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1.
Medicine (Baltimore) ; 98(39): e17300, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31574855

RESUMO

We investigated associations between inflammatory marker levels and hepatitis C virus (HCV)-related compensated liver cirrhosis risk in patients with chronic hepatitis C (CHC) infection in China. We used a case-control design and data from the records of 110 Chinese patients with CHC and cirrhosis for the study; 458 CHC patients who did not have a diagnosis of cirrhosis were matched to the case group by age and sex characteristics. We also investigated fatty liver disease risk factors. The group of patients with CHC infection and cirrhosis had lower platelet-to-lymphocyte ratio (PLR) values (60.63 [44.09, 89.31]) compared with the control group patients (80.24 [57.85, 111.08]). The results indicated that the group of patients with cirrhosis had higher 4-factor fibrosis index and aspartate aminotransferase (AST)-to-platelet ratio index (APRI) values compared with the group of patients with CHC-only (1.66 [0.98, 2.60] vs 0.71 [0.45, 1.17], respectively; P < .001 and 2.12 [0.97, 4.25] vs 0.99 [0.51, 2.01], respectively; P < .001). Compared with the control group, the AST/alanine aminotransferase ratio (AAR) values in the group of patients with cirrhosis were significantly higher (P < .001). Logistic regression analysis that included model adjustment for demographic characteristics and other factors that could affect cirrhosis risk revealed that greater 1/PLR values were associated with an increased odds of having cirrhosis (adjusted odds ratio [AOR], 95% confidence interval [CI] 0.991 [0.985-0.996]); APRI and AAR values were also independent predictors of the presence of compensated cirrhosis. We found that compared with the patients with CHC-only, the triglyceride, cholesterol, and low-density lipoprotein cholesterol levels in the patients with both CHC and fatty liver disease were significantly higher. The multivariate analysis of the risk of fatty liver development in patients with CHC infection found that cholesterol level was a statistically significant risk factor (AOR [95% CI] 1.380 [1.089-1.750], P = .008). Increased 1/PLR, APRI, and AAR values were associated with increased risks for development of cirrhosis in this population of Chinese patients with CHC infection. Higher cholesterol levels increased the risk of development of fatty liver disease in patients with CHC.


Assuntos
Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Hepatite C Crônica , Cirrose Hepática , Biomarcadores/sangue , Estudos de Casos e Controles , China/epidemiologia , Fígado Gorduroso/sangue , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/epidemiologia , Feminino , Hepacivirus/isolamento & purificação , Hepatite C Crônica/sangue , Hepatite C Crônica/complicações , Hepatite C Crônica/epidemiologia , Humanos , Lipoproteínas/sangue , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Cirrose Hepática/epidemiologia , Cirrose Hepática/etiologia , Contagem de Linfócitos/métodos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas/métodos , Fatores de Risco
2.
Gastroenterology ; 157(3): 705-719.e18, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31121167

RESUMO

BACKGROUND & AIMS: Alpha-1 antitrypsin deficiency (AATD) is among the most common genetic disorders. Severe AATD is caused by a homozygous mutation in the SERPINA1 gene that encodes the Glu342Lys substitution (called the Pi*Z mutation, Pi*ZZ genotype). Pi*ZZ carriers may develop lung and liver diseases. Mutation-associated lung disorders have been well studied, but less is known about the effects in liver. We assessed the liver disease burden and associated features in adults with this form of AATD. METHODS: We collected data from 554 Pi*ZZ adults (403 in an exploratory cohort, 151 in a confirmatory cohort), in 9 European countries, with AATD who were homozygous for the Pi*Z mutation, and 234 adults without the Pi*Z mutation (controls), all without pre-existing liver disease. We collected data on demographic parameters, comorbidities, lung- and liver-related health, and blood samples for laboratory analysis. Liver fibrosis was assessed non-invasively via the serum tests Aspartate Aminotransferase to Platelet Ratio Index and HepaScore and via transient elastography. Liver steatosis was determined via transient elastography-based controlled attenuation parameter. We performed histologic analyses of livers from transgenic mice that overexpress the AATD-associated Pi*Z variant. RESULTS: Serum levels of liver enzymes were significantly higher in Pi*ZZ carriers vs controls. Based on non-invasive tests for liver fibrosis, significant fibrosis was suspected in 20%-36% of Pi*ZZ carriers, whereas signs of advanced fibrosis were 9- to 20-fold more common in Pi*ZZ carriers compared to non-carriers. Male sex; age older than 50 years; increased levels of alanine aminotransferase, aspartate aminotransferase, or γ-glutamyl transferase; and low numbers of platelets were associated with higher liver fibrosis burden. We did not find evidence for a relationship between lung function and liver fibrosis. Controlled attenuation parameter ≥280 dB/m, suggesting severe steatosis, was detected in 39% of Pi*ZZ carriers vs 31% of controls. Carriers of Pi*ZZ had lower serum concentrations of triglyceride and low- and very-low-density lipoprotein cholesterol than controls, suggesting impaired hepatic secretion of lipid. Livers from Pi*Z-overexpressing mice had steatosis and down-regulation of genes involved in lipid secretion. CONCLUSIONS: In studies of AATD adults with the Pi*ZZ mutation, and of Pi*Z-overexpressing mice, we found evidence of liver steatosis and impaired lipid secretion. We identified factors associated with significant liver fibrosis in patients, which could facilitate hepatologic assessment and counseling of individuals who carry the Pi*ZZ mutation. ClinicalTrials.gov Number NCT02929940.


Assuntos
Fígado Gorduroso/etiologia , Metabolismo dos Lipídeos , Cirrose Hepática/etiologia , Fígado/metabolismo , Mutação , Deficiência de alfa 1-Antitripsina/complicações , alfa 1-Antitripsina/genética , Adulto , Fatores Etários , Idoso , Animais , Estudos de Casos e Controles , Técnicas de Imagem por Elasticidade , Europa (Continente) , Fígado Gorduroso/sangue , Fígado Gorduroso/diagnóstico , Feminino , Predisposição Genética para Doença , Homozigoto , Humanos , Fígado/diagnóstico por imagem , Fígado/patologia , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Testes de Função Hepática , Masculino , Camundongos Transgênicos , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco , Fatores Sexuais , Deficiência de alfa 1-Antitripsina/diagnóstico , Deficiência de alfa 1-Antitripsina/enzimologia , Deficiência de alfa 1-Antitripsina/genética
3.
Int J Mol Sci ; 20(9)2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31075962

RESUMO

This study focuses on the effect of honokiol (HON) on glucose homeostasis, insulin resistance, dyslipidemia, hepatic steatosis, and inflammation in type 2 diabetic db/db mice. Male C57BL/KsJ-db/db mice were fed a normal diet with or without HON (0.02%, w/w) or pioglitazone (PIO, anti-diabetic agent, 0.01%, w/w) for 5 weeks. Blood biomarker, tissue morphology and enzymatic and genetic parameters were determined. PIO significantly decreased food intake, fasting blood glucose, and glycosylated hemoglobin (HbA1c) levels, but markedly increased body weight, adipose tissue weight, and plasma leptin levels. HON did not significantly affect food intake, body weight, or levels of plasma leptin and blood glucose. However, HON led to significant decreases in adipose tissue weight, plasma insulin, blood HbA1c and HOMA-IR levels and improved glucose tolerance. The anti-diabetic and anti-adiposity effects of HON were partially related to the inhibition of gluconeogenic enzymes and their mRNA expression in the liver; and the inhibition of lipogenic enzymes in adipose tissue, respectively. Unlike PIO, HON did not affect dyslipidemia, but ameliorated hepatic steatosis by inhibiting hepatic lipogenic enzymes activity. Moreover, HON exhibited anti-inflammatory effects similar to PIO. These results suggest that HON can protect against type 2 diabetes by improving insulin resistance, glucose and lipid metabolism, and inflammation.


Assuntos
Compostos de Bifenilo/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fígado Gorduroso/tratamento farmacológico , Inflamação/tratamento farmacológico , Resistência à Insulina , Lignanas/uso terapêutico , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Compostos de Bifenilo/farmacologia , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/patologia , Dislipidemias/sangue , Dislipidemias/complicações , Fígado Gorduroso/sangue , Fígado Gorduroso/complicações , Fígado Gorduroso/patologia , Comportamento Alimentar/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Inflamação/sangue , Inflamação/complicações , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Leptina/sangue , Lignanas/farmacologia , Lipídeos/sangue , Masculino , Camundongos Endogâmicos C57BL , Tamanho do Órgão/efeitos dos fármacos
4.
Transl Res ; 210: 26-42, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31121128

RESUMO

Obesity is a major cause of metabolic syndrome and type II diabetes, and it presents with metabolic disorders, such as hyperglycemia, hyperlipidemia, and insulin resistance. Pigment epithelium-derived factor (PEDF), a protein isolated from retinal pigment epithelial cells, has multiple functions, including neuronal protection, antineoplastic effects, and anti-inflammatory activity. The aim of this study is to investigate the antiobesity effects of PEDF. The antiobesity effects of PEDF on fat accumulation, inflammation, energy expenditure, insulin resistance, and obesity-related physiological parameters and protein levels were assessed in high-fat diet (HFD)-induced obese mice in vivo and in 3T3-L1 adipocytes, palmitate (PA)-treated HepG2 cells, and C2C12 myotubes in vitro. In an in vivo assay, PEDF effectively decreased body weight gain, white adipose tissue mass, and inflammation and improved insulin resistance, dyslipidemia, and hyperglycemia in HFD-induced mice. In liver tissue, PEDF decreased lipid accumulation and fibrosis. In an in vitro assay, PEDF diminished the differentiation of 3T3-L1 preadipocytes. We also determined that PEDF promoted lipolysis and prolonged cell cycle progression, through the mTOR-S6K pathway and downstream transcription factors, such as peroxisome proliferator-activated receptor gamma, CCAAT/enhancer-binding protein α (CEBP-α), and CEBP-ß. In addition, PEDF decreased reactive oxygen species production in PA-induced HepG2 cells and improved glucose uptake ability in PA-induced HepG2 cells and C2C12 myotubes. In the present study, PEDF protected against HFD-induced obesity and metabolic disorders in mice, inhibited adipogenesis, and improved insulin resistance. These results provide a new potential treatment for obesity in the future.


Assuntos
Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Proteínas do Olho/farmacologia , Doenças Metabólicas/patologia , Fatores de Crescimento Neural/farmacologia , Obesidade/patologia , Obesidade/prevenção & controle , Serpinas/farmacologia , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Tecido Adiposo/patologia , Animais , Proliferação de Células/efeitos dos fármacos , Células Clonais , Dieta Hiperlipídica , Fígado Gorduroso/sangue , Fígado Gorduroso/complicações , Fígado Gorduroso/patologia , Células Hep G2 , Humanos , Inflamação/patologia , Resistência à Insulina , Masculino , Doenças Metabólicas/sangue , Camundongos , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Obesidade/sangue , Obesidade/complicações , Estresse Oxidativo/efeitos dos fármacos , Ácido Palmítico , Proteínas Quinases S6 Ribossômicas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
5.
Molecules ; 24(7)2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30987086

RESUMO

Mixtures of resveratrol (RSV) + quercetin (QRC) have antioxidant properties that probably impact on fatty liver in metabolic syndrome (MS) individuals. Here, we study the effects of a mixture of RSV + QRC on oxidative stress (OS) and fatty liver in a rat model of MS. Weanling male Wistar rats were separated into four groups (n = 8): MS rats with 30% sucrose in drinking water plus RSV + QRC (50 and 0.95 mg/kg/day, respectively), MS rats without treatment, control rats (C), and C rats plus RSV + QRC. MS rats had increased systolic blood pressure, triglycerides, insulin levels, insulin resistance index homeostasis model (HOMA), adiponectin, and leptin. The RSV + QRC mixture compensated these variables to C values (p < 0.01) in MS rats. Lipid peroxidation and carbonylation were increased in MS. Total antioxidant capacity and glutathione (GSH) were decreased in MS and compensated in MS plus RVS + QRC rats. Catalase, superoxide dismutase isoforms, peroxidases, glutathione-S-transferase, glutathione reductase, and the expression of Nrf2 were decreased in MS and reversed in MS plus RVS + QRC rats (p < 0.01). In conclusion, the mixture of RSV + QRC has benefic effects on OS in fatty liver in the MS rats through the improvement of the antioxidant capacity and by the over-expression of the master factor Nrf2, which increases the antioxidant enzymes and GSH recycling.


Assuntos
Antioxidantes/metabolismo , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Síndrome Metabólica/complicações , Síndrome Metabólica/metabolismo , Quercetina/administração & dosagem , Resveratrol/administração & dosagem , Animais , Biomarcadores , Modelos Animais de Doenças , Fígado Gorduroso/sangue , Fígado Gorduroso/prevenção & controle , Glutationa/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Síndrome Metabólica/sangue , Estresse Oxidativo/efeitos dos fármacos , Ratos
6.
Oxid Med Cell Longev ; 2019: 9417498, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31015892

RESUMO

Syzygium cumini is used worldwide for the treatment of metabolic syndrome-associated outcomes. Previously, we described the antihypertriglyceridemic effect of the hydroethanolic extract of S. cumini leaf (HESc) in monosodium L-glutamate- (MSG-) induced obese rats. This study sought to investigate the molecular mechanisms underlying the antihypertriglyceridemic effect of HESc in MSG-obese rats. Newborn male Wistar rats were injected subcutaneously with MSG (4.0 g/kg/day, obese group) or saline 1.25% (1.0 mL/kg/day, lean group), from 2nd through 10th postnatal day. At 8 weeks old, obese rats started to be orally treated with HESc (0.5 or 1.0 g/kg/day, n = 7) or saline 0.9% (1 mL/kg/day, n = 7). Lean rats received saline solution (1 mL/kg/day, n = 7). Upon 8-week treatment, animals were euthanized for blood and tissue collection. Another set of adult nonobese Wistar rats was used for the assessment of HESc acute effects on Triton WR1339-induced hypertriglyceridemia. HESc reduced weight gain, as well as adipose tissue fat pads, without altering food intake of obese rats. HESc restored fasting serum glucose, triglycerides, total cholesterol, and free fatty acids, as well as insulin sensitivity, to levels similar to lean rats. Additionally, HESc halved the triglyceride content into very low-density lipoprotein particles, as well as healed liver steatosis, in obese rats. Hepatic protein expression of the endoplasmic reticulum chaperone GRP94 was decreased by HESc, which also downregulated the hepatic triglyceride secretion pathway by reducing the splicing of X-box binding protein 1 (XBP-1s), as well as protein disulfide isomerase (PDI) and microsomal triglyceride transfer protein (MTP) translational levels. This action was further corroborated by the acute inhibitory effect of HESc on triglyceride accumulation on Triton WR1339-treated rats. Our data support the downregulation of the XBP-1s/PDI/MTP axis in the liver of MSG-obese rats as a novel feasible mechanism for the antihypertriglyceridemic effect promoted by the polyphenolic phytocomplex present in S. cumini leaf.


Assuntos
Regulação para Baixo , Hipertrigliceridemia/tratamento farmacológico , Fígado/metabolismo , Obesidade/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Folhas de Planta/química , Transdução de Sinais/efeitos dos fármacos , Syzygium/química , Tecido Adiposo/metabolismo , Animais , Animais Recém-Nascidos , Proteínas de Transporte/metabolismo , Regulação para Baixo/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fígado Gorduroso/sangue , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/fisiopatologia , Glicolipídeos/sangue , Hipertrigliceridemia/sangue , Hipertrigliceridemia/fisiopatologia , Lipoproteínas VLDL/sangue , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado/fisiopatologia , Masculino , Obesidade/sangue , Obesidade/metabolismo , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Polifenóis/química , Isomerases de Dissulfetos de Proteínas/metabolismo , Ratos Wistar , Glutamato de Sódio , Triglicerídeos/sangue , Proteína 1 de Ligação a X-Box/metabolismo
7.
Biomed Pharmacother ; 111: 926-933, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30841472

RESUMO

BACKGROUND: Non-alcoholic steatohepatitis (NASH) is a prevalent disease that is highly associated with the metabolic syndrome and type II diabetes. The development of in vivo models that reflect all nuances of the human NASH pathology is essential for drug discovery and development. We aimed to further characterise a dietary induced model of NASH both biochemically and histologically. In addition, we also investigated whether pioglitazone and liraglutide, drugs that have both been investigated as potential NASH treatments, could modulate the pathological changes induced by the NASH diet. Furthermore, to aid the translation of data from pre-clinical in vivo models, we aimed to adapt the NASH Clinical Research Network (CRN) histological score system for use in rodent studies. METHODS: Sprague Dawley rats were fed a high-fat diet (HFD) for 9 weeks, after which they were switched to a high fat, high cholesterol and cholate diet (HFCC) for 12 weeks. The rats were divided into treatment groups, receiving either 30 mg/kg pioglitazone p.o. SID or liraglutide s.c. 200 µg/kg BID or the respective vehicles. Serum levels of triglycerides (TG), cholesterol (Chol), LDL, HDL, AST and ALT, as well as body weight were assessed in all subjects. Upon termination, the liver was weighed and evaluated histologically using modified NASH-CRN criteria. RESULTS: HFCC feeding induced severe hepatic injury and hepatomegaly as indicated by significant increases in AST, ALT and an increased liver weight. Additionally, HFCC feeding induced dyslipidaemia, significant increases in circulating cholesterol and LDL were observed. No obesogenic effect of the HFCC diet was observed, though the diet did induce insulin resistance. Histological analysis showed that the HFCC diet induced several NASH like features, though it did not induce the development of severe fibrosis. However, microgranulomas were often prevalent in addition to lobular inflammatory foci. Pioglitazone showed little efficacy upon both biochemical and histological features. However, liraglutide induced weight loss, improved glycaemic control, reduced ALT and AST and showed some beneficial effects upon steatosis and lobular inflammation. CONCLUSION: Similar to previous reports we have shown that the atherogenic diet, HFCC, induces a phenotype akin to that seen in human NASH patients. Despite inducing all histological features of NASH, HFCC feeding does not promote the development of significant fibrosis within rodents. Pioglitazone and liraglutide have been investigated as potential NASH treatments. Within this model of NASH we have shown that pioglitazone has little efficacy, whereas liraglutide reduced the levels of circulating aminotransferases and had some beneficial effects upon NASH histological parameters.


Assuntos
Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Liraglutida/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , PPAR gama/agonistas , Pioglitazona/farmacologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Glicemia/efeitos dos fármacos , Colesterol/sangue , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Fígado Gorduroso/sangue , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Inflamação/sangue , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ratos , Ratos Sprague-Dawley , Roedores/sangue , Roedores/metabolismo , Triglicerídeos/sangue
8.
J Chin Med Assoc ; 82(2): 99-104, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30839498

RESUMO

BACKGROUND: Serum ferritin is an indicator of iron accumulation in a human body, and it is frequently elevated in patients with systemic inflammatory state in chronic hepatitis C (CHC). Iron accumulation is associated with hepatic fibrosis, steatosis, and unfavorable outcome in CHC patients. We studied the status of elevated serum ferritin level and its association with the liver fibrosis or steatosis in Taiwanese CHC patients. METHODS: Seven hundred and thirty-eight Taiwanese CHC patients were consecutively included in this study. Laboratory analysis, four indexes of fibrosis (FIB4), histological assessment of fibrosis, and steatosis were assessed by appropriate elevation of serum ferritin level. RESULTS: Three hundred and one patients (40.8%) had elevated serum ferritin level (sex-specific threshold >1.5 × upper limit of normal). Serum iron level (odds ratio [OR], 1.02; 95% CI, 1.01%-1.03%, p < 0.001), female gender (OR, 1.49; 95% CI, 1.07%-2.08%, p = 0.018), serum gamma-glutamyl transferase level (OR, 1.007; 95% CI, 1.003%-1.01%, p < 0.001), steatosis grade (OR, 1.56; 95% CI, 1.13%-2.16%, p = 0.006), and FIB4 ≥3.25 (OR, 1.63; 95% CI, 1.18%-2.27%, p = 0.003) indexes were associated with high serum ferritin level by multivariate logistic regression analysis. Patients with steatosis (>5%) were associated with older age (OR, 1.01; 95% CI, 1.00%-1.03%, p = 0.015), body mass index (OR, 1.10; 95% CI, 1.05%-1.15%, p < 0.001), and elevated serum ferritin level (OR, 1.001; 95% CI, 1.00%-1.001%, p = 0.024) by multivariate logistic regression analysis. Serum ferritin level also associated with high FIB4 (≥3.25) (OR, 1.001; 95% CI, 1.001%-1.002%, p = 0.010) when multivariate model adjusted together with advanced liver fibrosis by biopsy. CONCLUSION: Elevated serum ferritin level was noted in 40.8% of Taiwanese CHC patients, and the serum ferritin level was associated with liver steatosis and high FIB4.


Assuntos
Fígado Gorduroso/etiologia , Ferritinas/sangue , Hepatite C Crônica/complicações , Cirrose Hepática/etiologia , Adulto , Idoso , Fígado Gorduroso/sangue , Feminino , Hepatite C Crônica/sangue , Humanos , Cirrose Hepática/sangue , Modelos Logísticos , Masculino , Pessoa de Meia-Idade
9.
Nutrients ; 11(3)2019 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-30889905

RESUMO

BACKGROUND: Choline is essential for the synthesis of liver phosphatidylcholine (PC), parenchymal maintenance, bile formation, and lipoprotein assembly to secrete triglycerides. In choline deficiency, the liver accretes choline/PC at the expense of lung tissue, thereby impairing pulmonary PC homoeostasis. In cystic fibrosis (CF), exocrine pancreas insufficiency results in impaired cleavage of bile PC and subsequent fecal choline loss. In these patients, the plasma choline concentration is low and correlates with lung function. We therefore investigated the effect of choline supplementation on plasma choline/PC concentration and metabolism, lung function, and liver fat. METHODS: 10 adult male CF patients were recruited (11/2014⁻1/2016), and orally supplemented with 3 × 1 g choline chloride for 84 (84⁻91) days. Pre-/post-supplementation, patients were spiked with 3.6 mg/kg [methyl-D9]choline chloride to assess choline/PC metabolism. Mass spectrometry, spirometry, and hepatic nuclear resonance spectrometry served for analysis. RESULTS: Supplementation increased plasma choline from 4.8 (4.1⁻6.2) µmol/L to 10.5 (8.5⁻15.5) µmol/L at d84 (p < 0.01). Whereas plasma PC concentration remained unchanged, D9-labeled PC was decreased (12.2 [10.5⁻18.3] µmol/L vs. 17.7 [15.5⁻22.4] µmol/L, p < 0.01), indicating D9-tracer dilution due to higher choline pools. Supplementation increased Forced Expiratory Volume in 1 second percent of predicted (ppFEV1) from 70.0 (50.9⁻74.8)% to 78.3 (60.1⁻83.9)% (p < 0.05), and decreased liver fat from 1.58 (0.37⁻8.82)% to 0.84 (0.56⁻1.17)% (p < 0.01). Plasma choline returned to baseline concentration within 60 h. CONCLUSIONS: Choline supplementation normalized plasma choline concentration and increased choline-containing PC precursor pools in adult CF patients. Improved lung function and decreased liver fat suggest that in CF correcting choline deficiency is clinically important. Choline supplementation of CF patients should be further investigated in randomized, placebo-controlled trials.


Assuntos
Deficiência de Colina/tratamento farmacológico , Colina/uso terapêutico , Fibrose Cística/tratamento farmacológico , Volume Expiratório Forçado/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Adolescente , Adulto , Colina/sangue , Colina/farmacologia , Deficiência de Colina/sangue , Deficiência de Colina/complicações , Fibrose Cística/sangue , Fibrose Cística/patologia , Fibrose Cística/fisiopatologia , Suplementos Nutricionais , Insuficiência Pancreática Exócrina/sangue , Insuficiência Pancreática Exócrina/complicações , Insuficiência Pancreática Exócrina/tratamento farmacológico , Fígado Gorduroso/sangue , Fígado Gorduroso/etiologia , Fígado Gorduroso/prevenção & controle , Humanos , Fígado/metabolismo , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fosfatidilcolinas/sangue , Triglicerídeos/sangue , Adulto Jovem
10.
Environ Toxicol Pharmacol ; 66: 43-54, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30597379

RESUMO

The purpose of this work was to compare the influences of sulforaphane (SFN) to those of the standard insulin sensitizer pioglitazone (PIO) on high fructose diet (HFrD)-induced insulin resistance, dyslipidemia, hepatosteatosis, and vascular dysfunction in rats. Male Sprague Dawley rats (150-200 g) were fed on a standard diet (control) or a high fructose diet (HFrD, 60% w/w fructose) for 60 days. From day 16, two subgroups of HFrD-fed rats received either SFN (0.5 mg/kg/day, orally) or PIO (5 mg/kg/day, orally) along with HFrD until the end of the experiment. Fructose-fed rats showed significant decreases in food intake, body weight and feeding efficiency; effects that were not altered by either treatment. Data from insulin tolerance test (ITT), oral glucose tolerance test (OGTT), and HOMA-IR and HOMA-ß indices demonstrated impaired insulin sensitivity and glucose utilization in HFrD-fed rats. SFN and PIO treatments significantly reduced OGTTAUC (Glass's Delta values = 1.12 and 0.84, respectively), decreased ITTAUC (Glass's Delta values = 1.05 and 0.71, respectively), significantly diminished HOMA-IR index (by 55.6% and 77.6%, respectively), and increased HOMA-ß value (by 1.8 and 1.3 fold, respectively) compared to the HFrD rats. Moreover, SFN and PIO ameliorated hepatic oxidative stress and reduced serum levels of C-reactive protein and lactate dehydrogenase in HFrD-fed rats. Furthermore, SFN and PIO administrations improved insulin resistance-associated heaptosteatosis and enhanced vascular responsiveness to acetylcholine-induced relaxations. However, only SFN was able to enhance serum HDL-C levels in HFrD group. These finding suggests that SFN elicited insulin-sensitizing, hepatoprotective, and vasculoprotective effects in HFrD insulin-resistant rats that were comparable to those exerted by PIO.


Assuntos
Aorta Torácica/efeitos dos fármacos , Dislipidemias/tratamento farmacológico , Fígado Gorduroso/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Isotiocianatos/uso terapêutico , Pioglitazona/uso terapêutico , Animais , Aorta Torácica/fisiologia , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Proteína C-Reativa/análise , Dislipidemias/sangue , Dislipidemias/patologia , Fígado Gorduroso/sangue , Fígado Gorduroso/patologia , Frutose/administração & dosagem , L-Lactato Desidrogenase/sangue , Masculino , Ratos Sprague-Dawley
11.
Br J Biomed Sci ; 76(2): 70-76, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30691359

RESUMO

BACKGROUND AND AIM: This relatively comprehensive and multi-parametric study was conducted to investigate an association between hepatic fat percentage (HFP) values measured using high-field magnetic resonance imaging (MRI), anthropometric and biochemical measurements in healthy adults. METHODS: Abdominal MRI, anthropometric and biochemical measurements were determined in 156 healthy subjects. HFP values were derived from the MRI, whilst routine lipids, leptin, resistin, IL6 and adiponectin were measured by routine methods. RESULTS: Eighty per cent of the calculated HFP values were in the normal range of hepatic fat accumulation. Significant sex-adjusted correlations were found between HFP and waist circumference (WC) (measured by tape), BMI, leptin, resistin, WC (measured by MRI) and hip circumference (all p<0.001) and triglycerides (p=0.01). A significant inverse correlation was detected between HFP and adiponectin (p<0.001). CONCLUSIONS: A multi-parametric approach of MRI, biochemical and anthropometric measurements could be adopted to identify subjects at risk of developing non-alcoholic fatty liver disease.


Assuntos
Abdome/diagnóstico por imagem , Tecido Adiposo/diagnóstico por imagem , Fígado Gorduroso/diagnóstico por imagem , Fígado/diagnóstico por imagem , Abdome/patologia , Adiponectina/sangue , Tecido Adiposo/patologia , Adulto , Antropometria , Índice de Massa Corporal , Fígado Gorduroso/sangue , Fígado Gorduroso/epidemiologia , Fígado Gorduroso/patologia , Feminino , Voluntários Saudáveis , Humanos , Leptina/sangue , Fígado/patologia , Imagem por Ressonância Magnética , Masculino , Resistina/sangue , Fatores de Risco , Triglicerídeos/sangue , Circunferência da Cintura
12.
Food Chem Toxicol ; 123: 546-552, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30543894

RESUMO

We studied in rats the effects of cafeteria diet (CD) supplemented (or not) with fish oil (FO) during just the first 12 days of pregnancy, or during the whole of pregnancy and lactation in 14-month old offspring. Female rats were given standard diet (STD) or CD and after mating some animals remained on STD or CD; for some CD rats the diet was supplemented with 8.78% FO. After 12 days, half of the CD-FO group returned to CD (CD-FO12) and the others remained on CD-FO. From weaning all offspring were given STD. The adiposity index of male offspring of CD dams increased but was normal in CD-FO males. Plasma triacylglycerols (TAG) and individual fatty acid concentrations were similar among the groups. Liver total lipids, TAG, fatty acid concentrations, Δ9-desaturase indices and the mRNA expression of fatty acid synthase were higher in male offspring of CD than in those of STD; most of these differences disappeared in male offspring of CD-FO12 and CD-FO dams. Female offspring showed smaller changes. Thus, a moderate supplement with FO during just the first half of gestation or during pregnancy and lactation in rats on CD decreases the liver steatosis in male adult offspring.


Assuntos
Dieta/efeitos adversos , Suplementos Nutricionais/análise , Fígado Gorduroso/prevenção & controle , Óleos de Peixe/administração & dosagem , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Animais , Ácidos Graxos/sangue , Fígado Gorduroso/sangue , Fígado Gorduroso/etiologia , Feminino , Humanos , Fígado/metabolismo , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/etiologia , Ratos , Ratos Sprague-Dawley , Fatores Sexuais , Triglicerídeos/sangue
13.
Biochim Biophys Acta Mol Basis Dis ; 1865(1): 147-160, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30404040

RESUMO

OBJECTIVE: Diabetes exerts adverse effects on the initiation or progression of diabetes and metabolic syndrome in the next generation. In past studies, limited attention has been given to the fathers' role in shaping the metabolic landscape of offspring. Our study was designed to investigate how paternal hyperglycemia exerts an intergenerational effect in mammals as well as the underlying mechanisms. METHODS: Hyperglycemia was introduced in male rats by intraperitoneally injected streptozotocin and these males were bred with healthy females to generate offspring. The metabolic profiles of the progeny were assessed; DNA methylation profiles and gene expression were investigated. Mutagenesis constructs of the Ppara promoter region, and a luciferase reporter assay were used to determine transcription factor binding sites (TFBSs) and the effects of hypermethylation on Ppara transcription. RESULTS: Paternal hyperglycemia induced increased liver weight, and plasma TC, TG, LDL, accumulation of triglycerides in the liver. We discovered that CpG 13 in the amplified promoter region (-852 to -601) of Ppara was hypermethylated in adult offspring liver and expression of Ppara, Acox1, Cpt-1α, and Cd36 was down regulated. Hypermethylation of CpG site 13 in the Ppara promoter inhibited the gene transcription, probably through abrogation of SP1 binding. The same epigenetic alteration was discovered in the fetus (E16.5) liver of hyperglycemic father's progeny. CONCLUSIONS: Paternal hyperglycemia may induce epigenetic modification of Ppara in offspring's liver, probably through interaction with SP1 binding, causing impaired lipid metabolism. Our investigation may have implications for the understanding of father-offspring interactions with the potential to account for metabolic syndromes.


Assuntos
Metilação de DNA , Fígado Gorduroso/metabolismo , Hiperglicemia/metabolismo , PPAR alfa/genética , Herança Paterna , Regiões Promotoras Genéticas/genética , Animais , Sítios de Ligação , Filho de Pais Incapacitados , Diabetes Mellitus/metabolismo , Pai , Fígado Gorduroso/sangue , Feminino , Hepatócitos/metabolismo , Hepatócitos/patologia , Hiperglicemia/sangue , Fígado/metabolismo , Fígado/patologia , Masculino , Síndrome Metabólica/metabolismo , Mutagênese , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição
14.
Biochem Pharmacol ; 160: 46-61, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30529690

RESUMO

Alcoholic ketoacidosis and diabetic ketoacidosis are life-threatening complications that share the characteristic features of high anion gap metabolic acidosis. Ketoacidosis is attributed in part to the massive release of ketone bodies (e.g., ß-hydroxybutyrate; ßOHB) from the liver into the systemic circulation. To date, the impact of ethanol consumption on systemic ketone concentration, glycemic control, and hepatic gluconeogenesis and glycogenesis remains largely unknown, especially in the context of type 2 diabetes. In the present study, ethanol intake (36% ethanol- and 36% fat-derived calories) by type 2 diabetic db/db mice for 9 days resulted in significant decreases in weight gain (∼19.5% ↓) and caloric intake (∼30% ↓). This was accompanied by a transition from macrovesicular-to-microvesicular hepatic steatosis with a modest increase in hepatic TG (∼37% ↑). Importantly, ethanol increased systemic ßOHB concentration (∼8-fold ↑) with significant decreases in blood glucose (∼4-fold ↓) and plasma insulin and HOMA-IR index (∼3-fold ↓). In addition, ethanol enhanced hepatic ßOHB content (∼5-fold ↑) and hmgcs2 mRNA expression (∼3.7-fold ↑), downregulated key gluconeogenic mRNAs (e.g., Pcx, Pck1, and G6pc), and depleted hepatic glycogen (∼4-fold ↓). Furthermore, ethanol intake led to significant decreases in the mRNA/protein expression and allosteric activation of glycogen synthase (GS) in liver tissues regardless of changes in the phosphorylation of GS, GSK-3ß, or Akt. Together, our findings suggest that ethanol-induced ketonemia may occur in concomitance with significant lowering of blood glucose concentration, which may be attributed to suppression of gluconeogenesis in the setting of glycogen depletion in type 2 diabetes.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Gluconeogênese/genética , Cetose/metabolismo , Glicogênio Hepático/metabolismo , Animais , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Regulação para Baixo , Etanol , Fígado Gorduroso/sangue , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Regulação da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Corpos Cetônicos/metabolismo , Cetose/sangue , Cetose/induzido quimicamente , Masculino , Camundongos Knockout , Fosforilação
15.
Ann Agric Environ Med ; 25(4): 690-692, 2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30586966

RESUMO

OBJECTIVE: Evaluation of the neutrophil-lymphocyte ratio and mean platelet volume as predictive factors for liver fibrosis and steatosis in HBV patients qualified for antiviral treatment. MATERIAL AND METHODS: The study comprised 38 CHB patients who had commenced antiviral treatment, and 20 healthy volunteers who constituted the clinical control group. All patients had their blood count taken and underwent hepatic assessment using transient elastography with CAP (controlled attenuation parameter). RESULTS: It was found that the mean hepatic fibrosis was 8.7 kPa (±8.8) and the mean liver steatosis - 286 db/m (±64). Mean NLR - 2.78(±1.1), whereas in the control group the mean NLR value was 1.64(±0.98). A negative linear correlation (r= -0.34; p=0.035) was found between liver fibrosis and the NLR value in the study group. No correlation was observed between hepatic steatosis and the NLR. Mean MPV - 12.6fl (±3.1), which was considerably higher in the CBH patients than in the control group. A positive correlation (r= 0.79, p= 0.001) was found between MPV and disease severity evaluated with transient elastography. CONCLUSIONS: The NLR and the MPV were significantly higher in the CHB patients than in the healthy volunteers. Both the NLR and the MPV can be treated as predictive factors for liver fibrosis in this group of patients.


Assuntos
Fígado Gorduroso/diagnóstico , Hepatite B Crônica/complicações , Cirrose Hepática/diagnóstico , Idoso , Contagem de Células Sanguíneas , Fígado Gorduroso/sangue , Fígado Gorduroso/etiologia , Feminino , Humanos , Cirrose Hepática/sangue , Cirrose Hepática/etiologia , Linfócitos/citologia , Masculino , Volume Plaquetário Médio , Pessoa de Meia-Idade , Neutrófilos/citologia , Estudos Retrospectivos
16.
Vopr Pitan ; 87(5): 13-19, 2018.
Artigo em Russo | MEDLINE | ID: mdl-30592886

RESUMO

It is assumed that in the progression of obesity, complicated by fatty hepatosis in adolescents, a significant role is given to the reactions of oxidative stress with deficiency of antioxidant factors. However, an important factor that remains outside the field of view of researchers is the ethnicity of the patient, which is an important element in the development of a personalized approach in the treatment and prevention of diseases. In connection with this, the purpose of this study was to study the changes in the lipid peroxidation-antioxidant defense processes in adolescent Mongoloids with exogenously constitutional obesity complicated by fatty hepatosis. 18 adolescent boys with fatty hepatosis were examined on the background of exogenous-constitutional obesity of the first degree; 38 adolescent boys with exogenously constitutional obesity without changes in the liver and 37 practically healthy adolescents (control group). All subjects surveyed for ethnicity belonged to the Mongoloids. Spectrophotometric and fluorometric methods were used in the research. The results of the study indicated a high intensity of lipid peroxidation reactions in Mongoloid boys with obesity and fatty hepatosis relative to control values: an increase in blood plasma content of compounds with unsaturated double bonds (p<0.001), diene conjugates (p=0.0012), ketodienes and conjugated trienes (p<0.0001), in the absence of significant differences in the level of TBA-active products. Increased values of total antioxidant activity in blood plasma (p=0.0023) and erythrocyte superoxide dismutase activity (p=0.0072), decreased levels of fat-soluble vitamins in blood plasma [α-tocopherol (p<0.0001) and retinol (p=0.0011)] and oxidized form of glutathione in erythrocytes (p=0.0083) have been found. The pronounced insufficiency of fatsoluble vitamins - α-tocopherol and retinol in patients of the main group was also noted in comparison with patients without morphological changes in the liver. Thus, in teenage Mongoloids with exogenously constitutional obesity and fatty hepatosis, it is possible to recommend antioxidant drugs in addition to basic metabolic therapy.


Assuntos
Grupo com Ancestrais do Continente Asiático , Fígado Gorduroso/sangue , Peroxidação de Lipídeos , Obesidade/sangue , Adolescente , Antioxidantes/metabolismo , Eritrócitos/metabolismo , Dissulfeto de Glutationa/sangue , Humanos , Masculino , Vitamina A/sangue , alfa-Tocoferol/sangue
17.
Drug Alcohol Depend ; 190: 195-199, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30048873

RESUMO

BACKGROUND: To analyze ultrasound findings of liver damage in alcohol use disorder (AUD) patients. METHODS: A cross-sectional analysis of detoxification patients. Clinical and laboratory parameters were obtained at admission. Analytical liver injury (ALI) was defined as at least two of the following: aspartate aminotransferase (AST) levels ≥74 < 300 U/L, AST/alanine aminotransferase (ALT) ratio >2, and total bilirubin >1.2 mg/dL. Advanced liver fibrosis (ALF) was defined as a FIB-4 score ≥3.25. Abdominal ultrasound was used to identify steatosis, hepatomegaly, heterogeneous liver, and portal hypertension. Predictors of these findings were determined by logistic regression. RESULTS: We included 301 patients (80% male) with a median age of 46 years (IQR: 39-51 years) and alcohol consumption of 180 g/day (IQR: 120-201 g). The prevalence of Hepatitis C virus (HCV) was 21.2%; AST and ALT serum levels were 42 U/L (IQR: 23-78 U/L) and 35 U/L (IQR: 19-60 U/L), respectively; 16% of patients had ALI and 24% ALF. Ultrasound findings were: 57.2% steatosis, 49.5% hepatomegaly, 17% heterogeneous liver, and 16% portal hypertension; 77% had at least one ultrasound abnormality, and 45% had ≥2. HCV infection was associated with heterogeneous liver (p = 0.046) and portal hypertension (p < 0.01). ALI and ALF were associated with steatosis (both p < 0.01) and hepatomegaly (both p < 0.01), ALI with portal hypertension (p = 0.08), and ALF with heterogeneous liver (p < 0.01). In logistic regression, ALI and ALF were associated with ≥2 abnormalities [OR (95%CI): 5.2 (2.1-12.8), p < 0.01 and 4.7 (2.2-9.7), p < 0.01; respectively]. CONCLUSIONS: Ultrasound findings of liver damage may facilitate clinical decisions and alcohol cessation in AUD patients.


Assuntos
Alcoolismo/diagnóstico por imagem , Alcoolismo/terapia , Hepatopatias/diagnóstico por imagem , Hepatopatias/terapia , Admissão do Paciente/tendências , Adulto , Alanina Transaminase/sangue , Consumo de Bebidas Alcoólicas/sangue , Consumo de Bebidas Alcoólicas/terapia , Alcoolismo/sangue , Aspartato Aminotransferases/sangue , Estudos Transversais , Fígado Gorduroso/sangue , Fígado Gorduroso/diagnóstico por imagem , Fígado Gorduroso/epidemiologia , Feminino , Hepatite C/sangue , Hepatite C/diagnóstico por imagem , Hepatite C/epidemiologia , Humanos , Hepatopatias/sangue , Masculino , Pessoa de Meia-Idade , Prevalência , Resultado do Tratamento
18.
Chem Biol Interact ; 291: 87-94, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29913120

RESUMO

Irinotecan is highly effective in the treatment of metastatic colorectal cancer as well as many other cancers. However, irinotecan is known to cause severe diarrhea, which pose significant problems in patients undergoing irinotecan based chemotherapy. Dietary and herbal components have shown promise in improving gastrointestinal health. Therefore, we compared the effect of grain-based chow diet containing phytoestrogens and corn/alfalfa as fat source to purified diets containing either animal-derived fat source (lard) or plant-derived fat source (soybean oil) on irinotecan-induced toxicities in mice. The concentration of the toxic metabolite, SN-38, was measured in the serum, and the activity of main enzyme, carboxylesterase (CEs) involved in biotransformation of irinotecan to SN-38 formation was measured in the liver. We found that the grain-based diet was protective against irinotecan-induced diarrhea. Interestingly, purified diet containing lard caused fatty liver in mice, while grain-based chow diet containing corn/alfa-alfa or purified diet with soybean oil did not cause fat deposition in the liver. Serum SN-38 concentration was significantly higher in the mice fed with purified diets compared to the chow-fed mice. Hepatic CEs activity was induced in the presence of irinotecan in mice on purified diets, but not chow diet. These results indicate that components of grain-based natural diet (presumably phytoestrogens and/or the macronutrients balance) compared to purified diets may have a beneficial effect by controlling the adverse effects of irinotecan in cancer patients.


Assuntos
Camptotecina/análogos & derivados , Dieta , Testes de Toxicidade , Animais , Peso Corporal/efeitos dos fármacos , Camptotecina/efeitos adversos , Camptotecina/sangue , Camptotecina/toxicidade , Carboxilesterase/metabolismo , Diarreia/sangue , Diarreia/induzido quimicamente , Fígado Gorduroso/sangue , Fígado Gorduroso/induzido quimicamente , Fígado Gorduroso/patologia , Glucuronidase/metabolismo , Irinotecano , Masculino , Metaboloma , Camundongos Endogâmicos C57BL
19.
Biomed Pharmacother ; 105: 299-311, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29860222

RESUMO

This study investigated the molecular effects of acylated (AG) and unacylated ghrelin (UAG) or their combination on hepatic lipogenesis pathways and DAG/PKC/JNK signaling in the livers of lean rats fed standard diet. Male rats (n = 10) were classified as control + vehicle (saline, 200 µl), AG, UAG, and AG + UAG-treated groups. All treatments were given at final doses of 200 ng/kg of for 14 days (twice/day, S.C). Administration of AG significantly enhanced circulatory levels of AG and UAG turning the normal ratio of AG/UAG from 1:2.5 to 1:1.2. However, while UAG didn't affect circulatory levels of AG, administration of UAG alone or in combination with AG resulted in AG/UAG ratios of 1:7 and 1:3, respectively. Independent of food intake nor the development of peripheral IR, AG increased hepatic DAG, TGs and CHOL contents and induced hepatic IR. Mechanism of action include 1) upregulation of mRNA and protein levels of DGAT-2 and mtGPAT-1, SREBP-1 and SCD-1, and 2) inhibition of fatty acids (FAs) oxidation mediated by inhibition of AMPK/ PPAR-α/CPT-1 axis. Consequently, AG induced membranous translocation of PKCδ and PKCε leading to activation of JNK and significant inhibition of insulin signaling under basal and insulin stimulation as evident by decreases in the phosphorylation levels of IRS (Tyr612) and Akt (Thr318) and increased phosphorylation of IRS (Ser307). However, while UAG only activated FAs oxidation in control rats, it reversed all alterations in all measured biochemical endpoints seen in the AG-treated group, when administered in combination with AG, leading to significant decreases in hepatic fat accumulation and prevention of hepatic IR. In conclusion, while exogenous administration of AG is at high risk of developing steatohepatitis and hepatic IR, co-administration of a balanced dose of UAG reduces this risk and inhibits hepatic lipid accumulation and enhance hepatic insulin signaling.


Assuntos
Diglicerídeos/metabolismo , Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Grelina/farmacologia , Resistência à Insulina , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteína Quinase C/metabolismo , Magreza/complicações , Acilação , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Fígado Gorduroso/sangue , Fígado Gorduroso/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Grelina/administração & dosagem , Grelina/uso terapêutico , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/patologia , Insulina/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Fosforilação/efeitos dos fármacos , Fosfotreonina/metabolismo , Transporte Proteico/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Wistar , Transdução de Sinais , Magreza/genética , Magreza/patologia
20.
Biochem Biophys Res Commun ; 501(4): 974-981, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29777706

RESUMO

Parenteral nutrition (PN) is one of the basic therapies for patients with intestinal failure; however, hepatic steatosis associated with PN limits the long-term use of PN. N-3 polyunsaturated fatty acids (PUFAs) have been used to improve clinical outcomes of patients receiving PN; however, the mechanisms by which n-3 PUFAs ameliorate hepatic steatosis remain unclear. In the present study, C57BL/6J mice were randomly assigned to three treatment groups, namely, enteral nutrition (EN), n-3 PUFAs, and n-6 PUFAs. Additionally, MK 886 was used to inhibit PPAR-α. After 7 days of intervention, mice were sacrificed, and liver tissue and serum samples were collected. Results from liver weight and liver triglyceride measurements and Oil Red O staining showed that n-3 PUFAs significantly reduced the liver triglyceride levels. In addition, treatment with n-3 PUFAs resulted in a greater decrease in serum triglyceride and low-density lipoprotein cholesterol levels compared to n-6 PUFAs. The key enzymes involved in FA oxidation, namely, PPAR-α and CPT-1α, were significantly restored at both the mRNA and protein levels in the n-3 PUFAs group. However, the benefits of n-3 PUFAs in improving serum and liver TG levels were abolished when the PPAR-α/CPT-1α pathway was blocked by MK 886. The results of this study indicated that n-3 PUFAs ameliorated the PN-associated hepatic steatosis by activating the PPAR-α/CPT-1α pathway. The present study provided a reliable scientific basis supporting the potential beneficial effects of n-3 PUFAs for improving hepatic steatosis in patients receiving long-term parenteral nutrition.


Assuntos
Carnitina O-Palmitoiltransferase/metabolismo , Ácidos Graxos Ômega-3/uso terapêutico , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , PPAR alfa/metabolismo , Nutrição Parenteral , Animais , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-6/metabolismo , Fígado Gorduroso/sangue , Fígado Gorduroso/patologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/sangue , Masculino , Camundongos Endogâmicos C57BL , Modelos Animais , Tamanho do Órgão/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
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