RESUMO
BACKGROUND & AIMS: Sirtuin 5, encoded by the SIRT5 gene, is a NAD+-dependent deacylase that modulates mitochondrial metabolic processes through post-translational modifications. In this study, we aimed to examine the impact of the SIRT5 rs12216101 T>G non-coding single nucleotide polymorphism on disease severity in patients with non-alcoholic fatty liver disease (NAFLD). METHODS: The rs12216101 variant was genotyped in 2,606 consecutive European patients with biopsy-proven NAFLD. Transcriptomic analysis, expression of mitochondrial complexes and oxidative stress levels were measured in liver samples from a subset of bariatric patients. Effects of SIRT5 pharmacological inhibition were evaluated in HepG2 cells exposed to excess free fatty acids. Mitochondrial energetics in vitro were investigated by high-performance liquid chromatography. RESULTS: In the whole cohort, the frequency distribution of SIRT5 rs12216101 TT, TG and GG genotypes was 47.0%, 42.3% and 10.7%, respectively. At multivariate logistic regression analysis adjusted for sex, age >50 years, diabetes, and PNPLA3 rs738409 status, the SIRT5 rs12216101 T>G variant was associated with the presence of non-alcoholic steatohepatitis (odds ratio 1.20, 95% CI 1.03-1.40) and F2-F4 fibrosis (odds ratio 1.18; 95% CI 1.00-1.37). Transcriptomic analysis showed that the SIRT5 rs12216101 T>G variant was associated with upregulation of transcripts involved in mitochondrial metabolic pathways, including the oxidative phosphorylation system. In patients carrying the G allele, western blot analysis confirmed an upregulation of oxidative phosphorylation complexes III, IV, V and consistently higher levels of reactive oxygen species, reactive nitrogen species and malondialdehyde, and lower ATP levels. Administration of a pharmacological SIRT5 inhibitor preserved mitochondrial energetic homeostasis in HepG2 cells, as evidenced by restored ATP/ADP, NAD+/NADH, NADP+/NADPH ratios and glutathione levels. CONCLUSIONS: The SIRT5 rs12216101 T>G variant, heightening SIRT5 activity, is associated with liver damage, mitochondrial dysfunction, and oxidative stress in patients with NAFLD. IMPACT AND IMPLICATIONS: In this study we discovered that the SIRT5 rs12216101 T>G variant is associated with higher disease severity in patients with non-alcoholic fatty liver disease (NAFLD). This risk variant leads to a SIRT5 gain-of-function, enhancing mitochondrial oxidative phosphorylation and thus leading to oxidative stress. SIRT5 may represent a novel disease modulator in NAFLD.
Assuntos
Doenças Mitocondriais , Hepatopatia Gordurosa não Alcoólica , Sirtuínas , Humanos , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/complicações , Genótipo , Polimorfismo de Nucleotídeo Único , Fígado , Doenças Mitocondriais/complicações , Trifosfato de Adenosina , Predisposição Genética para Doença , Sirtuínas/genéticaRESUMO
Colorectal Cancer (CRC) is one of the most common cancers accounting for 1.8 million new cases worldwide every year. Therefore, the identification of new potential therapeutic targets represents a continuous challenge to improve survival and quality of CRC patient's life. We performed a microarray analysis dataset consisting of colon biopsies of healthy subjects (HS) and CRC patients. These results were further confirmed in a clinical setting evaluating a series of CRC patients to assess the expression of Resistin-Like Beta (RETNLB) and to correlate it with their clinical data. Our results showed a significant reduction of RETNLB expression in CRC biopsies compared to the HS mucosa. Furthermore, such reduction was significantly associated with the TNM grade and patients' age. Furthermore, a significantly positive correlation was found within mutated subjects for KRAS, TP53, and BRAF. In particular, patients with poor prognosis at 5 years exhibited RETNLB lower levels. In-silico analysis data were confirmed by histochemical analysis in a series of CRC patients recruited by our group. The results obtained provided that RETNLB low levels are associated with an unfavorable prognosis in CRC patients and its expression is also dependent on adjuvant therapy. Further studies are warranted in order to evaluate the molecular mechanisms underlying the role of RETNLB in CRC progression.
Assuntos
Neoplasias Colorretais , Humanos , Biópsia , Neoplasias Colorretais/genética , Neoplasias Colorretais/terapia , Neoplasias Colorretais/metabolismo , Prognóstico , Resistina , Taxa de SobrevidaRESUMO
Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease in industrialized countries because of the worldwide epidemic of obesity. Beyond metabolic complications, a subset of patients with NAFLD develop non-alcoholic steatohepatitis (NASH) with fibrosis, which is emerging as a leading cause of liver transplantation due to progression to cirrhosis and cancer. For these reasons, NAFLD is considered a public health burden. In recent years endoscopic bariatric and metabolic therapies (EBMT) have emerged as safe and effective for the treatment of obesity and type 2 diabetes mellitus. EBMT include gastric and duodenal devices and techniques such as intragastric balloons, endoscopic sleeve gastroplasty, endoscopic small bowel by-pass and duodenal mucosal resurfacing. Observational studies and pilot trials have revealed beneficial effects of EBMT on NAFLD as assessed by non-invasive parameters or histology. In this review we summarise current evidence for the efficacy and safety of EBMT in obese patients with NAFLD and examine future clinical applications.
Assuntos
Bariatria , Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Diabetes Mellitus Tipo 2/complicações , Humanos , Cirrose Hepática , Hepatopatia Gordurosa não Alcoólica/terapia , Obesidade/complicaçõesRESUMO
BACKGROUND & AIMS: Although antioxidants have a protective potential in nonalcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH), there is limited evidence regarding the role of dietary intake of antioxidants. The aim was to test the association between dietary vitamins E and C intake and NAFLD, NASH and fibrosis markers. METHODS: Cross-sectional study of a large cohort of subjects undergoing colonoscopy. The presence of NAFLD was evaluated by ultrasonography. The level of steatosis was defined using SteatoTest, moderate-severe NASH using new quantitative NashTest and borderline-significant fibrosisâ¯≥â¯F1-F2 using FibroTest. Nutritional intake was measured by food frequency questionnaire (FFQ). RESULTS: Overall, 789 subjects were included (52.6% men, age 58.83⯱â¯6.58â¯years), 714 had reliable FibroMax. Adjusting for BMI, dietary and lifestyle factors, the upper tertile of vitamin E intake/1000â¯Kcal was associated with lower odds of NASH (ORâ¯=â¯0.64, 0.43-0.94, Pâ¯=â¯0.024). There was an inverse association between reaching the recommended vitamin E intake and NASH (ORâ¯=â¯0.48, 0.30-0.77, Pâ¯=â¯0.002). The upper tertile of vitamin C intake/1000â¯Kcal was associated with lower odds of NAFLD and NASH (ORâ¯=â¯0.68, 0.47-0.99, Pâ¯=â¯0.045; ORâ¯=â¯0.57, 0.38-0.84, Pâ¯=â¯0.004, respectively). Both vitamins were related with the level of steatosis according to SteatoTest. CONCLUSION: Vitamin E and C intake may be protective from NAFLD-related liver damage.
Assuntos
Ácido Ascórbico , Dieta , Fígado , Hepatopatia Gordurosa não Alcoólica , Vitamina E , Antioxidantes/análise , Antioxidantes/metabolismo , Ácido Ascórbico/análise , Ácido Ascórbico/metabolismo , Correlação de Dados , Estudos Transversais , Feminino , Humanos , Israel/epidemiologia , Fígado/diagnóstico por imagem , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Avaliação Nutricional , Fatores de Proteção , Índice de Gravidade de Doença , Ultrassonografia/métodos , Vitamina E/análise , Vitamina E/metabolismoRESUMO
BACKGROUND & AIMS: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is likely due to the interaction between a deranged metabolic milieu and local mediators of hepatic inflammation and fibrosis. We undertook this study to elucidate the interplay between macrophage activation, insulin resistance (IR) in target organs/tissues and hepatic damage. METHODS: In 40 non-diabetic patients with biopsy-proven NAFLD we assessed: i) endogenous glucose production (EGP), glucose clearance and indexes of IR in the adipose tissue (Adipo-IR and Lipo-IR) and in the liver (Hep-IR) by tracer infusion ([6,6-2H2]glucose and [2H5]glycerol); ii) macrophage activity (by soluble sCD163) and iii) hepatic expression of CD163 (hCD163). RESULTS: We found that sCD163 levels paralleled both the plasma free fatty acid (FFA) levels and lipolysis from adipose tissue. Consistently, sCD163 significantly correlated with adipose tissue IR (Adipo-IR: râ¯=â¯0.32, pâ¯=â¯0.042; Lipo-IR: râ¯=â¯0.39, pâ¯=â¯0.012). At multiple regression analysis, sCD163 levels were associated with FFA levels (rpâ¯=â¯0.35, pâ¯=â¯0.026). In vitro exposure of human monocyte-derived macrophages to palmitate enhanced sCD163 secretion. Conversely, sCD163 did not correlate with EGP or with Hep-IR. In the liver, hCD163 positively correlated with sCD163 (râ¯=â¯0.58, pâ¯=â¯0.007) and the degree of steatosis (râ¯=â¯0.34, pâ¯=â¯0.048), but not with EGP or Hep-IR (râ¯=â¯-0.27 and râ¯=â¯0.11, respectively, p >0.10, both). CONCLUSIONS: Our findings suggest a link between deranged metabolism in the adipose tissue and activation of hepatic macrophages in patients with NAFLD, possibly in response to FFA overflow and independent of obesity and diabetes. Conversely, our findings do not support a link between activated hepatic macrophages and glucose metabolism (EGP or Hep-IR). The relationship between adipose tissue IR and hepatic macrophages should be considered to define therapeutic targets for NAFLD. LAY SUMMARY: The pathogenesis of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) is likely due to the interaction between a deranged metabolic milieu and local mediators of hepatic inflammation and fibrosis in the insulin resistant state. This study provides in vivo support for a possible link between deranged metabolism in the adipose tissue and activation of hepatic macrophages in patients with NAFLD, most likely in response to free fatty acid overflow and independent of obesity and diabetes.
Assuntos
Tecido Adiposo/metabolismo , Resistência à Insulina , Células de Kupffer/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Transdução de Sinais , Adulto , Antígenos CD/sangue , Antígenos de Diferenciação Mielomonocítica/sangue , Células Cultivadas , Estudos de Coortes , Diabetes Mellitus/metabolismo , Ácidos Graxos não Esterificados/sangue , Feminino , Glucose/metabolismo , Humanos , Lipólise , Fígado/patologia , Ativação de Macrófagos , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/metabolismo , Receptores de Superfície Celular/sangueRESUMO
Coffee consumption is inversely associated with the risk of non-alcoholic fatty liver disease (NAFLD). A gap in the literature still exists concerning the intestinal mechanisms that are involved in the protective effect of coffee consumption towards NAFLD. In this study, twenty-four C57BL/6J mice were divided into three groups each receiving a standard diet, a high-fat diet (HFD) or an HFD plus decaffeinated coffee (HFD+COFFEE) for 12 weeks. Coffee supplementation reduced HFD-induced liver macrovesicular steatosis (P < 0·01) and serum cholesterol (P < 0·001), alanine aminotransferase and glucose (P < 0·05). Accordingly, liver PPAR- α (P < 0·05) and acyl-CoA oxidase-1 (P < 0·05) as well as duodenal ATP-binding cassette (ABC) subfamily A1 (ABCA1) and subfamily G1 (ABCG1) (P < 0·05) mRNA expressions increased with coffee consumption. Compared with HFD animals, HFD+COFFEE mice had more undigested lipids in the caecal content and higher free fatty acid receptor-1 mRNA expression in the duodenum and colon. Furthermore, they showed an up-regulation of duodenal and colonic zonulin-1 (P < 0·05), duodenal claudin (P < 0·05) and duodenal peptide YY (P < 0·05) mRNA as well as a higher abundance of Alcaligenaceae in the faeces (P < 0·05). HFD+COFFEE mice had an energy intake comparable with HFD-fed mice but starting from the eighth intervention week they gained significantly less weight over time. Data altogether showed that coffee supplementation prevented HFD-induced NAFLD in mice by reducing hepatic fat deposition and metabolic derangement through modification of pathways underpinning liver fat oxidation, intestinal cholesterol efflux, energy metabolism and gut permeability. The hepatic and metabolic benefits induced by coffee were accompanied by changes in the gut microbiota.
Assuntos
Café/metabolismo , Dieta Hiperlipídica/efeitos adversos , Intestinos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Acil-CoA Oxidase/metabolismo , Alanina Transaminase/sangue , Alcaligenaceae , Animais , Glicemia , Colesterol/sangue , Claudinas/metabolismo , Suplementos Nutricionais , Fezes/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Haptoglobinas/metabolismo , Fígado/patologia , Masculino , Síndrome Metabólica , Camundongos , Camundongos Endogâmicos C57BL , PPAR alfa/metabolismo , Polifenóis/farmacologia , Precursores de Proteínas/metabolismo , RNA Mensageiro/metabolismoRESUMO
Nicotinamide adenine dinucleotide (NADâº) homeostasis is emerging as a key player in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and is tightly linked to the SIRT1/5'-AMP-activated protein kinase (AMPK) pathway. Silibinin, the main component of silymarin, has been proposed as a nutraceutical for the treatment of NAFLD. In this study, we aimed to identify whether silibinin may influence the NADâº/SIRT1 axis. To this end, C57BL/6 mice were fed a high fat diet (HFD) for 16 weeks, and were treated with silibinin or vehicle during the last 8 weeks. HepG2 cells were treated with 0.25 mM palmitate for 24 h with silibinin 25 µM or vehicle. HFD and palmitate administration led to oxidative stress, poly-(ADP-ribose)-polymerase (PARP) activation, NAD⺠consumption, and lower SIRT1 activity. In mice fed the HFD, and in HepG2 treated with palmitate, we consistently observed lower levels of phospho-AMPKThr172 and phospho-acetyl-CoA carboxylaseSer79 and higher levels of nuclear sterol regulatory element-binding protein 1 activity, indicating de novo lipogenesis. Treatment of mice and HepG2 with silibinin abolished oxidative stress, and inhibited PARP activation thus restoring the NAD⺠pool. In agreement with preserved NAD⺠levels, SIRT1 activity and AMPK phosphorylation returned to control levels in mice and HepG2. Our results further indicate silibinin as a promising molecule for the treatment of NAFLD.
Assuntos
Adenilato Quinase/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Silimarina/farmacologia , Sirtuína 1/metabolismo , Adenilato Quinase/genética , Animais , Dieta Hiperlipídica/efeitos adversos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , NAD , Obesidade/induzido quimicamente , SilibinaRESUMO
BACKGROUND: A meta-analysis was conducted to summarize the evidence from prospective cohort and case-control studies regarding the association between coffee intake and biliary tract cancer (BTC) and liver cancer risk. METHODS: Eligible studies were identified by searches of PubMed and EMBASE databases from the earliest available online indexing year to March 2017. The dose-response relationship was assessed by a restricted cubic spline model and multivariate random-effect meta-regression. A stratified and subgroup analysis by smoking status and hepatitis was performed to identify potential confounding factors. RESULTS: We identified five studies on BTC risk and 13 on liver cancer risk eligible for meta-analysis. A linear dose-response meta-analysis did not show a significant association between coffee consumption and BTC risk. However, there was evidence of inverse correlation between coffee consumption and liver cancer risk. The association was consistent throughout the various potential confounding factors explored including smoking status, hepatitis, etc. Increasing coffee consumption by one cup per day was associated with a 15% reduction in liver cancer risk (RR 0.85; 95% CI 0.82 to 0.88). CONCLUSIONS: The findings suggest that increased coffee consumption is associated with decreased risk of liver cancer, but not BTC.
Assuntos
Café , Medicina Baseada em Evidências , Comportamento Alimentar , Alimento Funcional , Neoplasias Hepáticas/prevenção & controle , Neoplasias do Sistema Biliar/epidemiologia , Neoplasias do Sistema Biliar/etiologia , Neoplasias do Sistema Biliar/prevenção & controle , Estudos de Casos e Controles , Café/efeitos adversos , Estudos de Coortes , Fatores de Confusão Epidemiológicos , Alimento Funcional/efeitos adversos , Humanos , Neoplasias Hepáticas/epidemiologia , Neoplasias Hepáticas/etiologia , Estudos Observacionais como Assunto , Estudos Prospectivos , Reprodutibilidade dos Testes , Fatores de RiscoRESUMO
Non-alcoholic fatty liver disease (NAFLD) has become a major global health burden, leading to increased risk for cirrhosis, hepatocellular carcinoma, type-2 diabetes and cardiovascular disease. Lifestyle intervention aiming at weight reduction is the most established treatment. However, changing the dietary composition even without weight loss can also reduce steatosis and improve metabolic alterations as insulin resistance and lipid profile. The Mediterranean diet (MD) pattern has been proposed as appropriate for this goal, and was recommended as the diet of choice for the treatment of NAFLD by the EASL-EASD-EASO Clinical Practice Guidelines. The MD has an established superiority in long term weight reduction over low fat diet, but it improves metabolic status and steatosis even without it. However, the effect on liver inflammation and fibrosis was tested only in few observational studies with positive results. Furthermore, considering the strong association between NAFLD and diabetes and CVD, the MD has a highly established advantage in prevention of these diseases, demonstrated in randomized clinical trials. The individual components of the MD such as olive oil, fish, nuts, whole grains, fruits, and vegetables, have been shown to beneficially effect or negatively correlate with NAFLD, while consumption of components that characterize a Western dietary pattern as soft drinks, fructose, meat and saturated fatty acids have been shown to have detrimental association with NAFLD. In this review we will cover the epidemiological evidence and the plausible molecular mechanisms by which the MD as a whole and each of its components can be of benefit in NAFLD.
Assuntos
Dieta Saudável , Dieta Mediterrânea , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Comportamento de Redução do Risco , Animais , Dieta Ocidental/efeitos adversos , Humanos , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Fatores de Risco , Resultado do TratamentoRESUMO
Coffee is the most consumed beverage worldwide. Epidemiological studies with prospective cohorts showed that coffee intake is associated with reduced cardiovascular and all-cause mortality independently of caffeine content. Cohort and case-control studies reported an inverse association between coffee consumption and the degree of liver fibrosis as well as the development of liver cancer. Furthermore, the beneficial effects of coffee have been recently confirmed by large meta-analyses. In the last two decades, various in vitro and in vivo studies evaluated the molecular determinants for the hepatoprotective effects of coffee. In the present article, we aimed to critically review experimental evidence regarding the active components and the molecular bases underlying the beneficial role of coffee against chronic liver diseases. Almost all studies highlighted the beneficial effects of this beverage against liver fibrosis with the most solid results indicating a pivot role for both caffeine and chlorogenic acids. In particular, in experimental models of fibrosis, caffeine was shown to inhibit hepatic stellate cell activation by blocking adenosine receptors, and emerging evidence indicated that caffeine may also favorably impact angiogenesis and hepatic hemodynamics. On the other side, chlorogenic acids, potent phenolic antioxidants, suppress liver fibrogenesis and carcinogenesis by reducing oxidative stress and counteract steatogenesis through the modulation of glucose and lipid homeostasis in the liver. Overall, these molecular insights may have translational significance and suggest that coffee components need clinical evaluation.
Assuntos
Café/química , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Animais , Cafeína/farmacologia , Ácido Clorogênico/farmacologia , Modelos Animais de Doenças , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/prevenção & controle , Humanos , Metabolismo dos Lipídeos , Fígado/metabolismo , Cirrose Hepática/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/prevenção & controle , Extratos Vegetais/farmacologia , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Non-alcoholic steatohepatitis (NASH), the progressive form of non-alcoholic fatty liver disease (NAFLD), is emerging as a main health problem in industrialized countries. Lifestyle modifications are effective in the treatment of NAFLD; however, the long-term compliance is low. Therefore, several pharmacological treatments have been proposed but none has shown significant efficacy or long-term safety. Natural polyphenols are a heterogeneous class of polyphenolic compounds contained in vegetables, which are being proposed for the treatment of different metabolic disorders. Although the beneficial effect of these compounds has traditionally related to their antioxidant properties, they also exert several beneficial effects on hepatic and extra-hepatic glucose and lipid homeostasis. Furthermore, natural polyphenols exert antifibrogenic and antitumoural effects in animal models, which appear relevant from a clinical point of view because of the association of NASH with cirrhosis and hepatocellular carcinoma. Several polyphenols, such anthocyanins, curcumin and resveratrol and those present in coffee, tea, soy are available in the diet and their consumption can be proposed as part of a healthy diet for the treatment of NAFLD. Other phenolic compounds, such as silymarin, are commonly consumed worldwide as nutraceuticals or food supplements. Natural antioxidants are reported to have beneficial effects in preclinical models of NAFLD and in pilot clinical trials, and thus need clinical evaluation. In this review, we summarize the existing evidence regarding the potential role of natural antioxidants in the treatment of NAFLD and examine possible future clinical applications.
Assuntos
Antioxidantes/farmacologia , Hepatopatia Gordurosa não Alcoólica , Polifenóis/farmacologia , Animais , Antineoplásicos Fitogênicos/farmacologia , Carcinoma Hepatocelular/etiologia , Carcinoma Hepatocelular/prevenção & controle , Suplementos Nutricionais , Descoberta de Drogas , Humanos , Cirrose Hepática/etiologia , Cirrose Hepática/prevenção & controle , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/terapia , Plantas MedicinaisRESUMO
Coffee consumption is inversely related to the degree of liver injury in patients with nonalcoholic fatty liver disease (NAFLD). Molecular mediators contributing to coffee's beneficial effects in NAFLD remain to be elucidated. In this study, we administrated decaffeinated espresso coffee or vehicle to rats fed an high-fat diet (HFD) for 12 weeks and examined the effects of coffee on liver injury by using two-dimensional polyacrylamide gel electrophoresis (2D-PAGE) proteomic analysis combined with mass spectrometry. Rats fed an HFD and water developed panacinar steatosis, lobular inflammation, and mild fibrosis, whereas rats fed an HFD and coffee exhibited only mild steatosis. Coffee consumption increased liver expression of the endoplasmic reticulum chaperones glucose-related protein 78 and protein disulfide-isomerase A3; similarly, coffee drinking enhanced the expression of the mitochondrial chaperones heat stress protein 70 and DJ-1. Furthermore, in agreement with reduced hepatic levels of 8-isoprostanes and 8-hydroxy-2'-deoxyguanosine, proteomic analysis showed that coffee consumption induces the expression of master regulators of redox status (i.e., peroxiredoxin 1, glutathione S-transferase α2, and D-dopachrome tautomerase). Last, proteomics revealed an association of coffee intake with decreased expression of electron transfer flavoprotein subunit α, a component of the mitochondrial respiratory chain, involved in de novo lipogenesis. In this study, we were able to identify by proteomic analysis the stress proteins mediating the antioxidant effects of coffee; moreover, we establish for the first time the contribution of specific coffee-induced endoplasmic reticulum and mitochondrial chaperones ensuring correct protein folding and degradation in the liver.
Assuntos
Café , Fígado Gorduroso/dietoterapia , Fígado Gorduroso/metabolismo , Chaperonas Moleculares/metabolismo , Animais , Antioxidantes/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Eletroforese em Gel Bidimensional , Retículo Endoplasmático/metabolismo , Fígado Gorduroso/genética , Expressão Gênica , Proteínas de Choque Térmico HSP70/genética , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico/biossíntese , Proteínas de Choque Térmico/genética , Masculino , Mitocôndrias Hepáticas/metabolismo , Hepatopatia Gordurosa não Alcoólica , Isomerases de Dissulfetos de Proteínas/genética , Isomerases de Dissulfetos de Proteínas/metabolismo , Proteômica , Ratos , Ratos Wistar , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Espectrometria de Massas em Tandem , Pesquisa Translacional BiomédicaRESUMO
OBJECTIVE: Acetaminophen intoxication is a leading cause of acute liver failure. Liver transplantation for acute liver failure is limited by the availability of donor organs. In this study, we aimed at identifying if the transplantation of adipose tissue-mesenchymal stem cells (ASCs) may exert therapeutic effects on acetaminophen-induced liver injury. METHODS: ASCs were isolated from human subcutaneous tissue and were transfected with a green fluorescent protein (GFP). Sprague-Dawley rats were administrated 300mg/kg of acetaminophen intraperitoneally and were transplanted with ASCs or vehicle. After 24h from acetaminophen administration, rats were sacrificed. Hepatic levels of isoprostanes, 8-hydroxyguanosine (8-OHG), nitrites/nitrates and reduced glutathione (GSH) were determined as markers of oxidative stress; JNK phosphorylation and hepatic levels of inflammatory cytokines and regeneration factors were also assessed. RESULTS: Transplantation of ASCs decreased AST, ALT and prothrombin time to the levels observed in control rats. Transplanted animals had normal plasma ammonia and did not display clinical encephalopathy. Liver sections of intoxicated rats treated with vehicle showed lobular necrosis and diffuse vacuolar degeneration; in rats transplanted with ASCs liver injury was almost absent. Transplantation of ASCs decreased liver isoprostanes, 8-OHG and nitrite-nitrates to the levels of control rats, while preserving GSH. Consistently, hepatic levels of TNF-α, MCP-1, IL-1ß, ICAM-1 and phospho-JNK were markedly increased in rats treated with vehicle and were restored to the levels of controls in animals transplanted with ASCs. Furthermore, ASC transplantation increased liver expression of cyclin D1 and PCNA, two established hepatocyte regeneration factors, whereas ASCs were not able to metabolize acetaminophen in vitro. CONCLUSION: In this study, we demonstrated that ASC transplantation is effective in treating acetaminophen liver injury by enhancing hepatocyte regeneration and inhibiting liver stress and inflammatory signaling.
Assuntos
Tecido Adiposo/citologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Acetaminofen/toxicidade , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Células Cultivadas , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Citocinas/genética , Citocinas/metabolismo , Feminino , Humanos , Fígado/fisiologia , Masculino , Células-Tronco Mesenquimais/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Regeneração , Adulto JovemRESUMO
BACKGROUND AND AIM: Oxidative stress is considered a key element in the progression of non-alcoholic fatty liver to non-alcoholic steatohepatitis (NASH). Unconjugated bilirubin is the main endogenous lipid antioxidant and is cytoprotective in different tissues and organs. In this study, it was evaluated if unconjugated bilirubin levels are associated with the degree of liver injury in patients with non-alcoholic fatty liver disease. METHODS: Two hundred and eighty-five patients were retrospectively evaluated with biopsy-confirmed non-alcoholic fatty liver disease. Multiple logistic regression models were used to assess the relationship of steatosis, inflammation, and fibrosis levels to the features of patients. RESULTS: Unconjugated bilirubin levels differed significantly according to inflammation and fibrosis scores. Unconjugated bilirubin was lower in patients with moderate-severe inflammation compared with those with absent-mild (P = 0.001) and in patients with moderate-severe fibrosis compared with those with absent-mild (P < 0.001), whereas no difference was observed for steatosis grades. At logistic regression analysis, low unconjugated bilirubin levels were associated with moderate-severe inflammation (odds ratio, 0.11; 95% confidence interval 0.02-0.76; P = 0.025) and moderate-severe fibrosis (odds ratio, 0.013; 95% confidence interval 0.001-0.253; P = 0.004). CONCLUSIONS: Low unconjugated bilirubin levels are independent predictors of advanced inflammation and fibrosis in patients with steatohepatitis, indicating the lack of antioxidant protection as a possible molecular determinant for the progression of liver injury.
Assuntos
Bilirrubina/sangue , Fígado Gorduroso/diagnóstico , Cirrose Hepática/diagnóstico , Adulto , Antioxidantes , Bilirrubina/fisiologia , Biomarcadores/sangue , Biomarcadores/metabolismo , Citoproteção , Fígado Gorduroso/etiologia , Feminino , Humanos , Cirrose Hepática/etiologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica , Estresse Oxidativo/fisiologia , Estudos Retrospectivos , Índice de Gravidade de DoençaRESUMO
BACKGROUND & AIMS: Patients with genotype 1 chronic hepatitis C (G1 CHC) frequently develop steatosis and insulin resistance (IR), caused by metabolic and viral factors. These accelerate the progression of liver disease and reduce the response to therapy. A sustained virologic response (SVR) to therapy in patients with G1 CHC is associated strongly with polymorphisms near the interleukin-28B (IL28B) gene, but the interaction between IL28B genotype and IR, and their combined effects on SVR, have not been defined. We tested the association between the IL28B rs12979860 single-nucleotide polymorphism and metabolic features, including IR, and evaluated their effects on SVR. METHODS: We performed genotype analysis of IL28B rs12979860 for 434 white G1 CHC patients who underwent consecutive biopsy analysis at 3 tertiary centers. Metabolic profile analyses included assessments of lipid levels and IR by the homeostasis model assessment. RESULTS: Patients with the CC polymorphism in IL28B had higher levels of total and low-density lipoprotein cholesterol, lower levels of triglycerides, and a lower prevalence of IR and moderate-severe steatosis (P < .05) than patients without this genotype. By multiple logistic regression analysis, body mass index (odds ratio [OR], 1.223; P < .001), level of triglycerides (OR, 1.007; P = .006), the CC polymorphism in IL28B (OR, 0.378; P = .001), and levels of HCV RNA greater than 850,000 IU/mL (OR, 1.803; P = .01) were associated with IR. The CC polymorphism in IL28B (OR, 8.350; P < .001) and IR (OR, 0.432; P = .005), but not steatosis (OR, 0.582; P = 0.25), was associated with an SVR. CONCLUSIONS: In white patients with G1 CHC, the IL28B rs12979860 CC genotype is associated with reduced IR. IL28B rs12979860 genotype and IR by the homeostasis model assessment strongly affect the outcome of antiviral therapy.