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1.
Life Sci ; 255: 117721, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32360617

RESUMO

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/metabolismo
2.
Chem Biol Interact ; 322: 109059, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32171850

RESUMO

Fatty liver is the earliest and most common response of the liver to consumption of excessive alcohol. Steatosis can predispose the fatty liver to develop progressive liver damage. Chief among the many mechanisms involved in development of hepatic steatosis is dysregulation of insulin-mediated adipose tissue metabolism. Particularly, it is the enhanced adipose lipolysis-derived free fatty acids and their delivery to the liver that ultimately results in hepatic steatosis. The adipose-liver axis is modulated by hormones, particularly insulin and adiponectin. In recent studies, we demonstrated that an alcohol-induced increase in serum ghrelin levels impairs insulin secretion from pancreatic ß-cells. The consequent reduction in circulating insulin levels promotes adipose lipolysis and mobilization of fatty acids to the liver to ultimately contribute to hepatic steatosis. Because many tissues, including adipose tissue, express ghrelin receptor we hypothesized that ghrelin may directly affect energy metabolism in adipocytes. We have exciting new preliminary data which shows that treatment of premature 3T3-L1 adipocytes with ghrelin impairs adipocyte differentiation and inhibits lipid accumulation in the tissue designed to store energy in the form of fat. We further observed that ghrelin treatment of differentiated adipocytes significantly inhibited secretion of adiponectin, a hepatoprotective hormone that reduces lipid synthesis and promotes lipid oxidation. These results were corroborated by our observations of a significant increase in serum adiponectin levels in ethanol-fed rats treated with a ghrelin receptor antagonist verses the un-treated ethanol-fed rats. Interestingly, in adipocytes, ghrelin also increases secretion of interleukin-6 (IL-6) and CCL2 (chemokine [C-C motif] ligand 2), cytokines which promote hepatic inflammation and progression of liver disease. To summarize, the alcohol-induced increase in serum ghrelin levels dysregulates adipose-liver interaction and promotes hepatic steatosis by increasing the free fatty acid released from adipose for hepatic uptake, and by altering adiponectin and cytokine secretion. Taken together, our data indicates that targeting the activity of ghrelin may be a powerful treatment strategy.


Assuntos
Tecido Adiposo/metabolismo , Fígado Gorduroso Alcoólico/patologia , Grelina/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Células 3T3-L1 , Adipocinas/metabolismo , Adiponectina/sangue , Adiponectina/metabolismo , Animais , Diferenciação Celular/efeitos dos fármacos , Quimiocina CCL2/metabolismo , Etanol/farmacologia , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/veterinária , Interleucina-6/metabolismo , Masculino , Camundongos , Oligopeptídeos/farmacologia , PPAR gama/metabolismo , Ratos , Ratos Wistar
3.
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
4.
Am J Physiol Gastrointest Liver Physiol ; 318(3): G428-G438, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31928222

RESUMO

Enhanced free fatty acid (FFA) flux from adipose tissue (AT) to liver plays an important role in the development of nonalcoholic steatohepatitis (NASH) and alcohol-associated liver disease (AALD). We determined the effectiveness of nanoformulated superoxide dismutase 1 (Nano) in attenuating liver injury in a mouse model exhibiting a combination of NASH and AALD. Male C57BL6/J mice were fed a chow diet (CD) or a high-fat diet (HF) for 10 wk followed by pair feeding of the Lieber-DeCarli control (control) or ethanol (ET) diet for 4 wk. Nano was administered once every other day for the last 2 wk of ET feeding. Mice were divided into 1) CD + control diet (CD + Cont), 2) high-fat diet (HF) + control diet (HF + Cont), 3) HF + Cont + Nano, 4) HF + ET diet (HF + ET), and 5) HF + ET + Nano. The total fat mass, visceral AT mass (VAT), and VAT perilipin 1 content were significantly lower only in HF + ET-fed mice but not in HF + ET + Nano-treated mice compared with controls. The HF + ET-fed mice showed an upregulation of VAT CYP2E1 protein, and Nano abrogated this effect. We noted a significant rise in plasma FFAs, ALT, and monocyte chemoattractant protein-1 in HF + ET-fed mice, which was blunted in HF + ET + Nano-treated mice. HF + ET-induced increases in hepatic steatosis and inflammatory markers were attenuated upon Nano treatment. Nano reduced hepatic CYP2E1 and enhanced catalase levels in HF + ET-fed mice with a concomitant increase in SOD1 protein and activity in liver. Nano was effective in attenuating AT and liver injury in mice exhibiting a combination of NASH and AALD, partly via reduced CYP2E1-mediated ET metabolism in these organs.NEW & NOTEWORTHY Increased free fatty acid flux from adipose tissue (AT) to liver accompanied by oxidative stress promotes nonalcoholic steatohepatitis (NASH) and alcohol-associated liver injury (AALD). Obesity increases the severity of AALD. Using a two-hit model involving a high-fat diet and chronic ethanol feeding to mice, and treating them with nanoformulated superoxide dismutase (nanoSOD), we have shown that nanoSOD improves AT lipid storage, reduces CYP2E1 in AT and liver, and attenuates the combined NASH/AALD in mice.


Assuntos
Citocromo P-450 CYP2E1/metabolismo , Fígado Gorduroso Alcoólico/prevenção & controle , Gordura Intra-Abdominal/efeitos dos fármacos , Fígado/efeitos dos fármacos , Nanopartículas , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Superóxido Dismutase-1/administração & dosagem , Adiposidade/efeitos dos fármacos , Animais , Catalase/metabolismo , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Modelos Animais de Doenças , Composição de Medicamentos , Fígado Gorduroso Alcoólico/enzimologia , Fígado Gorduroso Alcoólico/genética , Fígado Gorduroso Alcoólico/patologia , Regulação da Expressão Gênica , Gordura Intra-Abdominal/enzimologia , Gordura Intra-Abdominal/patologia , Lipólise/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Nanomedicina , Hepatopatia Gordurosa não Alcoólica/enzimologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo/efeitos dos fármacos , Perilipina-1/genética , Perilipina-1/metabolismo , Transdução de Sinais , Superóxido Dismutase-1/química
5.
Biochim Biophys Acta Mol Cell Biol Lipids ; 1864(12): 158521, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31479733

RESUMO

Although SREBP-1c regulates key enzymes required for hepatic de novo lipogenesis, the mechanisms underlying transcriptional regulation of SREBP-1c in pathogenesis of alcoholic fatty liver is still incompletely understood. In this study, we investigated the role of ERRγ in alcohol-mediated hepatic lipogenesis and examined the possibility to ameliorate alcoholic fatty liver through its inverse agonist. Hepatic ERRγ and SREBP-1c expression was increased by alcohol-mediated activation of CB1 receptor signaling. Deletion and mutation analyses of the Srebp-1c gene promoter showed that ERRγ directly regulates Srebp-1c gene transcription via binding to an ERR-response element. Overexpression of ERRγ significantly induced SREBP-1c expression and fat accumulation in liver of mice, which were blocked in Srebp-1c-knockout hepatocytes. Conversely, liver-specific ablation of ERRγ gene expression attenuated alcohol-mediated induction of SREBP-1c expression. Finally, an ERRγ inverse agonist, GSK5182, significantly ameliorates fatty liver disease in chronically alcohol-fed mice through inhibition of SREBP-1c-mediated fat accumulation. ERRγ mediates alcohol-induced hepatic lipogenesis by upregulating SREBP-1c expression, which can be blunted by the inverse agonist for ERRγ, which may be an attractive therapeutic strategy for the treatment of alcoholic fatty liver disease in human.


Assuntos
Fígado Gorduroso Alcoólico/genética , Receptores Estrogênicos/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Ativação Transcricional , Animais , Células Cultivadas , Fígado Gorduroso Alcoólico/patologia , Células Hep G2 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Receptores Estrogênicos/análise , Proteína de Ligação a Elemento Regulador de Esterol 1/análise , Regulação para Cima
6.
An Acad Bras Cienc ; 91(3): e20180646, 2019 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-31411259

RESUMO

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 Genética/genética , Triglicerídeos/metabolismo
7.
J Dig Dis ; 20(9): 476-485, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31298798

RESUMO

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


Assuntos
Endocitose/fisiologia , Fígado Gorduroso Alcoólico/fisiopatologia , Mucosa Intestinal/fisiopatologia , Ocludina/fisiologia , Animais , Células CACO-2 , Modelos Animais de Doenças , Endocitose/efeitos dos fármacos , Etanol/farmacologia , Fígado Gorduroso Alcoólico/patologia , Humanos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/ultraestrutura , Camundongos Endogâmicos C57BL , Microscopia Eletrônica , Microscopia de Fluorescência , Ocludina/metabolismo , Permeabilidade , Junções Íntimas/efeitos dos fármacos , Junções Íntimas/fisiologia , Junções Íntimas/ultraestrutura
8.
Food Chem Toxicol ; 131: 110582, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31220535

RESUMO

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 (10 mL/kg body weight) were orally administered every 12 h for inducing the hepatotoxicity in experimental mice. Interestingly, carvacrol pre-treatment (50 and 100 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 , Bebedeira , 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 Proteica
9.
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
10.
Phytomedicine ; 58: 152824, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30836218

RESUMO

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 (n = 8-10), namely the control group (CON), ethanol-induced liver injury group (ETH), 150 mg/kg PUE treated group (PUE), 60 mg/kg SIL treated group (SIL), 210 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 (5 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 , Cardo-Mariano/química , Substâncias Protetoras/farmacologia , Pueraria/química , Transdução de Sinais/efeitos dos fármacos , 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 fármacos
11.
Biochem Biophys Res Commun ; 512(1): 119-124, 2019 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-30876690

RESUMO

CYP2A5 is a major enzyme responsible for nicotine and cotinine metabolism in mice. Nicotine and cotinine enhance alcoholic fatty liver in wild type (WT) mice but not in CYP2A5 knockout (KO) mice, and reactive oxygen species (ROS) generated during the CYP2A5-mediated metabolism contributes to the enhancing effect. In combination with ethanol, nicotine and cotinine increased lipid peroxidation end product 4-hydroxynonenal (HNE) in WT mice but not in KO mice. In ethanol-fed KO mice, only 5 and 10 genes were regulated by nicotine and cotinine, respectively. However, in ethanol-fed WT mice, 59 and 104 genes were regulated by nicotine and cotinine, respectively, and 7 genes were up-regulated by both nicotine and cotinine. Plin 2 and Cdkn1a are among the 7 genes. Plin2 encodes adipose differentiation-related protein (ADRP), a lipid droplet-associated protein, which was confirmed to be increased by nicotine and cotinine in WT mice but not in KO mice. Cdkn1a encodes P21 and elevated P21 in nuclei was also confirmed. HNE can increase P21 and P21 inhibit cell proliferation. Consistently, hepatocyte proliferation markers proliferating cell nuclear antigen (PCNA) and Ki67 were decreased in WT mice but not in KO mice by nicotine/ethanol and cotinine/ethanol, respectively. These results suggest that inhibition of liver proliferation via a ROS-HNE-P21 pathway is involved in nicotine- and cotinine-enhanced alcoholic fatty liver.


Assuntos
Aldeídos/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/patologia , Animais , Hidrocarboneto de Aril Hidroxilases/deficiência , Hidrocarboneto de Aril Hidroxilases/genética , Proliferação de Células/efeitos dos fármacos , Cotinina/administração & dosagem , Inibidor de Quinase Dependente de Ciclina p21/genética , Família 2 do Citocromo P450/deficiência , Família 2 do Citocromo P450/genética , Modelos Animais de Doenças , Fígado Gorduroso Alcoólico/genética , Feminino , Hepatócitos/metabolismo , Hepatócitos/patologia , Regeneração Hepática/efeitos dos fármacos , Regeneração Hepática/genética , Camundongos , Camundongos Knockout , Nicotina/administração & dosagem , Perilipina-2/genética , Perilipina-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Regulação para Cima/efeitos dos fármacos
12.
J Clin Invest ; 129(6): 2305-2317, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30888335

RESUMO

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/metabolismo
13.
Am J Physiol Gastrointest Liver Physiol ; 316(4): G509-G518, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30714813

RESUMO

We are investigating the changes in hepatic lipid catabolism that contribute to alcohol-induced fatty liver. Following chronic ethanol (EtOH) exposure, abstinence from alcohol resolves steatosis. Here, we investigated the hepatocellular events that lead to this resolution by quantifying specific catabolic parameters that returned to control levels after EtOH was withdrawn. We hypothesized that, after its chronic consumption, EtOH withdrawal reactivates lipid catabolic processes that restore lipostasis. Male Wistar rats were fed control and EtOH liquid diets for 6 wk. Randomly chosen EtOH-fed rats were then fed control diet for 7 days. Liver triglycerides (TG), lipid peroxides, key markers of fatty acid (FA) metabolism, lipophagy, and autophagy were quantified. Compared with controls, EtOH-fed rats had higher hepatic triglycerides, lipid peroxides, and serum free fatty acids (FFA). The latter findings were associated with higher levels of FA transporters (FATP 2, 4, and 5) but lower quantities of peroxisome proliferator-activated receptor-α (PPAR-α), which governs FA oxidation. EtOH-fed animals also had lower nuclear levels of the autophagy-regulating transcription factor EB (TFEB), associated with lower hepatic lipophagy and autophagy. After EtOH-fed rats were refed control diet for 7 days, their serum FFA levels and those of FATPs fell to control (normal) levels, whereas PPAR-α levels rose to normal. Hepatic TG and malondialdehyde levels in EtOH-withdrawn rats declined to near control levels. EtOH withdrawal restored nuclear TFEB content, hepatic lipophagy, and autophagy activity to control levels. EtOH withdrawal reversed aberrant FA metabolism and restored lysosomal function to promote resolution of alcohol-induced fatty liver. NEW & NOTEWORTHY Here, using an animal model, we show mechanisms of reversal of fatty liver and injury following EtOH withdrawal. Our data indicate that reactivation of autophagy and lysosome function through the restoration of transcription factor EB contribute to reversal of fatty liver and injury following EtOH withdrawal.


Assuntos
Proteínas Relacionadas à Autofagia/metabolismo , Etanol/farmacocinética , Fígado Gorduroso Alcoólico , Hepatócitos/metabolismo , Regeneração Hepática/fisiologia , Abstinência de Álcool , Animais , Autofagia/fisiologia , Depressores do Sistema Nervoso Central/farmacocinética , Proteína Receptora de AMP Cíclico/metabolismo , Proteínas de Transporte de Ácido Graxo/metabolismo , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/patologia , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Ratos , Ratos Wistar
14.
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
15.
Alcohol ; 77: 147-154, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30660600

RESUMO

Alcohol has long been acknowledged to be one of the main causes of hepatic disorders. In recent years, with the advancements in antiviral therapies, the relative proportion that alcoholic liver disease contributes among liver diseases has increased, necessitating the establishment of a useful model for the elucidation of the mechanism of its development. In this study, we developed a model of alcoholic liver disease using medaka, a small-sized fish known for its usefulness as a model organism. After rearing medaka in water containing ethanol for 2 months, fat deposition was observed in their livers. In addition, on the basis of the metabolomic analysis of the liver to evaluate metabolic changes resulting from ethanol administration, the increases in ethanol metabolites and changes in lipid metabolism were assessed. As minimally invasive evaluation methods, transparent medaka enabled the macroscopic evaluation of the progression of alcoholic fatty liver, while ultrasonography enabled the quantification of the fatty deposition of the liver. Furthermore, intestinal microbiota, the composition of which is important for the development of alcoholic liver disease, was evaluated. Microbiota changes similar to those of humans with alcoholic liver disease were observed. This study demonstrates that the development of liver disease and its amelioration through drugs can be easily evaluated using the present model or modifications thereof. Thus, this study is expected to be useful in the elucidation of liver disease development.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Etanol/toxicidade , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/patologia , Metabolismo dos Lipídeos/fisiologia , Fatores Etários , Animais , Peixes , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino
16.
Clin Liver Dis ; 23(1): 11-23, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30454825

RESUMO

Excessive alcohol consumption can lead to a spectrum of liver histopathology, including steatosis, steatohepatitis, foamy degeneration, fatty liver with cholestasis, and cirrhosis. Although variability in sampling and pathologist interpretation are of some concern, liver biopsy remains the gold standard for distinguishing between steatohepatitis and noninflammatory histologic patterns of injury that can also cause the clinical syndrome of alcohol-related hepatitis. Liver biopsy is not routinely recommended to ascertain a diagnosis of alcohol-related liver disease in patients with an uncertain alcohol history, because the histologic features of alcohol-related liver diseases can be found in other diseases, including nonalcoholic steatohepatitis and drug-induced liver injury.


Assuntos
Hepatopatias Alcoólicas/patologia , Fígado/patologia , Biópsia , Colestase/patologia , Fígado Gorduroso Alcoólico/patologia , Hepatite Alcoólica/patologia , Humanos , Cirrose Hepática Alcoólica/patologia
17.
Hum Exp Toxicol ; 38(1): 65-81, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29792338

RESUMO

It is known that women develop alcoholic liver injury more rapidly and have a lower alcohol toxic threshold than men. However, the detailed molecular mechanisms remain unclear. The precise mechanism responsible for the sex difference needs to be determined. Female and male mice were given ethanol by intragastric infusion every day for 4 weeks. The pathological changes were detected by hematoxylin-eosin, Sirius red, oil red O, periodic acid-Schiff, and Hochest33258 staining in the liver of female and male mice. The related gene and protein expression of hepatocytes stress, proliferation and apoptosis, glycogen synthesis, lipid metabolism, and hepatic fibrosis were also systematically analyzed in the female and male mice. Livers from ethanol-treated female mice had more serious hepatocyte necrosis, liver fibrosis ( P < 0.01), substantial micro/macrovesicular steatosis ( p < 0.01), glycogen consumption ( p < 0.05), and hepatocytes apoptosis ( p < 0.05) than ethanol-treated male mice. The expression of heat shock protein 27 (HSP27), HSP70, proliferating cell nuclear antigen, B-cell lymphoma/leukemia-2 (Bcl-2), and phosphorylated signal transducer and activators of transcription 3 (p-STAT3) was higher in ethanol-treated male mice than ethanol-treated female mice ( P < 0.05 or P < 0.01). But, the expression of Bax (Bcl-2-associated X protein), Caspase 3, CYP2E1 (cytochrome P4502E1), and transforming growth factor ßl had the contrary results. Our study suggested that ethanol treatment induced more expression of HSP27 and HSP70, faster hepatocyte proliferation, higher level of glycogen, and interleukin-6 signaling pathway activation, but less hepatocyte apoptosis and CYP2E1 expression in male mice than female mice, which could be helpful to understand the molecular mechanism for the influence of sex difference on alcoholic liver injury.


Assuntos
Etanol/toxicidade , Fígado Gorduroso Alcoólico/metabolismo , Caracteres Sexuais , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose/metabolismo , Citocromo P-450 CYP2E1/metabolismo , Fígado Gorduroso Alcoólico/patologia , Feminino , Glicogênio/metabolismo , Proteínas de Choque Térmico HSP27/metabolismo , Proteínas de Choque Térmico HSP70/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Endogâmicos BALB C , Fator de Transcrição STAT3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
18.
PLoS One ; 13(11): e0207011, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30403751

RESUMO

The goal of this project was to establish the effect of alcohol consumption on the circulating levels of the adipose tissue derived protein C1q TNF Related Protein 3 (CTRP3). Adipose tissue secretes several adipokines, such as adiponectin and leptin, which exert a multitude of biological effects important for human health. However, adipose tissue is extremely sensitive to alcohol consumption, leading not only to disrupted fat storage, but also to disruptions in adipokine production. Changes to adipokine secretion could have widespread biological effects and potentially contribute to alcohol-induced ailments, such as alcoholic fatty liver disease (ALD). CTRP3 has been previously demonstrated to attenuate fatty liver disease, and suppression of CTRP3 with alcohol consumption could contribute to development of and progression to alcoholic fatty liver disease. To examine the effect of ethanol consumption on circulating adipokine levels, male and female mice were fed an ethanol containing diet (Lieber-DeCarli 5% (v/v) ethanol diet) for 10-days followed by a single gavage of 5 g/kg ethanol (the NIAAA model), or for 6-weeks with no binge added (chronic model). In female mice, adiponectin levels increased ~2-fold in both models of ethanol feeding, but in male mice increased adiponectin levels were only observed after chronic ethanol feeding. On the other hand, in female mice, circulating CTRP3 levels decreased by ~75% and ~50% in the NIAAA and chronic model, respectively, with no changes observed in the male mice in either feeding model. Leptin levels were unchanged with ethanol feeding regardless of model or sex of mice. Lastly, chronic ethanol feeding led to a significant increase in mortality (~50%) in female mice, with no difference in relative ethanol consumption. These findings indicate that ethanol consumption can dysregulate adipokine secretion, but that the effects vary by sex of animal, method of ethanol consumption, and adipokine examined. These findings also indicate that female mice are more sensitive to the chronic effects of ethanol than male mice. Notably, this is the first study to document the effects of ethanol consumption on the circulating levels of CTRP3. Understanding the impact of excessive alcohol consumption on adipokine production and secretion could identify novel mechanisms of alcohol-induced human disease. However, the mechanism responsible for the increased sensitivity remains elusive.


Assuntos
Adipocinas/sangue , Etanol/administração & dosagem , Adiponectina/sangue , Alcoolismo/sangue , Alcoolismo/mortalidade , Alcoolismo/patologia , Animais , Citocinas/sangue , Dieta , Modelos Animais de Doenças , Fígado Gorduroso Alcoólico/sangue , Fígado Gorduroso Alcoólico/mortalidade , Fígado Gorduroso Alcoólico/patologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores Sexuais , Taxa de Sobrevida , Transaminases/sangue
19.
Alcohol Clin Exp Res ; 42(12): 2313-2325, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30320890

RESUMO

BACKGROUND: There is strong evidence that alcoholism leads to dysbiosis in both humans and animals. However, it is unclear how changes in the intestinal microbiota (IM) relate to ethanol (EtOH)-induced disruption of gut-liver homeostasis. We investigated this issue using selectively bred Sardinian alcohol-preferring (sP) rats, a validated animal model of excessive EtOH consumption. METHODS: Independent groups of male adult sP rats were exposed to the standard, home-cage 2-bottle "EtOH (10% v/v) versus water" choice regimen with unlimited access for 24 h/d (Group Et) for 3 (T1), 6 (T2), and 12 (T3) consecutive months. Control groups (Group Ct) were composed of matched-age EtOH-naïve sP rats. We obtained samples from each rat at the end of each experimental time, and we used blood and colon tissues for intestinal barrier integrity and/or liver pathology assessments and used stool samples for IM analysis with 16S ribosomal RNA gene sequencing. RESULTS: Rats in Group Et developed hepatic steatosis and elevated serum transaminases and endotoxin/lipopolysaccharide (LPS) levels but no other liver pathological changes (i.e., necrosis/inflammation) or systemic inflammation. While we did not find any apparent alteration of the intestinal colonic mucosa, we found that rats in Group Et exhibited significant changes in IM composition compared to the rats in Group Ct. These changes were sustained throughout T1, T2, and T3. In particular, Ruminococcus, Coprococcus, and Streptococcus were the differentially abundant microbial genera at T3. The KEGG Ortholog profile revealed that IM functional modules, such as biosynthesis, transport, and export of LPS, were also enriched in Group Et rats at T3. CONCLUSIONS: We showed that chronic, voluntary EtOH consumption induced liver injury and endotoxemia together with dysbiotic changes in sP rats. This work sets the stage for improving our knowledge of the prevention and treatment of EtOH-related diseases.


Assuntos
Consumo de Bebidas Alcoólicas/psicologia , Endotoxemia/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatias Alcoólicas/microbiologia , Consumo de Bebidas Alcoólicas/genética , Animais , Colo/microbiologia , Fígado Gorduroso Alcoólico/microbiologia , Fígado Gorduroso Alcoólico/patologia , Intestinos/patologia , Lipopolissacarídeos/sangue , Fígado/patologia , Testes de Função Hepática , Masculino , RNA Ribossômico 16S , Ratos , Transaminases/sangue
20.
Nutrients ; 10(10)2018 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-30297615

RESUMO

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 terapêutico
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