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1.
Chem Biol Interact ; 327: 109176, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32534989

RESUMO

Alcoholic liver disease (ALD) is a progressively aggravated liver disease with high incidence in alcoholics. Ethanol-induced fat accumulation and the subsequent lipopolysaccharide (LPS)-driven inflammation bring liver from reversible steatosis, to irreversible hepatitis, fibrosis, cirrhosis, and even hepatocellular carcinoma. Peroxisome proliferator-activated receptor α (PPARα) is a member of the nuclear receptor superfamily of ligand-activated transcription factors and plays pivotal roles in the regulation of fatty acid homeostasis as well as the inflammation control in the liver. It has been well documented that PPARα activity and/or expression are downregulated in liver of mice exposed to ethanol, which is thought to be one of the prime contributors to ethanol-induced steatosis, hepatitis and fibrosis. This article summarizes the current evidences from in vitro and animal models for the critical roles of PPARα in the onset and progression of ALD. Importantly, it should be noted that the expression of PPARα in human liver is reported to be similar to that in mice, and PPARα expression is downregulated in the liver of patients with nonalcoholic fatty liver disease (NAFLD), a disease sharing many similarities with ALD. Therefore, clinical trials investigating the expression of PPARα in the liver of ALD patients and the efficacy of strong PPARα agonists for the prevention and treatment of ALD are warranted.


Assuntos
Fígado Gorduroso Alcoólico/etiologia , PPAR alfa/metabolismo , Adiponectina/metabolismo , Animais , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Regulação para Baixo , Etanol , Fígado Gorduroso Alcoólico/metabolismo , Humanos , Inflamação/induzido quimicamente , Inflamação/etiologia , Inflamação/metabolismo , Fígado/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/etiologia , Cirrose Hepática/metabolismo , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , PPAR alfa/agonistas , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
2.
Am J Physiol Gastrointest Liver Physiol ; 318(3): G410-G418, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31905026

RESUMO

Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are common causes of chronic liver disease. The overlap between ALD and NAFLD suggests the existence of metabolic steatohepatitis. Development of in vivo models that reflect various aspects of human steatohepatitis is essential for drug discovery. We aimed to characterize several models of steatohepatitis (SH) and to investigate whether the pathology could be modulated. Sprague-Dawley rats were fed a high-fat diet (HFD) for 9 wk, followed by either a high-fat, high-cholesterol and cholate diet (HFC) or a HFC diet containing 13% trans fat (HFC-TF). A subset received 15% ethanol-water twice a week for 12 wk. Serum triglycerides, cholesterol, LDL, HDL, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and rodent NH2-terminal propeptide of type III collagen (rPRO-C3) were assessed. The liver was weighed and evaluated using modified Nonalcoholic Steatohepatitis Clinical Research Network histological score system criteria. All diets induced hepatomegaly, but only HFC-TF increased the size of visceral adipose tissue. Trans fat augmented HFC-induced dyslipidemia, and cholesterol was higher and HDL was lower in the HFC-TF groups. Alcohol lowered triglycerides in both dietary groups. HFC elevated ALT and AST, which were lowered by trans fat. All diets induced histological SH, addition of trans fat induced more steatosis but less inflammation. Inclusion of alcohol augmented the HFC-induced inflammation. All diets induced mild fibrosis. Inclusion of trans fat and alcohol significantly increased rPRO-C3. The addition of trans fat reduced the HFC-induced inflammation but augmented steatosis and dyslipidemia. Inclusion of alcohol induced a more inflammatory and fibrogenic phenotype.NEW & NOTEWORTHY Alcoholic liver disease and nonalcoholic liver disease share significant overlap, which suggests the existence of metabolic steatohepatitis. Trans fat has been implicated in steatohepatitis development. Here, we show that the addition of trans fat to an atherogenic diet results in a more steatotic but less inflammatory phenotype, whereas the addition of alcohol to an atherogenic diet augments the inflammatory and fibrogenic properties of the diet.


Assuntos
Bebedeira/complicações , Dieta Aterogênica , Fígado Gorduroso Alcoólico/etiologia , Fígado/patologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Ácidos Graxos Trans , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Modelos Animais de Doenças , Dislipidemias/etiologia , Dislipidemias/metabolismo , Dislipidemias/patologia , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/patologia , Hepatomegalia/etiologia , Hepatomegalia/metabolismo , Hepatomegalia/patologia , Metabolismo dos Lipídeos , Fígado/metabolismo , Cirrose Hepática Alcoólica/etiologia , Cirrose Hepática Alcoólica/metabolismo , Cirrose Hepática Alcoólica/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Estresse Oxidativo , Fragmentos de Peptídeos/metabolismo , Pró-Colágeno/metabolismo , Ratos Sprague-Dawley
3.
J Agric Food Chem ; 68(6): 1750-1759, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31971384

RESUMO

Alcohol is a globally well-established cause of fatty liver disease (FLD). Increased salt consumption is associated with an increased prevalence of adipocyte hypertrophy and liver injury. In this study, high dietary salt potentiated chronic alcohol-induced hepatic damage. We explored the physiological mechanism of alcoholic FLD in the gastrointestinal tract. Male C57BL/6J mice (8-week-old) were fed a high-salt diet (HSD; 4% NaCl) with or without chronic ethanol (CE) for 1 month. The fecal microbiota, serum biochemical indices, intestinal permeability, level of liver damage, and liver mitochondria were evaluated. The HSD, CE, and their combination (HSDE) significantly changed the gut microbiota's structure, and the HSDE mice contained more probiotic species (e.g., Bifidobacterium and Lactobacillus). The serum aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels were increased, and the lipid was accumulated in the liver tissues in the CE, HSD, and HSDE groups, which indicated liver damage, especially in the HSDE group. The increased intestinal permeability and mitochondrial dysfunction in the liver cells caused greater injury in the HSDE group than in the other groups. Thus, consuming HSD with alcohol contributes to FLD development and progression.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Fígado Gorduroso Alcoólico/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Cloreto de Sódio na Dieta/metabolismo , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Etanol/efeitos adversos , Etanol/metabolismo , Fígado Gorduroso Alcoólico/etiologia , Fígado Gorduroso Alcoólico/metabolismo , Fezes/microbiologia , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Cloreto de Sódio na Dieta/efeitos adversos
4.
Am J Pathol ; 189(9): 1744-1762, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31199920

RESUMO

Alcoholic fatty liver disease is often complicated by other pathologic insults, such as viral infection or high-fat diet. Autophagy plays a homeostatic role in the liver but can be compromised by alcohol, high-fat diet, or viral infection, which in turn affects the disease process caused by these etiologies. To understand the full impact of autophagy modulation on alcohol-induced liver injury, several genetic models of autophagy deficiency, which have different levels of functional alterations, were examined after acute binge or chronic-plus-binge treatment. Mice given alcohol with either mode and induced with deficiency in liver-specific Atg7 shortly after the induction of Atg7 deletion had elevated liver injury, indicating the protective role of autophagy. Constitutive hepatic Atg7-deficient mice, in which Atg7 was deleted in embryos, were more susceptible with chronic-plus-binge but not with acute alcohol treatment. Constitutive hepatic Atg5-deficient mice, in which Atg5 was deleted in embryos, were more susceptible with acute alcohol treatment, but liver injury was unexpectedly improved with the chronic-plus-binge regimen. A prolonged autophagy deficiency may complicate the hepatic response to alcohol treatment, likely in part due to endogenous liver injury. The complexity of the relationship between autophagy deficiency and alcohol-induced liver injury can thus be affected by the timing of autophagy dysfunction, the exact autophagy gene being affected, and the alcohol treatment regimen.


Assuntos
Proteína 7 Relacionada à Autofagia/fisiologia , Autofagia , Depressores do Sistema Nervoso Central/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Etanol/toxicidade , Fígado Gorduroso Alcoólico/etiologia , Animais , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/patologia , Feminino , Masculino , Camundongos , Camundongos Knockout
5.
Am J Physiol Gastrointest Liver Physiol ; 317(2): G182-G194, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31188634

RESUMO

Metabolic and alcoholic liver injuries result in nonalcoholic (NAFLD) or alcoholic (ALD) fatty liver disease, respectively. In particular, presence of fibrosis in NAFLD and ALD requires treatment, but development of drugs is hampered by the lack of suitable models with significant fibrosis. The carbon tetrachloride (CCl4) liver fibrosis model does not reflect human NAFLD or ALD, but CCl4 may serve as a fibrosis accelerator in addition to another injury. Ethanol in drinking water (16%) or Western diet (WD) were administered for 7 wk in mice either alone or in combination with CCl4 intoxications. Extent of fibrosis, steatosis, and inflammation was assessed by histology, transcription, and biochemistry. Furthermore, transcription of fibrosis, proliferation, and inflammation-related genes was studied on human liver samples with fibrosis resulting from hepatitis C virus infection (n = 7), NAFLD (n = 8), or ALD (n = 7). WD or ethanol alone induced only mild steatosis and inflammation. Combination of CCl4 and WD induced the most severe steatosis together with significant liver fibrosis and moderate inflammation. Combination of CCl4 and ethanol induced the strongest inflammation, with significant liver fibrosis and moderate steatosis. The relationship pattern between fibrosis, proliferation, and inflammation of human ALD was mostly similar in mice treated with CCl4 and ethanol. The combination of CCl4 intoxication with WD validates previous data suggesting it as an appropriate model for human nonalcoholic steatohepatitis. Especially, CCl4 plus ethanol for 7 wk induces ALD in mice, providing a model suitable for further basic research and drug testing.NEW & NOTEWORTHY Alcoholic fatty liver disease with significant fibrosis is generated within 7 wk using carbon tetrachloride as a fibrosis accelerator and administering gradually ethanol (up to 16%) in mice. The similarity in the pattern of steatosis, inflammation, and fibrosis involved in alcoholic fatty liver disease to those of the human condition renders this mouse model suitable as a preclinical model for drug development.


Assuntos
Tetracloreto de Carbono , Etanol/metabolismo , Fígado Gorduroso Alcoólico , Fígado Gorduroso , Cirrose Hepática , Animais , Tetracloreto de Carbono/metabolismo , Tetracloreto de Carbono/toxicidade , Modelos Animais de Doenças , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/metabolismo , Fígado Gorduroso Alcoólico/etiologia , Fígado Gorduroso Alcoólico/metabolismo , Humanos , Inflamação/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/metabolismo , Camundongos , Solventes/metabolismo , Solventes/toxicidade
6.
FASEB J ; 33(6): 7274-7288, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30857422

RESUMO

Alcoholic beverages, which are consumed widely in most parts of the world, have long been identified as a major risk factor for all liver diseases, particularly alcoholic liver disease (ALD). Recent compositional analyses suggest that Chinese baijiu (CB), a clear alcoholic liquid distilled from fermented grains, contains large amounts of small molecule bioactive compounds in addition to a significant amount of ethanol (EtOH). Here, in an experimental mouse model, we show that CB caused lower degrees of liver injury than pure EtOH by protecting against the decrease of the relative abundance of Akkermansia and increase of the relative abundance of Prevotella in the gut, thereby preventing the destruction of the intestinal barrier. Furthermore, we demonstrated that EtOH-induced alteration of the gut microbiota profoundly affected the host metabolome. Compared with EtOH feeding, CB feeding resulted in higher concentrations of functional saturated long-chain fatty acids and short-chain fatty acids. The additional mouse models of low dosages of EtOH and of blending baijiu validated that volatile compounds in CB can attenuate EtOH-induced liver damages. Our results provide supporting evidence that ALD was profoundly influenced by host-gut microbiota metabolic interactions and that small molecule organic compounds in CB could attenuate ALD.-Fang, C., Du, H., Zheng, X., Zhao, A., Jia, W., Xu, Y. Solid-state fermented Chinese alcoholic beverage (baijiu) and ethanol resulted in distinct metabolic and microbiome responses.


Assuntos
Bebidas Alcoólicas , Disbiose/induzido quimicamente , Etanol/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatias Alcoólicas/etiologia , Fígado/efeitos dos fármacos , Metaboloma/efeitos dos fármacos , Bebidas Alcoólicas/toxicidade , Animais , Translocação Bacteriana/efeitos dos fármacos , Destilação , Disbiose/metabolismo , Disbiose/microbiologia , Etanol/toxicidade , Ácidos Graxos/metabolismo , Fígado Gorduroso Alcoólico/etiologia , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/microbiologia , Fermentação , Hepatopatias Alcoólicas/metabolismo , Hepatopatias Alcoólicas/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distribuição Aleatória , Ribotipagem , Organismos Livres de Patógenos Específicos , Substâncias Reativas com Ácido Tiobarbitúrico/análise , Verrucomicrobia/efeitos dos fármacos , Verrucomicrobia/isolamento & purificação
7.
Redox Biol ; 22: 101145, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30802717

RESUMO

Alcoholic fatty liver disease (AFLD) is a growing health problem for which no targeted therapy is available. We set out to study whether systemic inactivation of the main hypoxia-inducible factor prolyl 4-hydroxylase, HIF-P4H-2 (PHD2/EglN1), whose inactivation has been associated with protection against metabolic dysfunction, could ameliorate it. HIF-P4H-2-deficient and wild-type (WT) mice or HIF-P4H inhibitor-treated WT mice were subjected to an ethanol diet for 3-4 weeks and their metabolic health, liver and white adipose tissue (WAT) were analyzed. Primary hepatocytes from the mice were used to study cellular ethanol metabolism. The HIF-P4H-2-deficient mice retained a healthier metabolic profile, including less adiposity, better lipoprotein profile and restored insulin sensitivity, while on the ethanol diet than the WT. They also demonstrated protection from alcohol-induced steatosis and liver damage and had less WAT inflammation. In liver and WAT the expression of the key lipogenic and adipocytokine mRNAs, such as Fas and Ccl2, were downregulated, respectively. The upregulation of metabolic and antioxidant hypoxia-inducible factor (HIF) target genes, such as Slcs 16a1 and 16a3 and Gclc, respectively, and a higher catalytic activity of ALDH2 in the HIF-P4H-2-deficient hepatocytes improved handling of the toxic ethanol metabolites and oxidative stress. Pharmacological HIF-P4H inhibition in the WT mice phenocopied the protection against AFLD. Our data show that global genetic inactivation of HIF-P4H-2 and pharmacological HIF-P4H inhibition can protect mice from alcohol-induced steatosis and liver injury, suggesting that HIF-P4H inhibitors, now in clinical trials for renal anemia, could also be studied in randomized clinical trials for treatment of AFLD.


Assuntos
Fígado Gorduroso Alcoólico/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Animais , Biomarcadores , Glicemia , Linhagem Celular , Modelos Animais de Doenças , Ativação Enzimática , Fígado Gorduroso Alcoólico/etiologia , Fígado Gorduroso Alcoólico/patologia , Feminino , Expressão Gênica , Hepatócitos/metabolismo , Prolina Dioxigenases do Fator Induzível por Hipóxia/antagonistas & inibidores , Insulinas/metabolismo , Metabolismo dos Lipídeos , Fígado/metabolismo , Camundongos , Camundongos Transgênicos , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo
8.
Nutrients ; 11(1)2019 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-30621265

RESUMO

Gut dysbiosis and altered short-chain fatty acids are associated with ethanol-induced liver injury. SCFA are fermentation byproducts of the gut microbiota known to have many beneficial biological effects. We tested if a designer synbiotic could protect against ethanol-induced gut-liver injury. C57BL/6 female mice were exposed to chronic-binge ethanol feeding consisting of ethanol (5% vol/vol) for 10 days, followed by a single gavage (5 g/kg body weight) 6 h before euthanasia. A group of mice also received oral supplementation daily with a designer synbiotic, and another group received fecal slurry (FS); control animals received saline. Control mice were isocalorically substituted maltose dextran for ethanol over the entire exposure period. Ethanol exposure reduced expression of tight junction proteins in the proximal colon and induced hepatocyte injury and steatosis. Synbiotic supplementation not only mitigated losses in tight junction protein expression, but also prevented ethanol-induced steatosis and hepatocyte injury. Ethanol exposure also increased hepatic inflammation and oxidative stress, which was also attenuated by synbiotic supplementation. Mice receiving FS were not protected from ethanol-induced liver injury or steatosis. Results were associated with luminal SCFA levels and SCFA transporter expression in the proximal colon and liver. These results indicate supplementation with a designer synbiotic is effective in attenuating chronic-binge ethanol-induced gut-liver injury and steatosis in mice, and highlight the beneficial effects of the gut microbial fermentation byproducts.


Assuntos
Etanol/toxicidade , Enteropatias/induzido quimicamente , Enteropatias/prevenção & controle , Hepatopatias Alcoólicas/prevenção & controle , Simbióticos/administração & dosagem , Aldeídos/análise , Animais , Colo/química , Colo/metabolismo , Disbiose , Proteínas de Transporte de Ácido Graxo/análise , Ácidos Graxos Voláteis/análise , Ácidos Graxos Voláteis/metabolismo , Fígado Gorduroso Alcoólico/etiologia , Fezes , Feminino , Fermentação , Microbioma Gastrointestinal/fisiologia , Expressão Gênica/efeitos dos fármacos , Fígado/química , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Proteínas de Junções Íntimas/genética , Fator de Necrose Tumoral alfa/análise
9.
J Clin Ultrasound ; 47(3): 165-168, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30378127

RESUMO

We present three cases of chronic hepatic porphyria (CHP) in alcoholic patients, in which grayscale ultrasound (US) revealed multiple echogenic masses in the liver, mimicking multinodular hepatocellular carcinoma on alcoholic liver injury. In all cases, contrast-enhanced US (CEUS) showed iso-enhancement of the mass lesions throughout all vascular phases. Additionally, two-dimensional shear wave elastography (2DSWE) (performed in two cases) revealed the mass to have almost the same SWE value as the surrounding parenchyma. When encountering alcoholic patients with multiple echogenic masses in the liver, CHP must be included in the differential diagnosis. CEUS and 2DSWE allow us to increase our diagnostic confidence of CHP.


Assuntos
Fígado Gorduroso Alcoólico/diagnóstico por imagem , Porfirias Hepáticas/diagnóstico por imagem , Alcoolismo/complicações , Carcinoma Hepatocelular/diagnóstico por imagem , Meios de Contraste , Diagnóstico Diferencial , Técnicas de Imagem por Elasticidade/métodos , Fígado Gorduroso Alcoólico/etiologia , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Porfirias Hepáticas/etiologia , Ultrassonografia
10.
Arch Biochem Biophys ; 657: 65-73, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30222954

RESUMO

Tobacco and alcohol are often co-abused. Nicotine can enhance alcoholic fatty liver, and CYP2A6 (CYP2A5 in mice), a major metabolism enzyme for nicotine, can be induced by alcohol. CYP2A5 knockout (cyp2a5-/-) mice and their littermates (cyp2a5+/+) were used to test whether CYP2A5 has an effect on nicotine-enhanced alcoholic fatty liver. The results showed that alcoholic fatty liver was enhanced by nicotine in cyp2a5+/+ mice but not in the cyp2a5-/- mice. Combination of ethanol and nicotine increased serum triglyceride in cyp2a5+/+ mice but not in the cyp2a5-/- mice. Cotinine, a major metabolite of nicotine, also enhanced alcoholic fatty liver, which was also observed in cyp2a5+/+ mice but not in the cyp2a5-/- mice. Nitrotyrosine and malondialdehyde (MDA), markers of oxidative/nitrosative stress, were induced by alcohol and were further increased by nicotine and cotinine in cyp2a5+/+ mice but not in the cyp2a5-/- mice. Reactive oxygen species (ROS) production during microsomal metabolism of nicotine and cotinine was increased in microsomes from cyp2a5+/+ mice but not in microsomes from cyp2a5-/- mice. These results suggest that nicotine enhances alcoholic fatty liver in a CYP2A5-dependent manner, which is related to ROS produced during the process of CYP2A5-dependent nicotine metabolism.


Assuntos
Hidrocarboneto de Aril Hidroxilases/metabolismo , Família 2 do Citocromo P450/metabolismo , Fígado Gorduroso Alcoólico/etiologia , Nicotina/efeitos adversos , Nicotina/metabolismo , Animais , Hidrocarboneto de Aril Hidroxilases/genética , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Cotinina/efeitos adversos , Cotinina/sangue , Cotinina/metabolismo , Cotinina/urina , Família 2 do Citocromo P450/genética , Etanol/toxicidade , Fígado Gorduroso Alcoólico/metabolismo , Feminino , Técnicas de Inativação de Genes , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microssomos Hepáticos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
11.
Nat Rev Dis Primers ; 4(1): 16, 2018 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-30115921

RESUMO

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.


Assuntos
Hepatopatias Alcoólicas/complicações , Hepatopatias Alcoólicas/fisiopatologia , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/psicologia , Fígado Gorduroso Alcoólico/etiologia , Fígado Gorduroso Alcoólico/fisiopatologia , Carga Global da Doença/estatística & dados numéricos , Humanos , Hepatopatias Alcoólicas/epidemiologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/fisiopatologia , Transplante de Fígado/estatística & dados numéricos , Qualidade de Vida/psicologia
12.
Exp Mol Pathol ; 105(1): 63-70, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29859945

RESUMO

Disease progression in alcoholic and non-alcoholic fatty liver disease shows sex-specific differences and is influenced by mechanisms linked to oxidative stress. Acetaldehyde plays a critical pathogenic role but its effects are mitigated by the activity of aldehyde dehydrogenases. Aldehyde dehydrogenase 1b1 (Aldh1b1) is the aldehyde dehydrogenase isoform with the second highest affinity for acetaldehyde after Aldh2, and is highly expressed in the intestine and liver. We examined sex differences and the effect of Aldh1b1 depletion in a murine model of chronic alcohol-induced liver disease. Male and female wild-type and Aldh1b1-depleted mice received either ethanol (10-20% v/v) in drinking water or water alone for one year, and livers were examined histopathologically, histochemically and by immunohistochemistry. A significant increase in hepatic steatosis was observed in female mice after one year of ethanol consumption, and expression of ethanol-metabolising enzymes and up-regulation by ethanol was also sex-dependent. Ethanol-induced hyperproliferation of hepatocytes was observed in female and male wild-type mice, and Aldh1b1 depletion enhanced this effect in males. Further, one ethanol-treated, Aldh1b1-depleted male developed a steatohepatitic hepatocellular carcinoma. These sex-specific differences in susceptibility to hepatic steatosis and disease progression may be related to differences in expression of ethanol-metabolising enzymes, informing the clinically significant differences. Aldh1b1 plays a role in protection from ethanol-induced hepatocellular hyperproliferation and may protect from tumour development.


Assuntos
Consumo de Bebidas Alcoólicas/patologia , Aldeído Desidrogenase/deficiência , Carcinoma Hepatocelular/patologia , Fígado Gorduroso Alcoólico/patologia , Neoplasias Hepáticas/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Caracteres Sexuais , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/metabolismo , Aldeído Desidrogenase 1 , Aldeído-Desidrogenase Mitocondrial , Animais , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/metabolismo , Suscetibilidade a Doenças , Fígado Gorduroso Alcoólico/etiologia , Fígado Gorduroso Alcoólico/metabolismo , Feminino , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo
13.
Nutrients ; 10(3)2018 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-29534433

RESUMO

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.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fígado Gorduroso Alcoólico/etiologia , Lactação , Fígado/efeitos dos fármacos , Fenômenos Fisiológicos da Nutrição Materna , Efeitos Tardios da Exposição Pré-Natal , Proteínas de Soja/efeitos adversos , Animais , Ácidos e Sais Biliares/sangue , Biomarcadores/sangue , Suplementos Nutricionais , Dislipidemias/etiologia , Dislipidemias/patologia , Dislipidemias/fisiopatologia , Dislipidemias/prevenção & controle , Etanol/toxicidade , Fígado Gorduroso Alcoólico/patologia , Fígado Gorduroso Alcoólico/fisiopatologia , Fígado Gorduroso Alcoólico/prevenção & controle , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Genisteína/uso terapêutico , Fígado/patologia , Fígado/fisiopatologia , Masculino , Tamanho do Órgão/efeitos dos fármacos , Gravidez , Substâncias Protetoras/uso terapêutico , Distribuição Aleatória , Ratos Sprague-Dawley
14.
J Gastroenterol ; 53(5): 660-669, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29063269

RESUMO

BACKGROUND: Genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B; rs1229984, His48Arg) and aldehyde dehydrogenase-2 (ALDH2; rs671, Glu504Lys) affect body weight, body fat, and lipid metabolism in individuals with alcohol dependence, and the aim of this study was to identify their determinants in relation to the development of fatty liver. METHODS: We evaluated associations between the presence of fatty liver and ADH1B and ALDH2 genotypes and other factors in 1604 Japanese men who had been admitted for treatment of alcohol dependence. RESULTS: Fatty liver was diagnosed when ultrasonography showed both hepatorenal contrast and liver brightness. Age-adjusted usual alcohol intake did not differ according to ADH1B or ALDH2 genotypes. A multivariate analysis showed that the adjusted odds ratio (OR, 95% confidence interval) of slow-metabolizing ADH1B Arg/Arg carriers was 1.61 (1.27-2.03) for fatty liver and 1.82 (1.37-2.41) for fatty liver with deep attenuation in comparison with the ADH1B His/Arg or His/His carriers, and that the OR of inactive heterozygous ALDH2 Glu/Lys carriers was 1.43 (1.08-1.91) for fatty liver and 1.84 (1.31-2.59) for fatty liver with deep attenuation in comparison with the ALDH2 Glu/Glu carriers. Younger age, shorter interval between the last drink and the ultrasound examination, larger body mass index, and absence of cirrhosis were identified as other positive determinants for fatty liver. CONCLUSIONS: The ADH1B Arg/Arg genotype and the ALDH2 Glu/Lys genotype were positive determinants of fatty liver in the subjects. These results suggest that slow ethanol and acetaldehyde metabolism accelerates the development of alcoholic fatty liver in heavy drinkers.


Assuntos
Álcool Desidrogenase/genética , Alcoolismo/complicações , Aldeído-Desidrogenase Mitocondrial/genética , Fígado Gorduroso Alcoólico/genética , Adulto , Fatores Etários , Idoso , Índice de Massa Corporal , Fígado Gorduroso Alcoólico/diagnóstico por imagem , Fígado Gorduroso Alcoólico/etiologia , Heterozigoto , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Ultrassonografia
15.
J Biol Chem ; 293(1): 1-17, 2018 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-29123032

RESUMO

The pregnane X receptor (PXR, NR1I2) is a xenobiotic-sensing nuclear receptor that modulates the metabolic response to drugs and toxic agents. Both PXR activation and deficiency promote hepatic triglyceride accumulation, a hallmark feature of alcoholic liver disease. However, the molecular mechanism of PXR-mediated activation of ethanol (EtOH)-induced steatosis is unclear. Here, using male wildtype (WT) and Pxr-null mice, we examined PXR-mediated regulation of chronic EtOH-induced hepatic lipid accumulation and hepatotoxicity. EtOH ingestion for 8 weeks significantly (1.8-fold) up-regulated Pxr mRNA levels in WT mice. The EtOH exposure also increased mRNAs encoding hepatic constitutive androstane receptor (3-fold) and its target, Cyp2b10 (220-fold), in a PXR-dependent manner. Furthermore, WT mice had higher serum EtOH levels and developed hepatic steatosis characterized by micro- and macrovesicular lipid accumulation. Consistent with the development of steatosis, lipogenic gene induction was significantly increased in WT mice, including sterol regulatory element-binding protein 1c target gene fatty-acid synthase (3.0-fold), early growth response-1 (3.2-fold), and TNFα (3.0-fold), whereas the expression of peroxisome proliferator-activated receptor α target genes was suppressed. Of note, PXR deficiency suppressed these changes and steatosis. Protein levels, but not mRNAs levels, of EtOH-metabolizing enzymes, including alcohol dehydrogenase 1, aldehyde dehydrogenase 1A1, and catalase, as well as the microsomal triglyceride transfer protein, involved in regulating lipid output were higher in Pxr-null than in WT mice. These findings establish that PXR signaling contributes to ALD development and suggest that PXR antagonists may provide a new approach for ALD therapy.


Assuntos
Fígado Gorduroso Alcoólico/genética , Receptores de Esteroides/genética , Regulação para Cima , Animais , Etanol/efeitos adversos , Fígado Gorduroso Alcoólico/etiologia , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/patologia , Deleção de Genes , Lipogênese , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptor de Pregnano X , RNA Mensageiro/genética , Receptores de Esteroides/metabolismo
16.
FASEB J ; 32(1): 130-142, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28864659

RESUMO

Perilipin 2 (PLIN2) is a lipid-droplet protein that is up-regulated in alcoholic steatosis and associated with hepatic accumulation of ceramides, bioactive lipids implicated in alcoholic liver disease pathogenesis. The specific role of ceramide synthetic enzymes in the regulation of PLIN2 and promotion of hepatocellular lipid accumulation is not well understood. We examined the effects of pharmacologic ceramide synthesis inhibition on hepatic PLIN2 expression, steatosis, and glucose and lipid homeostasis in mice with alcoholic steatosis and in ethanol-incubated human hepatoma VL17A cells. In cells, pharmacologic inhibition of ceramide synthase reduced lipid accumulation by reducing PLIN2 RNA stability. The subtype ceramide synthase (CerS)6 was specifically up-regulated in experimental alcoholic steatosis in vivo and in vitro and was up-regulated in zone 3 hepatocytes in human alcoholic steatosis. In vivo ceramide reduction by inhibition of de novo ceramide synthesis reduced PLIN2 and hepatic steatosis in alcohol-fed mice, but only de novo synthesis inhibition, not sphingomyelin hydrolysis, improved glucose tolerance and dyslipidemia. These findings implicate CerS6 as a novel regulator of PLIN2 and suggest that ceramide synthetic enzymes may promote the earliest stage of alcoholic liver disease, alcoholic steatosis.-Williams, B., Correnti, J., Oranu, A., Lin, A., Scott, V., Annoh, M., Beck, J., Furth, E., Mitchell, V., Senkal, C. E., Obeid, L., Carr, R. M. A novel role for ceramide synthase 6 in mouse and human alcoholic steatosis.


Assuntos
Fígado Gorduroso Alcoólico/enzimologia , Proteínas de Membrana/metabolismo , Esfingosina N-Aciltransferase/metabolismo , Animais , Vias Biossintéticas , Linhagem Celular , Ceramidas/biossíntese , Modelos Animais de Doenças , Etanol , Fígado Gorduroso Alcoólico/etiologia , Fígado Gorduroso Alcoólico/genética , Glucose/metabolismo , Humanos , Metabolismo dos Lipídeos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Perilipina-2/genética , Perilipina-2/metabolismo , Estabilidade de RNA , Esfingomielina Fosfodiesterase/antagonistas & inibidores , Esfingomielina Fosfodiesterase/metabolismo , Esfingosina N-Aciltransferase/antagonistas & inibidores , Esfingosina N-Aciltransferase/genética , Regulação para Cima/efeitos dos fármacos
17.
Toxicology ; 390: 53-60, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28882574

RESUMO

Kupffer cells (KCs) have been suggested to play critical roles in chronic ethanol induced early liver injury, but the role of KCs in binge drinking-induced hepatic steatosis remains unclear. This study was designed to investigate the roles of KCs inhibitor (GdCl3) and TNF-α antagonist (etanercept) on binge drinking-induced liver steatosis and to explore the underlying mechanisms. C57BL/6 mice were exposed to three doses of ethanol (6g/kg body weight) to mimic binge drinking-induced fatty liver. The results showed that both GdCl3 and etanercept partially but significantly alleviated binge drinking-induced increase of hepatic triglyceride (TG) level, and reduced fat droplets accumulation in mice liver. GdCl3 but not etanercept significantly blocked binge drinking-induced activation of KCs. However, neither GdCl3 nor etanercept could affect binge drinking-induced decrease of PPAR-α, ACOX, FAS, ACC and SCD protein levels, or increase of the LC3 II/LC3 I ratio and p62 protein level. Interestingly, both GdCl3 and etanercept significantly suppressed binge drinking-induced phosphorylation of HSL in epididymal adipose tissues. Results of in vitro studies with cultured epididymal adipose tissues showed that TNF-α could increase the phosphorylation of HSL in adipose tissues and upgrade the secretion of free fatty acid (FFA) in the culture medium. Taken together, KCs inhibitor and TNF-α antagonist could partially attenuate binge drinking-induced liver steatosis, which might be attributed to the suppression of mobilization of white adipose tissues. These results suggest that KCs activation may promote binge drinking-induced fatty liver by TNF-α mediated activation of lipolysis in white adipose tissues.


Assuntos
Tecido Adiposo Branco/metabolismo , Bebedeira , Etanol , Fígado Gorduroso Alcoólico/metabolismo , Macrófagos do Fígado/metabolismo , Lipólise , Fígado/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/patologia , Animais , Autofagia/efeitos dos fármacos , Modelos Animais de Doenças , Etanercepte/farmacologia , Fígado Gorduroso Alcoólico/etiologia , Fígado Gorduroso Alcoólico/patologia , Fígado Gorduroso Alcoólico/prevenção & controle , Gadolínio/farmacologia , Macrófagos do Fígado/efeitos dos fármacos , Macrófagos do Fígado/patologia , Gotículas Lipídicas/metabolismo , Lipogênese/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , PPAR alfa/genética , PPAR alfa/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Técnicas de Cultura de Tecidos , Triglicerídeos/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo
18.
PLoS One ; 12(3): e0174544, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28350851

RESUMO

BACKGROUND: Alcohol-induced intestinal dysbiosis disrupts homeostatic gut-liver axis function and is essential in the development of alcoholic liver disease. Here, we investigate changes in enteric microbiome composition in a model of early alcoholic steatohepatitis and dissect the pathogenic role of intestinal microbes in alcohol-induced liver pathology. MATERIALS AND METHODS: Wild type mice received a 10-day diet that was either 5% alcohol-containing or an isocaloric control diet plus a single binge. 16S rDNA sequencing defined the bacterial communities in the cecum of alcohol- and pair-fed animals. Some mice were treated with an antibiotic cocktail prior to and throughout alcohol feeding. Liver neutrophils, cytokines and steatosis were evaluated. RESULTS: Acute-on-chronic alcohol administration induced shifts in various bacterial phyla in the cecum, including increased Actinobacteria and a reduction in Verrucomicrobia driven entirely by a reduction in the genus Akkermansia. Antibiotic treatment reduced the gut bacterial load and circulating bacterial wall component lipopolysaccharide (LPS). We found that bacterial load suppression prevented alcohol-related increases in the number of myeloperoxidase- (MPO) positive infiltrating neutrophils in the liver. Expression of liver mRNA tumor necrosis factor alpha (Tnfα), C-X-C motif chemokine ligand 1 (Cxcl1) and circulating protein monocyte chemoattractant protein-1 (MCP-1) were also reduced in antibiotic-treated alcohol-fed mice. Alcohol-induced hepatic steatosis measured by Oil-Red O staining was significantly reduced in antibiotic treated mice. Genes regulating lipid production and storage were also altered by alcohol and antibiotic treatment. Interestingly, antibiotic treatment did not protect from alcohol-induced increases in serum aminotransferases (ALT/AST). CONCLUSIONS: Our data indicate that acute-on-chronic alcohol feeding alters the microflora at multiple taxonomic levels and identifies loss of Akkermansia as an early marker of alcohol-induced gut dysbiosis. We conclude that gut microbes influence liver inflammation, neutrophil infiltration and liver steatosis following alcohol consumption and these data further emphasize the role of the gut-liver axis in early alcoholic liver disease.


Assuntos
Fígado Gorduroso/genética , Microbioma Gastrointestinal/genética , Hepatite Alcoólica/genética , Inflamação/genética , Infiltração de Neutrófilos/genética , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacologia , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Depressores do Sistema Nervoso Central/administração & dosagem , Depressores do Sistema Nervoso Central/toxicidade , Etanol/administração & dosagem , Etanol/toxicidade , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso Alcoólico/etiologia , Fígado Gorduroso Alcoólico/genética , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Hepatite Alcoólica/etiologia , Inflamação/induzido quimicamente , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Camundongos Endogâmicos C57BL , Infiltração de Neutrófilos/efeitos dos fármacos , RNA Ribossômico 16S/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
19.
Toxicology ; 379: 12-21, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28131861

RESUMO

BACKGROUND & AIMS: Cytochrome P450 2A5 (CYP2A5) is induced by ethanol, and the ethanol induction of CYP2A5 is regulated by nuclear factor-erythroid 2-related factor 2 (NRF2). Cyp2a5 knockout (Cyp2a5-/-) mice develop more severe alcoholic fatty liver than Cyp2a5+/+ mice. Fibroblast growth factor 21 (FGF21), a PPARα-regulated liver hormone, is involved in hepatic lipid metabolism. Alcoholic and non-alcoholic fatty liver are enhanced in Pparα knockout (Pparα-/-) mice. This study investigates the relationship between the PPARα-FGF21 axis and the enhanced alcoholic fatty liver in Cyp2a5-/- mice. METHODS: Mice were fed the Lieber-Decarli ethanol diet to induce alcoholic fatty liver. RESULTS: More severe alcoholic fatty liver disease was developed in Cyp2a5-/- mice than in Cyp2a5+/+ mice. Basal FGF21 levels were higher in Cyp2a5-/- mice than in Cyp2a5+/+ mice, but ethanol did not further increase the elevated FGF21 levels in Cyp2a5-/- mice while FGF21 was induced by ethanol in Cyp2a5+/+ mice. Basal levels of serum FGF21 were lower in Pparα-/- mice than in Pparα+/+ mice; ethanol induced FGF21 in Pparα+/+ mice but not in Pparα-/- mice, whereas ethanol induced hypertriglyceridemia in Pparα-/- mice but not in Pparα+/+ mice. Administration of recombinant FGF21 normalized serum FGF21 and triglyceride in Pparα-/- mice. Alcoholic fatty liver was enhanced in liver-specific Fgf21 knockout mice. Pparα and Cyp2a5 double knockout (Pparα-/-/Cyp2a5-/-) mice developed more severe alcoholic fatty liver than Pparα+/+/Cyp2a5-/- mice. CONCLUSIONS: These results suggest that CYP2A5 protects against the development of alcoholic fatty liver disease, and the PPARα-FGF21 axis contributes to the protective effects of CYP2A5 on alcoholic fatty liver disease.


Assuntos
Hidrocarboneto de Aril Hidroxilases/fisiologia , Família 2 do Citocromo P450/fisiologia , Fígado Gorduroso Alcoólico/prevenção & controle , Fatores de Crescimento de Fibroblastos/fisiologia , PPAR alfa/fisiologia , Animais , Fígado Gorduroso Alcoólico/etiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 2 Relacionado a NF-E2/fisiologia
20.
Food Funct ; 8(1): 397-405, 2017 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-28074952

RESUMO

Excessive alcohol uptake exerts hepatocellular toxicity, ultimately leading to multiple liver diseases such as steatohepatitis and liver cirrhosis. Here, we aimed to explore the effects of mulberry leaf extract (MLE) and its major components chlorogenic acid (CGA) and neochlorogenic acid (nCGA) on alcoholic steatohepatitis. We determined the composition of MLE using liquid chromatography-mass spectrometric (LC-MS) analysis, which showed that MLE consisted of mainly chlorogenic acid derivatives and other polyphenols. Next, we utilized a high alcohol-fed mouse model and demonstrated that MLE alleviated alcohol-induced hepatocellular disorders, resulting in lowered hepatic injury markers and lipid accumulation. In addition, MLE reduced lipid peroxidation and meanwhile elevated hepatic superoxide dismutase (SOD). Immunohistochemical (IHC) staining revealed that MLE elevated the expression of caveolin-1 but reduced the expressions of epidermal growth factor receptor (EGFR), signal transducer and activator of transcription (STAT), inducible nitric oxide synthase (iNOS) and receptor interacting protein (RIP) 1/3. Major components of MLE, CGA and nCGA, not only exerted a similar biological activity as MLE but also inhibited alcohol-induced pro-apoptotic signals. Involvement of caveolin-1 in MLE, CGA and nCGA was demonstrated by using specific small inhibitory RNA. In conclusion, MLE and its chlorogenic derivatives CGA and nCGA upregulate caveolin-1 expression and diminish EGFR/STAT3/iNOS signalling, which may contribute to lowered hepatic lipid accumulation and peroxidation and inhibited pro-apoptotic cascades.


Assuntos
Caveolina 1/genética , Ácido Clorogênico/administração & dosagem , Fígado Gorduroso Alcoólico/tratamento farmacológico , Morus/química , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Animais , Caveolina 1/metabolismo , Ácido Clorogênico/química , Etanol/efeitos adversos , Fígado Gorduroso Alcoólico/etiologia , Fígado Gorduroso Alcoólico/genética , Fígado Gorduroso Alcoólico/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Folhas de Planta/química , Regulação para Cima/efeitos dos fármacos
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