-defensins synergistically affected alcohol-perturbed bacterial composition and the gut barrier and exaggerated PAMP translocation and liver damage. Administration of HD5 effectively altered cecal microbial composition, especially increased Akkermansia muciniphila, and reversed the alcohol-induced deleterious effects. Zinc-regulated PC homeostasis and α-defensins function at multiple levels, and dietary zinc deficiency exaggerated the deleterious effect of alcohol on PC bactericidal activity. CONCLUSIONS: Taken together, the study suggests that alcohol-induced PC α-defensin dysfunction is mediated by zinc deficiency and involved in the pathogenesis of AH. HD5 administration may represent a promising therapeutic approach for treating AH.


Asunto(s)
Traslocación Bacteriana , Hígado Graso Alcohólico/microbiología , Hígado Graso Alcohólico/fisiopatología , Microbiota/fisiología , Células de Paneth/fisiología , Zinc/deficiencia , alfa-Defensinas/deficiencia , Animales , Modelos Animales de Enfermedad , Disbiosis/etiología , Etanol/toxicidad , Hígado Graso Alcohólico/complicaciones , Humanos , Metaloproteinasa 7 de la Matriz/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microbiota/efectos de los fármacos
4.
J Dig Dis ; 20(9): 476-485, 2019 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-31298798

RESUMEN

OBJECTIVE: We aimed to investigate the involvement of the endocytosis of occludin, a key component of tight junction (TJ), in the ethanol-induced disassembly of TJ in a model of alcoholic steatohepatitis. METHODS: Wild-type mice were fed an ethanol-containing or isocaloric liquid diet for 8 weeks and then assessed for liver injury (histopathology and measurement of serum enzymes), gut permeability (in vivo lactulose/mannitol and ex vivo dye leakage assays), intestinal epithelium ultrastructure (transmission electron microscopy), and intestinal occludin localization (immunofluorescence microscopy). The human intestinal epithelial cell line Caco-2 was also analyzed in vitro for the effects of ethanol on the barrier function (transepithelial electrical resistance), occludin localization (immunofluorescence microscopy and Western blotting), and endocytosis pathways (double-labeling immunofluorescence microscopy with selective pathway inhibitors). RESULTS: The ethanol-fed mice developed steatohepatitis and displayed intestinal barrier dysfunction, the disruption of intestinal TJ, and enhanced intestinal endocytosis of occluding compared with the control mice. In the Caco-2 monolayers, ethanol treatment decreased transepithelial electrical resistance, disrupted TJ formation, and enhanced occludin endocytosis in a dose- and time-dependent manner. These deleterious events were reversed by pretreating the Caco-2 cells with a selective pharmacological inhibitor of macropinocytosis, but not with the inhibitors of clathrin or caveolin-mediated endocytic pathways. CONCLUSION: Chronic ethanol exposure may increase intestinal permeability by inducing the micropinocytosis of occludin, resulting in the disruption of intestinal TJ.


Asunto(s)
Endocitosis/fisiología , Hígado Graso Alcohólico/fisiopatología , Mucosa Intestinal/fisiopatología , Ocludina/fisiología , Animales , Células CACO-2 , Modelos Animales de Enfermedad , Endocitosis/efectos de los fármacos , Etanol/farmacología , Hígado Graso Alcohólico/patología , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/ultraestructura , Ratones Endogámicos C57BL , Microscopía Electrónica , Microscopía Fluorescente , Ocludina/metabolismo , Permeabilidad , Uniones Estrechas/efectos de los fármacos , Uniones Estrechas/fisiología , Uniones Estrechas/ultraestructura
5.
J Gastroenterol ; 54(3): 209-217, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30392013

RESUMEN

Alterations of gut microbes play a role in the pathogenesis and progression of many disorders including liver and gastrointestinal diseases. Both qualitative and quantitative changes in gut microbiota have been associated with liver disease. Intestinal dysbiosis can disrupt the integrity of the intestinal barrier leading to pathological bacterial translocation and the initiation of an inflammatory response in the liver. In order to sustain symbiosis and protect from pathological bacterial translocation, antimicrobial proteins (AMPs) such as a-defensins and C-type lectins are expressed in the gastrointestinal tract. In this review, we provide an overview of the role of AMPs in different chronic liver disease such as alcoholic steatohepatitis, non-alcoholic fatty liver disease, and cirrhosis. In addition, potential approaches to modulate the function of AMPs and prevent bacterial translocation are discussed.


Asunto(s)
Proteínas Bacterianas/fisiología , Disbiosis/microbiología , Microbioma Gastrointestinal/fisiología , Intestinos/microbiología , Hepatopatías/prevención & control , Hepatopatías/fisiopatología , Traslocación Bacteriana/fisiología , Defensinas/fisiología , Disbiosis/fisiopatología , Hígado Graso Alcohólico/microbiología , Hígado Graso Alcohólico/fisiopatología , Hígado Graso Alcohólico/prevención & control , Humanos , Inmunidad Innata/fisiología , Intestinos/fisiopatología , Lectinas Tipo C/fisiología , Cirrosis Hepática/microbiología , Cirrosis Hepática/fisiopatología , Cirrosis Hepática/prevención & control , Hepatopatías/microbiología , Enfermedad del Hígado Graso no Alcohólico/microbiología , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Simbiosis/fisiología
6.
Adv Exp Med Biol ; 1032: 145-151, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-30362097

RESUMEN

Alcohol-induced steatohepatitis (ASH) increases the risk for both clinically-severe acute alcoholic hepatitis and eventual cirrhosis. The mechanisms that control ASH pathogenesis and progression are unclear but processes that regulate liver cell plasticity seem to be critically involved. In injured adult livers, morphogenic signaling pathways that modulate cell fate decisions during fetal development and in adult liver progenitors become reactivated. Overly-exuberant activation of such morphogenic signaling causes dysregulated liver repair and increases short- and long-term mortality by promoting acute liver failure, as well as progressive fibrosis. Hence, these pathways may be novel therapeutic targets to optimize liver cell reprogramming and prevent defective regenerative responses that cause acute liver failure and cirrhosis.


Asunto(s)
Reprogramación Celular , Hígado Graso Alcohólico/fisiopatología , Hepatocitos/citología , Transducción de Señal , Progresión de la Enfermedad , Hígado Graso Alcohólico/complicaciones , Humanos , Hígado/fisiopatología , Cirrosis Hepática/etiología , Fallo Hepático/etiología , Regeneración
7.
Nat Rev Dis Primers ; 4(1): 16, 2018 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-30115921

RESUMEN

Alcoholic liver disease (ALD) is the most prevalent type of chronic liver disease worldwide. ALD can progress from alcoholic fatty liver (AFL) to alcoholic steatohepatitis (ASH), which is characterized by hepatic inflammation. Chronic ASH can eventually lead to fibrosis and cirrhosis and in some cases hepatocellular cancer (HCC). In addition, severe ASH (with or without cirrhosis) can lead to alcoholic hepatitis, which is an acute clinical presentation of ALD that is associated with liver failure and high mortality. Most individuals consuming >40 g of alcohol per day develop AFL; however, only a subset of individuals will develop more advanced disease. Genetic, epigenetic and non-genetic factors might explain the considerable interindividual variation in ALD phenotype. The pathogenesis of ALD includes hepatic steatosis, oxidative stress, acetaldehyde-mediated toxicity and cytokine and chemokine-induced inflammation. Diagnosis of ALD involves assessing patients for alcohol use disorder and signs of advanced liver disease. The degree of AFL and liver fibrosis can be determined by ultrasonography, transient elastography, MRI, measurement of serum biomarkers and liver biopsy histology. Alcohol abstinence achieved by psychosomatic intervention is the best treatment for all stages of ALD. In the case of advanced disease such as cirrhosis or HCC, liver transplantation may be required. Thus, new therapies are urgently needed.


Asunto(s)
Hepatopatías Alcohólicas/complicaciones , Hepatopatías Alcohólicas/fisiopatología , Consumo de Bebidas Alcohólicas/efectos adversos , Consumo de Bebidas Alcohólicas/psicología , Hígado Graso Alcohólico/etiología , Hígado Graso Alcohólico/fisiopatología , Carga Global de Enfermedades/estadística & datos numéricos , Humanos , Hepatopatías Alcohólicas/epidemiología , Neoplasias Hepáticas/etiología , Neoplasias Hepáticas/fisiopatología , Trasplante de Hígado/estadística & datos numéricos , Calidad de Vida/psicología
8.
Nutrients ; 10(3)2018 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-29534433

RESUMEN

Offspring of female rats fed either a casein (CAS) diet or a low-isoflavone soy protein isolate (SPI) diet were compared in an animal model of chronic ethanol consumption to investigate whether maternal diet regulates the adaptive responses of offspring to postnatal ethanol exposure and potentially affects the development of liver disease in later life. Female rats were fed either a CAS or an SPI diet before mating, and during pregnancy and lactation. Male offspring from the same litter were pair-fed either a control or ethanol diet for six weeks (CAS/CON, CAS/EtOH, SPI/CON, and SPI/EtOH groups). Serum aminotransferase activities and hepatic inflammatory indicators were higher in the SPI/EtOH group than in the CAS/EtOH group. Ethanol consumption increased serum homocysteine levels, hepatic S-adenosylmethionine:S-adenosylhomocysteine ratio, and hepatic endoplasmic reticulum stress only in offspring of SPI-fed female rats. Total and high-density lipoprotein (HDL) cholesterol levels and mRNA levels of hepatic genes involved in HDL cholesterol assembly were reduced in the SPI group in response to ethanol consumption. In conclusion, offspring of SPI-fed female rats were more susceptible to the later development of alcoholic liver disease than offspring of CAS-fed female rats. Furthermore, maternal SPI consumption altered one-carbon metabolism and cholesterol metabolism of offspring fed an ethanol diet.


Asunto(s)
Estrés del Retículo Endoplásmico/efectos de los fármacos , Hígado Graso Alcohólico/etiología , Lactancia , Hígado/efectos de los fármacos , Fenómenos Fisiologicos Nutricionales Maternos , Efectos Tardíos de la Exposición Prenatal , Proteínas de Soja/efectos adversos , Animales , Ácidos y Sales Biliares/sangre , Biomarcadores/sangre , Suplementos Dietéticos , Dislipidemias/etiología , Dislipidemias/patología , Dislipidemias/fisiopatología , Dislipidemias/prevención & control , Etanol/toxicidad , Hígado Graso Alcohólico/patología , Hígado Graso Alcohólico/fisiopatología , Hígado Graso Alcohólico/prevención & control , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Genisteína/uso terapéutico , Hígado/patología , Hígado/fisiopatología , Masculino , Tamaño de los Órganos/efectos de los fármacos , Embarazo , Sustancias Protectoras/uso terapéutico , Distribución Aleatoria , Ratas Sprague-Dawley
9.
Mol Med Rep ; 16(4): 5225-5234, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28849079

RESUMEN

Betaine has previously been demonstrated to protect the liver against alcohol­induced fat accumulation. However, the mechanism through which betaine affects alcohol­induced hepatic lipid metabolic disorders has not been extensively studied. The present study aimed to investigate the effect of betaine on alcoholic simple fatty liver and hepatic lipid metabolism disorders. A total of 36 rats were randomly divided into control, ethanol and ethanol + betaine groups. Liver function, morphological alterations, lipid content and tumor necrosis factor (TNF)­α levels were determined. Hepatic expression levels of diacylglycerol acyltransferase (DGAT) 1, DGAT2, sterol regulatory element binding protein (SREBP)­1c, SREBP­2, fatty acid synthase (FAS), 3­hydroxy­3­methyl­glutaryl (HMG)­CoA reductase, peroxisome proliferator-activated receptor λ coactivator (PGC)­1α, adiponectin receptor (AdipoR) 1 and AdipoR2 were quantified. Serum and adipose tissue adiponectin levels were assessed using an enzyme­linked immunoassay. The results demonstrated that alcohol­induced ultramicrostructural alterations in hepatocytes, including the presence of lipid droplets and swollen mitochondria, were attenuated by betaine. Hepatic triglyceride, free fatty acid, total cholesterol and cholesterol ester contents and the expression of DGAT1, DGAT2, SREBP­1c, SREBP­2, FAS and HMG­CoA reductase were increased following ethanol consumption, however were maintained at control levels following betaine supplementation. Alcohol­induced decreases in hepatic PGC­1α mRNA levels and serum and adipose tissue adiponectin concentrations were prevented by betaine. The downregulation of hepatic AdipoR1 which resulted from alcohol exposure was partially attenuated by betaine. No significant differences in liver function, TNF­α, phospholipid and AdipoR2 levels were observed among the control, ethanol and ethanol + betaine groups. Overall, these results indicated that betaine attenuated the alcoholic simple fatty liver by improving hepatic lipid metabolism via suppression of DGAT1, DGAT2, SREBP­1c, FAS, SREBP­2 and HMG­CoA reductase and upregulation of PGC­1α.


Asunto(s)
Betaína/farmacología , Betaína/uso terapéutico , Hígado Graso Alcohólico/tratamiento farmacológico , Hígado Graso Alcohólico/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/metabolismo , Adiponectina/sangre , Adiponectina/metabolismo , Consumo de Bebidas Alcohólicas/metabolismo , Animales , Diacilglicerol O-Acetiltransferasa/genética , Diacilglicerol O-Acetiltransferasa/metabolismo , Ácido Graso Sintasas/metabolismo , Hígado Graso Alcohólico/fisiopatología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hepatocitos/patología , Hepatocitos/ultraestructura , Hidroximetilglutaril-CoA Reductasas/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Hígado/fisiopatología , Masculino , Estado Nutricional/efectos de los fármacos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Ratas Wistar , Receptores de Adiponectina/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
10.
Exp Biol Med (Maywood) ; 242(11): 1117-1125, 2017 06.
Artículo en Inglés | MEDLINE | ID: mdl-28467182

RESUMEN

Alcohol exposure is a major reason of morbidity and mortality all over the world, with much of detrimental consequences attributing to alcoholic liver disease (ALD). With the continued ethanol consumption, alcoholic fatty liver disease (AFLD, the earliest and reversible form of ALD) can further develop to more serious forms of alcoholic liver damage, including alcoholic steatohepatitis, fibrosis/cirrhosis, and even eventually progress to hepatocellular carcinoma and liver failure. Furthermore, cell trauma, inflammation, oxidative stress, regeneration, and bacterial translocation are crucial promoters of ethanol-mediated liver lesions. AFLD is characterized by excessive fat deposition in liver induced by excessive drinking, which is related closely to the raised synthesis of fatty acids and triglyceride, reduction of mitochondrial fatty acid ß-oxidation, and the aggregation of very-low-density lipoprotein (VLDL). Although little is known about the cellular and molecular mechanisms of AFLD, it seems to be correlated to diverse signal channels. Massive studies have suggested that liver steatosis is closely associated with the inhibition of silent information regulator 1 (SIRT1) and the augment of lipin1 ß/α ratio mediated by ethanol. Recently, serine/arginine-rich splicing factor 10 (SFRS10), a specific molecule functioning in alternative splicing of lipin 1 (LPIN1) pre-mRNAs, has emerged as the central connection between SIRT1 and lipin1 signaling. It seems a new signaling axis, SIRT1-SFRS10-LPIN1 axis, acting in the pathogenesis of AFLD exists. This article aims to further explore the interactions among the above three molecules and their influences on the development of AFLD. Impact statement ALD is a major health burden in industrialized countries as well as China. AFLD, the earliest and reversible form of ALD, can progress to hepatitis, fibrosis/cirrhosis, even hepatoma. While the mechanisms, by which ethanol consumption leads to AFLD, are complicated and multiple, and remain incompletely understood. SIRT1, SFRS10, and LIPIN1 had been separately reported to participate in lipid metabolism and the pathogenesis of AFLD. Noteworthy, we found the connection among them via searching articles in PubMed and we had elaborated the connection in detail in this minireview. It seems a new signaling axis, SIRT1-SFRS10-LIPIN1 axis, acting in the pathogenesis of AFLD exists. Further study aimed at SIRT1-SFRS10-LIPIN1 signaling system will possibly offer a more effective therapeutic target for AFLD.


Asunto(s)
Proteínas de Ciclo Celular/metabolismo , Hígado Graso Alcohólico/fisiopatología , Hígado/patología , Fosfatidato Fosfatasa/metabolismo , Proteínas Represoras/metabolismo , Factores de Empalme Serina-Arginina/metabolismo , Transducción de Señal , Sirtuina 1/metabolismo , Animales , Regulación de la Expresión Génica , Humanos , Metabolismo de los Lípidos
11.
Eur J Clin Nutr ; 71(8): 995-1001, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28378853

RESUMEN

BACKGROUND/OBJECTIVES: Fatty liver disease (FLD) is an important intermediate trait along the cardiometabolic disease spectrum and strongly associates with type 2 diabetes. Knowledge of biological pathways implicated in FLD is limited. An untargeted metabolomic approach might unravel novel pathways related to FLD. SUBJECTS/METHODS: In a population-based sample (n=555) from Northern Germany, liver fat content was quantified as liver signal intensity using magnetic resonance imaging. Serum metabolites were determined using a non-targeted approach. Partial least squares regression was applied to derive a metabolomic score, explaining variation in serum metabolites and liver signal intensity. Associations of the metabolomic score with liver signal intensity and FLD were investigated in multivariable-adjusted robust linear and logistic regression models, respectively. Metabolites with a variable importance in the projection >1 were entered in in silico overrepresentation and pathway analyses. RESULTS: In univariate analysis, the metabolomics score explained 23.9% variation in liver signal intensity. A 1-unit increment in the metabolomic score was positively associated with FLD (n=219; odds ratio: 1.36; 95% confidence interval: 1.27-1.45) adjusting for age, sex, education, smoking and physical activity. A simplified score based on the 15 metabolites with highest variable importance in the projection statistic showed similar associations. Overrepresentation and pathway analyses highlighted branched-chain amino acids and derived gamma-glutamyl dipeptides as significant correlates of FLD. CONCLUSIONS: A serum metabolomic profile was associated with FLD and liver fat content. We identified a simplified metabolomics score, which should be evaluated in prospective studies.


Asunto(s)
Hígado Graso Alcohólico/sangre , Metabolismo de los Lípidos , Hígado/metabolismo , Enfermedad del Hígado Graso no Alcohólico/sangre , Anciano , Consumo de Bebidas Alcohólicas/efectos adversos , Bancos de Muestras Biológicas , Biomarcadores/sangre , Estudios de Cohortes , Biología Computacional , Estudios Transversales , Dipéptidos/sangre , Sistemas Especialistas , Hígado Graso Alcohólico/diagnóstico por imagen , Hígado Graso Alcohólico/metabolismo , Hígado Graso Alcohólico/fisiopatología , Femenino , Ácido Glutámico/análogos & derivados , Ácido Glutámico/sangre , Humanos , Hígado/diagnóstico por imagen , Hígado/fisiopatología , Imagen por Resonancia Magnética , Masculino , Metabolómica/métodos , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Autoinforme , Índice de Severidad de la Enfermedad
13.
Am J Chin Med ; 44(6): 1207-1220, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27627919

RESUMEN

Alcoholic fatty liver (AFL) is early stage of alcoholic liver disease, which can progress to steatohepatitis, fibrosis, and cirrhosis if alcohol consumption is continued. The pathogenesis of AFL is associated with excessive lipid accumulation in hepatocytes. Resveratrol (RES), a dietary polyphenol found in red wines and grapes, has been shown to have a hepatoprotective effect. Autophagy is a crucial physiological process in cellular catabolism that involves the regulation of lipid droplets. Autophagy maintains a balance between protein synthesis, degradation and self-recycling. In the present study, we evaluated the protective effects of RES (10[Formula: see text]mg/kg, 30[Formula: see text]mg/kg, 100[Formula: see text]mg/kg) on AFL mice fed with an ethanol Lieber-DeCarli liquid diet, and HepG2 cells in the presence of oleic acid and alcohol to investigate whether resveratrol could induce autophagy to attenuate lipid accumulation. The results showed that RES (30[Formula: see text]mg/kg and 100[Formula: see text]mg/kg) treatment significantly attenuated hepatic steatosis and lowered the activities of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), low density lipoprotein cholesterol (LDL-C). H&E staining showed that RES reduced hepatic lipid accumulation. Transmission electron microscopy (TEM) images showed that RES treatment increased the number of autophagosomes and promoted the formation of autophagy. Western blot analysis showed that RES treatment increased the levels of microtubule-associated protein light chain3- II (LC3-II) and Beclin1, decreased expression of p62 protein. In addition, in vitro studies also demonstrated that RES led to the formation of acidic vesicular organelles (AVOs), however, 3-Methyladenine (3-MA), a specific inhibitor of autophagy, obviously inhibited the above effects of RES. In conclusion, RES has protective effects on alcoholic hepatic steatosis, and the potential mechanism might be involved in inducing autophagy.


Asunto(s)
Autofagia/efectos de los fármacos , Hígado Graso Alcohólico/tratamiento farmacológico , Hígado Graso Alcohólico/fisiopatología , Hepatocitos/metabolismo , Gotas Lipídicas/metabolismo , Estilbenos/farmacología , Animales , Autofagia/fisiología , Modelos Animales de Enfermedad , Hígado Graso Alcohólico/etiología , Hígado Graso Alcohólico/metabolismo , Células Hep G2 , Humanos , Masculino , Ratones Endogámicos C57BL , Fitoterapia , Resveratrol , Estilbenos/administración & dosificación , Estilbenos/uso terapéutico , Vitis , Vino
14.
Ann Hepatol ; 15(4): 463-73, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27236145

RESUMEN

 The burden of alcoholic liver disease continues to be a major public health problem worldwide. The spectrum of disease ranges from fatty liver to cirrhosis and hepatocellular carcinoma. Alcoholic hepatitis (AH) is a type of acute-on-chronic liver failure and the most severe form of alcoholic liver disease. Severe AH carries a poor short-term prognosis and its management is still challenging, with scarce advances in the last decades. Corticosteroids are still the first line of therapy in severe cases. Unfortunately, many patients do not respond and novel targeted therapies are urgently needed. Liver transplantation has shown extraordinary results in non-responders to corticosteroids however; its applicability is very low. This review summarizes the epidemiology, natural history, risk factors and pathogenesis of alcoholic liver disease with special focus on the latest advances in prognostic stratification and therapy of patients with alcoholic hepatitis.


Asunto(s)
Insuficiencia Hepática Crónica Agudizada/fisiopatología , Hígado Graso Alcohólico/fisiopatología , Hepatitis Alcohólica/fisiopatología , Insuficiencia Hepática Crónica Agudizada/epidemiología , Insuficiencia Hepática Crónica Agudizada/terapia , Corticoesteroides/uso terapéutico , Hígado Graso Alcohólico/epidemiología , Hígado Graso Alcohólico/terapia , Hepatitis Alcohólica/epidemiología , Hepatitis Alcohólica/terapia , Humanos , Cirrosis Hepática Alcohólica/epidemiología , Cirrosis Hepática Alcohólica/fisiopatología , Cirrosis Hepática Alcohólica/terapia , Trasplante de Hígado , Pronóstico , Factores de Riesgo
15.
Ann Hepatol ; 15(2): 183-9, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26845595

RESUMEN

BACKGROUND AND OBJECTIVE: Steatohepatitis is a common cause of liver disease due to alcohol (ALD) or non-alcoholic fatty liver disease (NAFLD). We performed this study to compare natural history of ALD and NAFLD. MATERIAL AND METHODS: Retrospective analysis of ALD or NAFLD patients managed at our center (2007-2011). ALD diagnosed by excluding other liver diseases (except HCV) and alcohol abuse of > 40 g/d in women and > 60 g/d in men for > 5 years. NAFLD diagnosed by excluding other liver diseases and a history of alcohol use of < 10 g/d. Cirrhosis was diagnosed using biopsy for uncertain clinical diagnosis. RESULTS: Compared to patients with NAFLD (n = 365; mean age 50 yrs; 43% males; 53% diabetic), ALD patients (n = 206; mean age 51 yrs; 68% males; 24% diabetic) presented more often with cirrhosis or complications(46vs. 12%; P< 0.0001) with a higher MELD score (13 ± 7 vs. 8 ± 8; P<0.0001). On logistic regression, ALD diagnosis was associated with presence of cirrhosis by over 4-fold (4.1 [1.8-9.1]) even after excluding 23 patients with concomitant HCV. Over median follow up of about 3 and 4 yrs among ALD and NAFLD patients respectively, ALD patients more frequently developed cirrhosis or its complications including HCC with worse transplant free survival (90 vs. 95%; P = 0.038). CONCLUSIONS: Compared to NAFLD, ALD patients present at an advanced stage of liver disease with a faster progression on follow-up. Prospective multicenter studies are needed to identify potential barriers to early referral of ALD patients as basis for development of strategies to improve outcome of patients with ALD.


Asunto(s)
Hígado Graso Alcohólico/fisiopatología , Cirrosis Hepática Alcohólica/fisiopatología , Enfermedad del Hígado Graso no Alcohólico/fisiopatología , Adulto , Comorbilidad , Progresión de la Enfermedad , Hígado Graso Alcohólico/diagnóstico , Hígado Graso Alcohólico/epidemiología , Femenino , Humanos , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/epidemiología , Cirrosis Hepática/fisiopatología , Cirrosis Hepática Alcohólica/diagnóstico , Cirrosis Hepática Alcohólica/epidemiología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad
16.
J Nutr ; 145(12): 2690-8, 2015 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-26468492

RESUMEN

BACKGROUND: Zinc deficiency has been well documented in alcoholic liver disease. OBJECTIVE: This study was undertaken to determine whether dietary zinc supplementation provides beneficial effects in treating alcohol-induced gut leakiness and endotoxemia. METHODS: Male Sprague Dawley rats were divided into 3 groups and pair-fed (PF) Lieber-DeCarli liquid diet for 8 wk: 1) control (PF); 2) alcohol-fed (AF; 5.00-5.42% wt:vol ethanol); and 3) AF with zinc supplementation (AF/Zn) at 220 ppm zinc sulfate heptahydrate. The PF and AF/Zn groups were pair-fed with the AF group. Hepatic inflammation and endotoxin signaling were determined by immunofluorescence and quantitative polymerase chain reaction (qPCR). Alterations in intestinal tight junctions and aldehyde dehydrogenases were assessed by qPCR and Western blot analysis. RESULTS: The AF rats had greater macrophage activation and cytokine production (P < 0.05) in the liver compared with the PF rats, whereas the AF/Zn rats showed no significant differences (P > 0.05). Plasma endotoxin concentrations of the AF rats were 136% greater than those of the PF rats, whereas the AF/Zn rats did not differ from the PF rats. Ileal permeability was 255% greater in the AF rats and 19% greater in the AF/Zn rats than in the PF rats. The AF group had reduced intestinal claudin-1, occludin, and zona occludens-1 (ZO-1) expression, and the AF/Zn group had upregulated claudin-1 and ZO-1 expression (P < 0.05) compared with the PF group. The intestinal epithelial expression and activity of aldehyde dehydrogenases were elevated (P < 0.05) in the AF/Zn rats compared with those of the AF rats. Furthermore, the ileal expression and function of hepatocyte nuclear factor 4α, which was impaired in the AF group, was significantly elevated in the AF/Zn group compared with the PF group. CONCLUSIONS: The results demonstrate that attenuating hepatic endotoxin signaling by preserving the intestinal barrier contributes to the protective effect of zinc on alcohol-induced steatohepatitis in rats.


Asunto(s)
Suplementos Dietéticos , Endotoxemia/prevención & control , Hígado Graso Alcohólico/prevención & control , Enfermedades Intestinales/prevención & control , Zinc/administración & dosificación , Aldehído Deshidrogenasa/metabolismo , Animales , Claudina-1/análisis , Citocinas/biosíntesis , Endotoxinas/análisis , Etanol/efectos adversos , Hígado Graso Alcohólico/fisiopatología , Enfermedades Intestinales/inducido químicamente , Mucosa Intestinal/metabolismo , Intestinos/química , Intestinos/enzimología , Hígado/patología , Hígado/fisiopatología , Activación de Macrófagos , Masculino , Ocludina/análisis , Permeabilidad/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Proteínas de Uniones Estrechas/análisis , Zinc/deficiencia , Proteína de la Zonula Occludens-1/análisis
17.
Zebrafish ; 12(4): 271-80, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25923904

RESUMEN

Alcoholic liver disease (ALD) continues to be a major cause of liver-related morbidity and mortality worldwide. To date, no zebrafish animal model has demonstrated the characteristic manifestations of ALD in the setting of chronic alcohol exposure. The aim of this study was to develop a zebrafish animal model for ALD. Male adult zebrafish were housed in a 1% (v/v) ethanol solution up to 3 months. A histopathological study showed the characteristic features of alcoholic liver steatosis and steatohepatitis in the early stages of alcohol exposure, including fat droplet accumulation, ballooning degeneration of the hepatocytes, and Mallory body formation. As the exposure time increased, collagen deposition in the extracellular matrix was observed by Sirius red staining and immunofluorescence staining. Finally, anaplastic hepatocytes with pleomorphic nuclei were arranged in trabecular patterns and formed nodules in the zebrafish liver. Over the time course of 1% ethanol exposure, upregulations of lipogenesis, fibrosis, and tumor-related genes were also revealed by semiquantitative and quantitative real-time reverse transcription-polymerase chain reaction. As these data reflect characteristic liver damage by alcohol in humans, this zebrafish animal model may serve as a powerful tool to study the pathogenesis and treatment of ALD and its related disorders in humans.


Asunto(s)
Modelos Animales de Enfermedad , Hepatopatías Alcohólicas/etiología , Hígado/patología , Pez Cebra , Animales , Hígado Graso Alcohólico/etiología , Hígado Graso Alcohólico/patología , Hígado Graso Alcohólico/fisiopatología , Humanos , Hígado/fisiopatología , Hepatopatías Alcohólicas/patología , Hepatopatías Alcohólicas/fisiopatología , Masculino
18.
Pharmacology ; 94(1-2): 71-7, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25228362

RESUMEN

The liver plays a central role in ethanol (EtOH) metabolism, and oxidative stress is implicated in alcohol-mediated liver injury. The present study aimed to investigate the role of emodin in EtOH-induced fatty liver injury. Liver histology, biochemistry and gene-expression studies were performed. Mice fed with an EtOH-containing diet exhibited severe macrovesicular steatosis and higher serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. However, emodin ameliorated liver steatosis and lowered ALT and AST. Emodin also decreased hepatic triglyceride in mice fed with EtOH. In addition, emodin attenuates Oil Red O staining in alcoholic fatty liver in mice. Hepatic cytochrome P450 2E1 protein levels were upregulated in EtOH-fed mice, but downregulated in emodin-treated mice. In addition, emodin decreased hepatic oxidative stress. Furthermore, emodin significantly reduced liver α-smooth muscle actin and collagen type I, whereas it increased the mRNA levels of PPAR-γ. Taken together, emodin plays protective roles in alcohol-mediated liver steatosis.


Asunto(s)
Emodina/farmacología , Hígado Graso Alcohólico/prevención & control , Estrés Oxidativo/efectos de los fármacos , Triglicéridos/metabolismo , Actinas/metabolismo , Alanina Transaminasa/sangre , Animales , Aspartato Aminotransferasas/sangre , Colágeno Tipo I/metabolismo , Citocromo P-450 CYP2E1/genética , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Hígado Graso Alcohólico/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , PPAR gamma/genética , Regulación hacia Arriba/efectos de los fármacos
19.
J Hepatol ; 61(4): 903-11, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-24859453

RESUMEN

BACKGROUND & AIMS: Heat shock protein 90 (hsp90) is an emerging therapeutic target in chronic liver diseases. Hsp90 plays an important role in liver immune cell activation; however its role in alcoholic liver disease (ALD) remains elusive. Here we hypothesize that hsp90 is crucial in alcohol induced steatosis and pro-inflammatory cytokine production. To test this hypothesis, we employed a pharmacological inhibitor of hsp90, 17-DMAG (17-Dimethylamino-ethylamino-17-demethoxygeldanamycin) in an in vivo mouse model of acute and chronic alcoholic liver injury. METHODS: C57BL/6 mice were given either a single dose of ethanol via oral gavage (acute) or chronically fed alcohol for 2 weeks followed by oral gavage (chronic-binge). 17-DMAG was administered during or at the end of feeding. Liver injury parameters, inflammatory cytokines and lipid metabolism genes were analysed. RESULTS: Our results reveal increased expression of hsp90 in human and mouse alcoholic livers. In vivo inhibition of hsp90, using 17-DMAG, not only prevented but also alleviated alcoholic liver injury, determined by lower serum ALT, AST and reduced hepatic triglycerides. Mechanistic analysis showed that 17-DMAG decreased alcohol mediated oxidative stress, reduced serum endotoxin, decreased inflammatory cells, and diminished sensitization of liver macrophages to LPS, resulting in downregulation of CD14, NFκB inhibition, and decreased pro-inflammatory cytokine production. Hsp90 inhibition decreased fatty acid synthesis genes via reduced nuclear SREBP-1 and favoured fatty acid oxidation genes via PPARα. CONCLUSIONS: Inhibition of hsp90 decreased alcohol induced steatosis and pro-inflammatory cytokines and inhibited alcoholic liver injury. Hsp90 is therefore relevant in human alcoholic cirrhosis and a promising therapeutic target in ALD.


Asunto(s)
Benzoquinonas/farmacología , Ácidos Grasos , Hígado Graso Alcohólico , Proteínas HSP90 de Choque Térmico , Lactamas Macrocíclicas/farmacología , Lipogénesis/efectos de los fármacos , Activación de Macrófagos/efectos de los fármacos , Triglicéridos , Adulto , Anciano , Animales , Citocinas/metabolismo , Relación Dosis-Respuesta a Droga , Ácidos Grasos/biosíntesis , Ácidos Grasos/metabolismo , Hígado Graso Alcohólico/diagnóstico , Hígado Graso Alcohólico/tratamiento farmacológico , Hígado Graso Alcohólico/metabolismo , Hígado Graso Alcohólico/fisiopatología , Femenino , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Proteínas HSP90 de Choque Térmico/metabolismo , Humanos , Hígado/patología , Pruebas de Función Hepática , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Estrés Oxidativo/efectos de los fármacos , PPAR alfa/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , Triglicéridos/biosíntesis , Triglicéridos/metabolismo
20.
Mitochondrion ; 15: 40-51, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24727595

RESUMEN

Exercise is considered a non-pharmacological tool against several lifestyle disorders in which mitochondrial dysfunction is involved. The present study aimed to analyze the preventive (voluntary physical activity-VPA) and therapeutic (endurance training-ET) role of exercise against non-alcoholic steatohepatitis (NASH)-induced liver mitochondrial dysfunction. Sixty male Sprague-Dawley rats were divided into standard-diet sedentary (SS, n=20), standard-diet VPA (SVPA, n=10), high-fat diet sedentary (HS, n=20) and high-fat diet VPA (HVPA, n=10). After 9weeks of diet-treatment, half of SS and HS animals were engaged in an ET program (SET and HET) for 8weeks, 5days/week and 60min/day. Liver mitochondrial oxygen consumption and transmembrane-electric potential (ΔΨ) were evaluated in the presence of glutamate-malate (G/M), palmitoyl-malate (P/M) and succinate (S/R). Mitochondrial enzymes activity, lipid and protein oxidation, oxidative phosphorylation (OXPHOS) subunits, cytochrome c, adenine nucleotide translocator (ANT) and uncoupling protein-2 (UCP2) content were assessed. HS groups show the histological features of NASH in parallel with decreased ΔΨ and respiratory control (RCR) and ADP/O ratios (G/M and P/M). A state 3 decrease (G/M and S/R), FCCP-induced uncoupling respiration (S/R) and ANT content were also observed. Both exercise types counteracted oxygen consumption (RCR, ADP/O and FCCP-uncoupling state) impairments and improved ΔΨ (lag-phase). In conclusion, exercise prevented or reverted (VPA and ET, respectively) the bioenergetic impairment induced by NASH, but only ET positively remodeled NASH-induced liver structural damage and abnormal mitochondria. It is possible that alterations in inner membrane integrity and fatty acid oxidation may be related to the observed phenotypes induced by exercise.


Asunto(s)
Metabolismo Energético , Hígado Graso Alcohólico/fisiopatología , Hígado/patología , Hígado/fisiopatología , Mitocondrias/patología , Mitocondrias/fisiología , Condicionamiento Físico Animal , Animales , Modelos Animales de Enfermedad , Hígado Graso Alcohólico/terapia , Mitocondrias/ultraestructura , Ratas Sprague-Dawley
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