RESUMO
BACKGROUND: Asperosaponin VI (AVI) is a natural triterpenoid saponin isolated from Dipsacus asper Wall with documented anti-inflammatory and bone protective effects. Our previous work reported that AVI protects the liver of septic mice from acute inflammatory damage. In this paper, we further explored the protective effect and the potential mechanisms of AVI in alcoholic fatty liver disease (AFLD). METHODS: The Lieber-Decarli model was constructed to evaluate the effect of AVI on AFLD in C57BL/6 J mice. Additional in vitro work was performed to investigate HepG2 cells exposed to alcohol, then analyzed the degree of liver injury by detecting the ALT and AST levels both in the liver and serum. H&E staining and Sirius red staining were used to evaluate the histopathology variations in the liver. Further, observe lipid droplets in the cytoplasm by Oil Red O staining. We detected the expression of inflammatory cytokines with qualitative PCR; ROS, MDA, SOD, and GSH-px levels were analyzed to observe oxidative stress. Finally, exploring the activation of AMPK signaling pathway by real-time PCR and Western blotting. RESULTS: Histological examination of liver tissue combined with serum ALT and AST levels showed a significant protective effect of AVI against alcoholic liver injury in AFLD mice. Compared with the model group, AVI evidently improved antioxidant capacity, reduced inflammatory response and lipid accumulation both in vitro and in vivo. For mechanically, it was found that AVI up-regulated phosphorylation level of AMP-activated protein kinase (AMPK) and inhibited the endoplasmic reticulum stress (ER) pathway in AFLD. CONCLUSION: AVI protects mice from alcohol-induced hepatic steatosis and liver injury through activating AMPK signaling and repress ER stress, suggesting that it might be a potential therapeutic agent for AFLD.
Assuntos
Fígado Gorduroso Alcoólico , Saponinas , Camundongos , Animais , Fígado Gorduroso Alcoólico/tratamento farmacológico , Fígado Gorduroso Alcoólico/patologia , Metabolismo dos Lipídeos , Proteínas Quinases Ativadas por AMP/metabolismo , Camundongos Endogâmicos C57BL , Fígado , Saponinas/metabolismo , Estresse Oxidativo , Estresse do Retículo EndoplasmáticoRESUMO
Ampelopsis grossedentata (AG) is an ancient medicinal plant that is mainly distributed and used in southwest China. It exerts therapeutic effects, such as antioxidant, anti-diabetic, and anti-inflammatory activities, reductions in blood pressure and cholesterol and hepatoprotective effects. Researchers in China recently reported the anti-obesity effects of AG extract in diet-induced obese mice and rats. To verify these findings, we herein investigated the effects of AG extract and its principal compound, ampelopsin, in high-fat diet (HFD)- and alcohol diet-fed mice, olive oil-loaded mice, and differentiated 3T3-L1 cells. The results obtained showed that AG extract and ampelopsin significantly suppressed increases in the weights of body, livers and abdominal fat and also up-regulated the expression of carnitine palmitoyltransferase 1A in HFD-fed mice. In olive oil-loaded mice, AG extract and ampelopsin significantly attenuated increases in serum triglyceride (TG) levels. In differentiated 3T3-L1 cells, AG extract and ampelopsin promoted TG decomposition, which appeared to be attributed to the expression of hormone-sensitive lipase. In alcohol diet-fed mice, AG extract and ampelopsin reduced serum levels of ethanol, glutamic oxaloacetic transaminase (GOT), and glutamic pyruvic transaminase (GPT) and liver TG. An examination of metabolic enzyme expression patterns revealed that AG extract and ampelopsin mainly enhanced the expression of aldehyde dehydrogenase and suppressed that of cytochrome P450, family 2, subfamily e1. In conclusion, AG extract and ampelopsin suppressed diet-induced intestinal fat accumulation and reduced the risk of fatty liver associated with HFD and alcohol consumption.
Assuntos
Fármacos Antiobesidade/farmacologia , Dieta Hiperlipídica , Fígado Gorduroso Alcoólico/tratamento farmacológico , Flavonoides/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Extratos Vegetais/farmacologia , Chá/química , Células 3T3-L1 , Adiposidade , Animais , Antioxidantes/farmacologia , Fígado Gorduroso Alcoólico/etiologia , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/patologia , Metabolismo dos Lipídeos , Lipogênese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/tratamento farmacológico , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Fitoterapia , Ratos , Ratos Sprague-DawleyRESUMO
Alcoholic fatty liver disease (AFLD) is a common chronic liver disease and has become a critical global public health problem. Green tea is a popular drink worldwide and contains several bioactive compounds. Different green teas could contain diverse compounds and possess distinct bioactivities. In the present study, the effects of 10 green teas on chronic alcohol induced-fatty liver disease in mice were explored and compared. The results showed that several green teas significantly reduced triacylglycerol levels in serum and liver as well as the aminotransferase activities in mice at a dose of 200 mg/kg, suggesting that they possess hepatoprotective effects. Moreover, several green teas remarkably decreased the expression of cytochrome P450 2E1, the levels of malondialdehyde and 4-hydroxynonenoic acid, and the contents of proinflammatory cytokines, indicating that they could alleviate oxidation damage and inflammation induced by chronic alcohol exposure. In addition, Seven Star Matcha Tea and Selenium-Enriched Matcha Tea could increase glutathione level. Furthermore, the main phytochemical components in green teas were determined and quantified by high-performance liquid chromatography, and the correlation analysis showed that gallic acid, gallocatechin, catechin, chlorogenic acid, and epigallocatechin gallate might at least partially contribute to protective effects on AFLD. In conclusion, Selenium-Enriched Chaoqing Green Tea, Xihu Longjing Tea, Taiping Houkui Tea, and Selenium-Enriched Matcha Tea showed the strongest preventive effects on AFLD. This research also provides the public with new insights about the effects of different green teas on AFLD.
Assuntos
Doença Crônica/tratamento farmacológico , Fígado Gorduroso Alcoólico/tratamento farmacológico , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/química , Chá/química , Animais , Fígado Gorduroso Alcoólico/patologia , Humanos , Masculino , CamundongosRESUMO
Exessive drinking is commonly associated with a wide spectrum of liver injuries. The term alcoholic liver disease (ALD) is generally used to refer to this spectrum of hepatic abnormalities, and the term hepatic steatosis denotes early lesions. Puerariae Lobatae Radix (PLR) is a common traditional Chinese medicine and has been widely used as an efficient treatment for alcohol-induced damage. Flavonoids are the principal components of PLR that could potentially be responsible for the activation of alcohol metabolism and lipid-lowering effects. However, little is known about the mechanisms underlying their activity against alcoholic injury. In this study, PLR flavonoids (PLF) were obtained by microwave extraction. A 2% ethanol solution was used to establish a model of alcoholic fatty liver disease by exposure of zebrafish larvae for 32 h, and then the zebrafish were administered PLF and puerarin. The results showed that PLF and puerarin significantly decreased lipid accumulation and the levels of total cholesterol and triglycerides in zebrafish larvae. Moreover, PLF and puerarin downregulated the expression of genes related to alcohol and lipid metabolism (CYP2y3, CYP3a65, ADH8a, ADH8b, HMGCRB, and FASN), endoplasmic reticulum stress, and DNA damage (CHOP, EDEM1, GADD45αa, and ATF6) and reduced levels of inflammatory factors (IL-1ß, TNF-α) in zebrafish larvae. PLF and puerarin increased the phosphorylation of AMP-activated protein kinase-α (AMPKα) and decreased the total protein level of ACC1. The findings suggested that PLF and puerarin alleviated alcohol-induced hepatic steatosis in zebrafish larvae by regulating alcohol and lipid metabolism, which was closely related to the regulation of the AMPKα-ACC signaling pathway. In conclusion, the study provided a possible therapeutic drug for ALD treatment.
Assuntos
Etanol/metabolismo , Fígado Gorduroso Alcoólico/prevenção & controle , Flavonoides/farmacologia , Isoflavonas/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Pueraria , Proteínas Quinases Ativadas por AMP/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/patologia , Flavonoides/isolamento & purificação , Regulação Enzimológica da Expressão Gênica , Mediadores da Inflamação/metabolismo , Isoflavonas/isolamento & purificação , Fígado/metabolismo , Fígado/patologia , Pueraria/química , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
Alcoholic fatty liver disease (AFLD), a major public health problem, has drawn clinical and scientific attention. The study aims to investigate the effect of Ganmeijian [crude extract of malt root, phosphoesterase complex (Pho)] on AFLD, and explore the possible mechanisms. An AFLD rat model was made. 30 and 60 mg/kg Pho were administrated through intestinal fistula for 5 weeks. Compared with those in model group, AST, LDL-C and TC in 30 mg/kg Pho group and TC in 60 mg/kg Pho group decreased. The mRNA level of Fas, Gpat1 and Srebp-1c in Pho groups was significantly reduced. The level of GSH-Px was increased, mitochondrial activity was improved, and the level of MDA and ROS was reduced in Pho groups. Pho shows a beneficial effect on AFLD. The mechanisms are possibly related to Pho inhibiting the expression of fat synthesis genes, protecting the function and increasing the activity of mitochondria in hepatocytes, then reducing the accumulation of ROS and the level of oxidative stress in the liver.
Assuntos
Fígado Gorduroso Alcoólico/tratamento farmacológico , Hepatócitos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Fígado Gorduroso Alcoólico/patologia , Hepatócitos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Mitocôndrias/metabolismo , Extratos Vegetais/administração & dosagem , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismoAssuntos
Microbioma Gastrointestinal/fisiologia , Hepatopatias/microbiologia , Hepatopatias/terapia , Terapia por Fagos , Animais , Bacteriófagos/fisiologia , Etanol/metabolismo , Fígado Gorduroso Alcoólico/genética , Fígado Gorduroso Alcoólico/microbiologia , Fígado Gorduroso Alcoólico/patologia , Fígado Gorduroso Alcoólico/terapia , Transplante de Microbiota Fecal/métodos , Predisposição Genética para Doença , Humanos , Klebsiella pneumoniae/metabolismo , Klebsiella pneumoniae/virologia , Hepatopatias/genética , Camundongos , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/microbiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/terapia , Distúrbios Nutricionais/complicações , Distúrbios Nutricionais/genética , Distúrbios Nutricionais/microbiologia , Distúrbios Nutricionais/prevenção & controle , Terapia por Fagos/métodos , Saccharomyces/metabolismoRESUMO
Ethanol-mediated down-regulation of carnitine palmitoyltransferase-1 (CPT-1A) gene expression plays a major role in the development of hepatic steatosis; however, the underlying mechanisms are not completely elucidated. Tributyrin, a butyrate prodrug that can inhibit histone deacetylase (HDAC) activity, attenuates hepatic steatosis and injury. The present study examined the beneficial effect of tributyrin/butyrate in attenuating ethanol-induced pathogenic epigenetic mechanisms affecting CPT-1A promoter-histone modifications and gene expression and hepatic steatosis/injury. METHODS: Mice were fed a liquid Lieber-DeCarli diet (Research Diet Inc, New Brunswick, NJ) with or without ethanol for 4 weeks. In a subset of mice, tributyrin (2 g/kg) was administered orally by gavage. Primary rat hepatocytes were treated with 50 mmol/L ethanol and/or 2 mmol/L butyrate. Gene expression and epigenetic modifications at the CPT-1A promoter were analyzed by chromatin immunoprecipitation analysis. RESULTS: In vivo, ethanol induced hepatic CPT-1A promoter histone H3K9 deacetylation, which is indicative of a repressive chromatin state, and decreased CPT-1A gene expression. Our data identified HDAC1 as the predominant HDAC causing CPT-1A promoter histone H3K9 deacetylation and epigenetic down-regulation of gene expression. Significantly, Specificity Protein 1 (SP1) and Hepatocyte Nuclear Factor 4 Alpha (HNF4α) participated in the recruitment of HDAC1 to the proximal and distal regions of CPT-1A promoter, respectively, and mediated transcriptional repression. Importantly, butyrate, a dietary HDAC inhibitor, attenuated ethanol-induced recruitment of HDAC1 and facilitated p300-HAT binding by enabling SP1/p300 interaction at the proximal region and HNF4α/peroxisomal proliferator-activated receptor-γ coactivator-1α/p300 interactions at the distal region, leading to promoter histone acetylation and enhanced CPT-1A transcription. CONCLUSIONS: This study identifies HDAC1-mediated repressive epigenetic mechanisms that underlie an ethanol-mediated decrease in CPT-1A expression. Importantly, tributyrin/butyrate inhibits HDAC1, rescues CPT-1A expression, and attenuates ethanol-mediated hepatic steatosis and injury, suggesting its potential use in therapeutic strategies for alcoholic liver disease.
Assuntos
Carnitina O-Palmitoiltransferase/genética , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Fígado Gorduroso Alcoólico/tratamento farmacológico , Inibidores de Histona Desacetilases/farmacologia , Triglicerídeos/farmacologia , Acetilação/efeitos dos fármacos , Administração Oral , Animais , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Hepática Induzida por Substâncias e Drogas/patologia , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Repressão Epigenética/efeitos dos fármacos , Etanol/toxicidade , Fígado Gorduroso Alcoólico/diagnóstico , Fígado Gorduroso Alcoólico/patologia , Hepatócitos , Inibidores de Histona Desacetilases/uso terapêutico , Histonas/metabolismo , Humanos , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/patologia , Testes de Função Hepática , Masculino , Camundongos , Cultura Primária de Células , Regiões Promotoras Genéticas/genética , Triglicerídeos/uso terapêuticoRESUMO
The hepatoprotective effects of the ethanolic extracts of propolis (EEP) on alcohol-induced liver steatosis were investigated in Wistar rats. Chronic alcoholic fatty liver was induced by administration of 52% alcohol to male Wistar rats at the dose of 1% body weight for 7 weeks. Then animals were simultaneously treated with 50% ethanol solutions of EEP or normal saline at the dose of 0.1% body weight for 4 further weeks. Serological analyses and liver histopathology studies were performed to investigate the development of steatosis. Microarray analysis was conducted to investigate the alterations of hepatic gene expression profiling. Our results showed that 4-week treatment of EEP helped to restore the levels of various blood indices, liver function enzymes and the histopathology of liver tissue to normal levels. Results from the microarray analysis revealed that the hepatic expressions of genes involved in lipogenesis were significantly down-regulated by EEP treatment, while the transcriptional expressions of functional genes participating in fatty acids oxidation were markedly increased. The ability of EEP to reduce the negative effects of alcohol on liver makes propolis a potential natural product for the alternative treatment of alcoholic fatty liver.
Assuntos
Fígado Gorduroso Alcoólico/metabolismo , Hepatopatias Alcoólicas/metabolismo , Extratos Vegetais/metabolismo , Própole/metabolismo , Substâncias Protetoras/metabolismo , Alanina Transaminase/metabolismo , Animais , Apiterapia/métodos , Aspartato Aminotransferases/metabolismo , Colesterol/metabolismo , Modelos Animais de Doenças , Etanol , Ácidos Graxos/biossíntese , Fígado Gorduroso Alcoólico/tratamento farmacológico , Fígado Gorduroso Alcoólico/genética , Fígado Gorduroso Alcoólico/patologia , Hepatopatias Alcoólicas/tratamento farmacológico , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/patologia , Masculino , Oxirredução , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Própole/química , Própole/uso terapêutico , Substâncias Protetoras/química , Substâncias Protetoras/uso terapêutico , Ratos Wistar , Análise Serial de Tecidos/métodos , Transcrição Gênica/genética , Triglicerídeos/metabolismoRESUMO
Alcoholism is a serious addiction that can lead to various health complications such as liver fibrosis, steatosis, and cirrhosis. Carvacrol is present in many plant-based essential oils and used as a preservative in the food industry. In this study, we have investigated the hepatoprotective role of carvacrol against ethanol-induced liver toxicity in mice. To determine the effect of carvacrol on liver injury parameters, 5 doses of 50% ethanol (10â¯mL/kg body weight) were orally administered every 12â¯h for inducing the hepatotoxicity in experimental mice. Interestingly, carvacrol pre-treatment (50 and 100â¯mg/kg) reversed the ethanol-induced effects on liver function, antioxidant markers, matrix metalloproteinases activities, and histological changes. Moreover, carvacrol binds to the active pocket of cytochrome P450 (Cyt P450) and inhibits its expression. Thus, our finding suggests carvacrol can be used as an adjuvant for the amelioration of alcohol-induced hepatotoxicity.
Assuntos
Inibidores das Enzimas do Citocromo P-450/uso terapêutico , Fígado Gorduroso Alcoólico/prevenção & controle , Monoterpenos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Animais , Autofagia/efeitos dos fármacos , Consumo Excessivo de Bebidas Alcoólicas , Domínio Catalítico , Cimenos , Inibidores das Enzimas do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/química , Sistema Enzimático do Citocromo P-450/metabolismo , Fígado Gorduroso Alcoólico/patologia , Fígado/patologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Metaloproteinases da Matriz/metabolismo , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Monoterpenos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/metabolismo , Ligação ProteicaRESUMO
Chronic alcohol consumption causes liver injury, inflammation and fibrosis, thereby increasing morbidity and mortality. Paradoxically, modest drinking is believed to confer metabolic improvement, but the underlying mechanism remains elusive. Here, we have identified a novel hepatoprotective brain/brown adipose tissue (BAT)/liver axis. Alcohol consumption or direct alcohol administration into the brain stimulated hypothalamic neural circuits and sympathetic nerves innervating BAT, and dramatically increased BAT uncoupling protein 1 (Ucp1) expression and activity in a BAT sympathetic nerve-dependent manner. BAT and beige fat oxidized fatty acids to fuel Ucp1-mediated thermogenesis, thereby inhibiting lipid trafficking into the liver. BAT also secreted several adipokines, including adiponectin that suppressed hepatocyte injury and death. Genetic deletion of Ucp1 profoundly augmented alcohol-induced liver steatosis, injury, inflammation and fibrosis in male and female mice. Conversely, activation of BAT and beige fat through cold exposure suppressed alcoholic liver disease development. Our results unravel an unrecognized brain alcohol-sensing/sympathetic nerve/BAT/liver axis that counteracts liver steatosis and injury.
Assuntos
Tecido Adiposo Marrom/metabolismo , Etanol/efeitos adversos , Fígado Gorduroso Alcoólico/metabolismo , Fígado/metabolismo , Tecido Adiposo Bege/metabolismo , Tecido Adiposo Bege/patologia , Tecido Adiposo Marrom/patologia , Animais , Temperatura Baixa , Etanol/farmacologia , Fígado Gorduroso Alcoólico/genética , Fígado Gorduroso Alcoólico/patologia , Feminino , Hipotálamo/metabolismo , Hipotálamo/patologia , Fígado/patologia , Masculino , Camundongos , Camundongos Knockout , Sistema Nervoso Simpático/metabolismo , Sistema Nervoso Simpático/patologia , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismoRESUMO
BACKGROUND: Excess alcohol exposure leads to alcoholic liver disease (ALD). Pueraria lobata (PUE) and Silybum marianum (SIL) are two well-known hepatoprotective herbal remedies with various activities. The possible effect of combination of PUE and SIL on ALD has not been elucidated yet. PURPOSE: We aimed to demonstrate that the combination of PUE and SIL prevents against alcoholic liver injury in mice using a model of chronic-plus-single-binge ethanol feeding. STUDY DESIGN: Male C57BL/6 mice were randomly divided into five groups (nâ¯=â¯8-10), namely the control group (CON), ethanol-induced liver injury group (ETH), 150â¯mg/kg PUE treated group (PUE), 60â¯mg/kg SIL treated group (SIL), 210â¯mg/kg PUE+SIL treatment group (PUE+SIL). Except control group, all animals were fed a modified Lieber-DeCarli ethanol liquid diet for 10 days. While, control group received Lieber-DeCarli control diet containing isocaloric maltose dextrin substituted for ethanol. On day 11, the mice orally received a single dose of 31.5% (v/v) ethanol (5â¯g/kg BW) or an isocaloric maltose solution. RESULTS: Ethanol exposure caused liver injury, as demonstrated by remarkably increased plasma parameters, histopathological changes, the increased lipid accumulation, oxidative stress and inflammation in liver. These alterations were ameliorated by the treatments of PUE, SIL and PUE+SIL. While, the PUE+SIL treatment showed the most effective protection, which was associated with reducing alcohol-induced hepatic steatosis via upregulating LKB1/AMPK/ACC signaling, and inhibiting hepatic inflammation via LPS-triggered TLR4-mediated NF-κB signaling pathway. Our results also indicated that the hepatoprotective effects of SIL+PUE might mainly attribute to the protection of SIL and PUE alone in alcohol-induced hepatic steatosis and hepatic inflammation, respectively. CONCLUSION: These findings also suggest that the combination of PUE and SIL has a potential to be developed as a functional food for the management of ALD.
Assuntos
Hepatopatias Alcoólicas/prevenção & controle , Substâncias Protetoras/farmacologia , Pueraria/química , Transdução de Sinais/efeitos dos fármacos , Silybum marianum/química , Animais , Antioxidantes/metabolismo , Modelos Animais de Doenças , Quimioterapia Combinada , Etanol/efeitos adversos , Fígado Gorduroso Alcoólico/patologia , Fígado Gorduroso Alcoólico/prevenção & controle , Medicina Herbária , Inflamação/tratamento farmacológico , Fígado/efeitos dos fármacos , Fígado/patologia , Hepatopatias Alcoólicas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Plantas Medicinais , Substâncias Protetoras/química , Distribuição Aleatória , Regulação para Cima/efeitos dos fármacosRESUMO
A variety of dietary natural products have shown hepatoprotective effects. Increasing evidence has also demonstrated that gut microorganisms play an important role in the hepatoprotection contributed by natural products. Gut dysbiosis could increase permeability of the gut barrier, resulting in translocated bacteria and leaked gut-derived products, which can reach the liver through the portal vein and might lead to increased oxidative stress and inflammation, thereby threatening liver health. Targeting gut microbiota modulation represents a promising strategy for hepatoprotection. Many natural products could protect the liver from various injuries or mitigate hepatic disorders by reverting gut dysbiosis, improving intestinal permeability, altering the primary bile acid, and inhibiting hepatic fatty acid accumulation. The mechanisms underlying their beneficial effects also include reducing oxidative stress, suppressing inflammation, attenuating fibrosis, and decreasing apoptosis. This review discusses the hepatoprotective effects of dietary natural products via modulating the gut microbiota, mainly focusing on the mechanisms of action.
Assuntos
Produtos Biológicos/farmacologia , Dieta , Fígado Gorduroso/microbiologia , Microbioma Gastrointestinal , Neoplasias Hepáticas/microbiologia , Fígado , Probióticos , Apoptose/efeitos dos fármacos , Produtos Biológicos/uso terapêutico , Disbiose/complicações , Disbiose/tratamento farmacológico , Ácidos Graxos/metabolismo , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado Gorduroso/prevenção & controle , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/microbiologia , Fígado Gorduroso Alcoólico/patologia , Fígado Gorduroso Alcoólico/prevenção & controle , Fibrose/tratamento farmacológico , Humanos , Inflamação/tratamento farmacológico , Intestinos/efeitos dos fármacos , Intestinos/microbiologia , Intestinos/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/microbiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêuticoRESUMO
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-DawleyRESUMO
Alcohol-induced hepatic steatosis and inflammation are key drivers of alcohol-induced liver injury, mainly caused by oxidative stress. The roots bark of Ulmus davidiana var. japonica is well known for its substantial antioxidative and antitumorigenic potency. In this study, we examined whether this plant can ameliorate alcohol-induced liver injuries characterized by hepatic steatosis and inflammation through its antioxidative activity. C57BL/6J mice were treated with the root bark extract of Ulmus davidiana var. japonica (RUE; 100 mg of extract/kg bodyweight; oral gavage) and alcohol (1 g/kg of bodyweight; oral gavage) for 5 days. Markers of acute alcohol-induced hepatic steatosis were determined and putative molecular mechanisms responsible for the protection of RUE were investigated. RUE noticeably protected against alcohol-induced hepatic steatosis and inflammation. Reactive oxygen species (ROS), over-produced by alcohol, negatively orchestrated various signaling pathways involved in the lipid metabolism and inflammation. These pathways were restored through the ROS scavenging activity of RUE in the liver. In particular, the expression of lipogenic genes (e.g., SREBP-1, ACC, and FAS) and inflammatory cytokines (e.g., IL-1ß, and NF-κB p65) significantly decreased with RUE treatment. Conversely, the expression of fatty acid oxidation-related genes (e.g., SIRT1, AMPKα, and PGC1α) were increased in mice treated with RUE. Thus, the results indicate that RUE counteracts and thus attenuates alcoholic hepatic steatosis onset in mice, possibly by suppressing ROS-mediated steatosis and inflammation.
Assuntos
Fígado Gorduroso Alcoólico/tratamento farmacológico , Casca de Planta/química , Extratos Vegetais/uso terapêutico , Raízes de Plantas/química , Espécies Reativas de Oxigênio/metabolismo , Ulmus/química , Animais , Biomarcadores/metabolismo , Catequina/análise , Citocinas/metabolismo , Etanol , Fígado Gorduroso Alcoólico/genética , Fígado Gorduroso Alcoólico/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Inflamação/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos Endogâmicos C57BL , Proteínas Quinases Ativadas por Mitógeno/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Transdução de Sinais/efeitos dos fármacosRESUMO
Chronic alcohol consumption leads to hepatic lipid accumulation and alcoholic fatty liver disease. Previously, we demonstrated that barley sprout extract, which contains saponarin as an active compound, reduces hepatic steatosis. In this study, we investigated the effect of barley sprout extracts (BSE) on hepatic lipid accumulation in a mouse model of alcoholic fatty liver disease. Seven-week-old C57BL/6 mice were fed an alcohol-containing diet (5% ethanol) and a low or high dose of BSE (100 or 200mg/kg body weight, respectively) for 10days. The high dose of BSE significantly decreased hepatic lipid accumulation compared with the ethanol-only control group. In the second animal study, mice were fed an alcohol-containing diet for 10days, followed by a 45% high-fat diet with oral administration of BSE (100 or 200mg/day/kg body weight) for 4weeks. Mice in both BSE-fed groups showed reduced hepatic steatosis. In the livers of mice fed BSE, phosphorylation of AMP-activated protein kinase (AMPK) was increased, and expression of hepatic autophagy markers was elevated. In cultured hepatocytes, BSE (200µg/mL) increased the rate of fatty acid oxidation and reduced that of fatty acid synthesis. Taken together, these findings suggest that BSE promotes degradation of lipid droplets and subsequent activation of fat oxidation by activating AMPK in the liver, thus protecting against development of hepatic steatosis in alcohol-fed mice. Saponarin, a major flavonoid in BSE and an activator of AMPK, increased the activity of microsomal triglyceride transfer protein, which suggests that the reduction in hepatic triglyceride levels was mediated by this component of BSE. In conclusion, BSE ameliorated hepatic steatosis in a mouse model of ethanol-induced fatty liver by activating AMPK, an effect possibly mediated by the saponarin component.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Etanol/efeitos adversos , Fígado Gorduroso Alcoólico/tratamento farmacológico , Fígado Gorduroso/tratamento farmacológico , Hordeum/química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Extratos Vegetais/farmacologia , Administração Oral , Animais , Autofagia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado Gorduroso Alcoólico/patologia , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Corpos Cetônicos/análise , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução , Fosforilação , Extratos Vegetais/administração & dosagem , Triglicerídeos/sangueRESUMO
Ethanol abuse is a serious public health problem that is associated with several stages of alcoholic liver disease (ALD) and a high incidence of morbidity and mortality. Alcoholic fatty liver disease (AFLD), the earliest stage of ALD, is a multifactorial injury that involves oxidative stress and disruptions of lipid metabolism. Although benign and reversible, no pharmacological treatments are available for this condition. In the present study, we induced AFLD in mice with 10% ethanol and a low-protein diet and then orally treated them with a hydroethanolic extract of Baccharis trimera (HEBT; 30 mg kg-1). HEBT reversed ethanol-induced oxidative stress in the liver, reduced lipoperoxidation, normalized GPx, GST, SOD and Cat activity, and GSH and total ROS levels. The reverser effect of HEBT was observed upon ethanol-induced increases in the levels of plasma and hepatic triglycerides, plasma cholesterol, plasma high-density lipoprotein, and plasma and hepatic low-density lipoprotein. Moreover, HEBT increased fecal triglycerides and reduced the histological ethanol-induced lesions in the liver. HEBT also altered the expression of genes that are involved in ethanol metabolism, antioxidant systems, and lipogenesis (i.e., CypE1, Nrf2, and Scd1, respectively). No signs of toxicity were observed in HEBT-treated mice. We propose that HEBT may be a promising pharmacological treatment for AFLD.
Assuntos
Baccharis/química , Etanol/química , Fígado Gorduroso Alcoólico/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Água/química , Animais , Biomarcadores/metabolismo , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Fígado Gorduroso Alcoólico/sangue , Fígado Gorduroso Alcoólico/genética , Fígado Gorduroso Alcoólico/patologia , Fezes/química , Comportamento Alimentar/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/ultraestrutura , Masculino , Camundongos , Modelos Biológicos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologiaRESUMO
BACKGROUND: Mitochondrial dysfunction and bioenergetic stress play an important role in the etiology of alcoholic liver disease. Previous studies from our laboratory show that the primary methyl donor S-Adenosylmethionine (SAM) minimizes alcohol-induced disruptions in several mitochondrial functions in the liver. Herein, we expand on these earlier observations to determine whether the beneficial actions of SAM against alcohol toxicity extend to changes in the responsiveness of mitochondrial respiration to inhibition by nitric oxide (NO), induction of the mitochondrial permeability transition (MPT) pore, and the hypoxic state of the liver. METHODS: For this, male Sprague-Dawley rats were pair-fed control and alcohol-containing liquid diets with and without SAM for 5 weeks and liver hypoxia, mitochondrial respiration, MPT pore induction, and NO-dependent control of respiration were examined. RESULTS: Chronic alcohol feeding significantly enhanced liver hypoxia, whereas SAM supplementation attenuated hypoxia in livers of alcohol-fed rats. SAM supplementation prevented alcohol-mediated decreases in mitochondrial state 3 respiration and cytochrome c oxidase activity. Mitochondria isolated from livers of alcohol-fed rats were more sensitive to calcium-mediated MPT pore induction (i.e., mitochondrial swelling) than mitochondria from pair-fed controls, whereas SAM treatment normalized sensitivity for calcium-induced swelling in mitochondria from alcohol-fed rats. Liver mitochondria from alcohol-fed rats showed increased sensitivity to NO-dependent inhibition of respiration compared with pair-fed controls. In contrast, mitochondria isolated from the livers of SAM treated alcohol-fed rats showed no change in the sensitivity to NO-mediated inhibition of respiration. CONCLUSION: Collectively, these findings indicate that the hepato-protective effects of SAM against alcohol toxicity are mediated, in part, through a mitochondrial mechanism involving preservation of key mitochondrial bioenergetic parameters and the attenuation of hypoxic stress.
Assuntos
Fígado Gorduroso Alcoólico/metabolismo , Hipóxia/metabolismo , Fígado/metabolismo , Mitocôndrias Hepáticas/metabolismo , Biogênese de Organelas , S-Adenosilmetionina/metabolismo , Animais , Biomarcadores , Respiração Celular , Modelos Animais de Doenças , Complexo I de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Etanol/efeitos adversos , Etanol/metabolismo , Fígado Gorduroso Alcoólico/patologia , Fígado/efeitos dos fármacos , Fígado/patologia , Mitocôndrias Hepáticas/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Óxido Nítrico/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , S-Adenosilmetionina/farmacologiaRESUMO
PURPOSE: To explore the effects of the combination of blueberry juice and probiotics on the apoptosis of alcoholic fatty liver disease (AFLD). METHODS: Healthy C57BL/6J mice were used in the control group (CG). AFLD mice models were established with Lieber-DeCarli ethanol diet and evenly assigned to six groups with different treatments: MG (model), SI (SIRT1 [sirtuin type 1] small interfering RNA [siRNA]), BJ (blueberry juice), BJSI (blueberry juice and SIRT1 siRNA), BJP (blueberry juice and probiotics), and BJPSI (blueberry juice, probiotics, and SIRT1 siRNA). Hepatic tissue was observed using hematoxylin and eosin (HE) and Oil Red O (ORO) staining. Biochemical indexes of the blood serum were analyzed. The levels of SIRT1, caspase-3, forkhead box protein O1 (FOXO1), FasL (tumor necrosis factor ligand superfamily member 6), BAX, and Bcl-2 were measured by reverse transcription-polymerase chain reaction and Western blotting. RESULTS: HE and ORO staining showed that the hepatocytes were heavily destroyed with large lipid droplets in MG and SI groups, while the severity was reduced in the CG, BJ, and BJP groups (P<0.05). The levels of superoxide dismutase (SOD), reduced glutathione (GSH), and high-density lipoprotein-cholesterol (HDL-C) were increased in BJ and BJP groups when compared with the model group (P<0.05). In contrast, the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), total triglycerides (TGs), total cholesterol, low-density lipoprotein-cholesterol (LDL-C), and malondialdehyde (MDA) were lower in BJ and BJP groups than in the model group (P<0.05). The level of SIRT1 was increased, while the levels of FOXO1, phosphorylated FOXO1, acetylated FOXO1, FasL, caspase-3, BAX, and Bcl-2 were decreased in CG, BJ, and BJP groups (P<0.05). Meanwhile, SIRT1 silence resulted in increase of the levels of FOXO1, phosphorylated FOXO1, acetylated FOXO1, FasL, caspase-3, BAX, and Bcl-2. CONCLUSION: The combination of blueberry juice and probiotics reduces apoptosis in AFLD by suppressing FOXO1, phosphorylated FOXO1, acetylated FOXO1, FasL, caspase-3, BAX, and Bcl-2 via the upregulation of SIRT1.
Assuntos
Apoptose/efeitos dos fármacos , Bebidas , Mirtilos Azuis (Planta)/química , Fígado Gorduroso Alcoólico/dietoterapia , Probióticos/farmacologia , Probióticos/uso terapêutico , Sirtuína 1/metabolismo , Animais , Relação Dose-Resposta a Droga , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/patologia , Feminino , Camundongos , Camundongos Endogâmicos C57BLAssuntos
Ácidos Docosa-Hexaenoicos/administração & dosagem , Fígado Gorduroso Alcoólico/dietoterapia , Animais , Citocromo P-450 CYP2E1/metabolismo , Suplementos Nutricionais , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/patologia , Fígado/metabolismo , Fígado/patologia , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , PPAR alfa/metabolismo , Triglicerídeos/sangue , Triglicerídeos/metabolismoRESUMO
Chronic ethanol-induced downregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1ß) affect hepatic lipid oxidation and lipogenesis, respectively, leading to fatty liver injury. Low-ω3 fatty acid (Low-ω3FA) that primarily regulates PGC1α and soy protein (SP) that seems to have its major regulatory effect on PGC1ß were evaluated for their protective effects against ethanol-induced hepatosteatosis in rats fed with Lieber-deCarli control or ethanol liquid diets with high or low ω3FA fish oil and soy protein. Low-ω3FA and SP opposed the actions of chronic ethanol by reducing serum and liver lipids with concomitant decreased fatty liver. They also prevented the downregulation of hepatic Sirtuin 1 (SIRT1) and PGC1α and their target fatty acid oxidation pathway genes and attenuated the upregulation of hepatic PGC1ß and sterol regulatory element-binding protein 1c (SREBP1c) and their target lipogenic pathway genes via the phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK). Thus, these two novel modulators attenuate ethanol-induced hepatosteatosis and consequent liver injury potentially by regulating the two opposing lipid oxidation and lipogenic pathways.