Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.258
Filtrar
1.
Nature ; 574(7776): 63-68, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31554967

RESUMO

The gp130 receptor cytokines IL-6 and CNTF improve metabolic homeostasis but have limited therapeutic use for the treatment of type 2 diabetes. Accordingly, we engineered the gp130 ligand IC7Fc, in which one gp130-binding site is removed from IL-6 and replaced with the LIF-receptor-binding site from CNTF, fused with the Fc domain of immunoglobulin G, creating a cytokine with CNTF-like, but IL-6-receptor-dependent, signalling. Here we show that IC7Fc improves glucose tolerance and hyperglycaemia and prevents weight gain and liver steatosis in mice. In addition, IC7Fc either increases, or prevents the loss of, skeletal muscle mass by activation of the transcriptional regulator YAP1. In human-cell-based assays, and in non-human primates, IC7Fc treatment results in no signs of inflammation or immunogenicity. Thus, IC7Fc is a realistic next-generation biological agent for the treatment of type 2 diabetes and muscle atrophy, disorders that are currently pandemic.


Assuntos
Receptor gp130 de Citocina/metabolismo , Citocinas/síntese química , Citocinas/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Ligação Competitiva , Citocinas/química , Diabetes Mellitus Tipo 2/metabolismo , Desenho de Drogas , Fígado Gorduroso/prevenção & controle , Teste de Tolerância a Glucose , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Incretinas/metabolismo , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Masculino , Camundongos , Músculo Esquelético/efeitos dos fármacos , Obesidade/metabolismo , Pâncreas/metabolismo , Fosfoproteínas/metabolismo , Engenharia de Proteínas , Receptores de Interleucina-6/metabolismo , Transdução de Sinais , Fatores de Transcrição , Ganho de Peso/efeitos dos fármacos
2.
Am J Chin Med ; 47(6): 1253-1270, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31488034

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disorder associated with features of metabolic syndrome and oxidative stress. We examined the mechanism by which the combined extracts of Rhus verniciflua and Eucommia ulmoides extracts (ILF-RE) regulate hepatic dyslipidemia in an established NAFLD model, high-fat diet (HFD)-induced lipid dysmetabolism in rats. ILF-RE attenuated alanine aminotransferase (ALT) by 1.5% (p<0.05), aspartate aminotransferase (AST) by 1.5% (p<0.05), triglycerides by 1.5% (p<0.05), cholesterol by 2.0% (p<0.05), and lipid peroxidation by 1.5% (p<0.05) in the NAFLD model. ILF-RE, recently shown to have anti-oxidant properties, also inhibited hepatic ROS accumulation by 1.68% (p<0.05) and regulated ER-redox imbalance, a key phenomenon of ER stress. Due to nutrient overload stress-associated protein folding, ER stress and downstream SREBP-lipogenic transcription signaling were highly activated, and the mTORC1-AMPK axis was also disturbed, leading to hepatic steatosis. ILF-RE results in recovery from hepatic conditions induced by nutrient-based protein folding stress signaling and the ER stress-SREBP and AMPK-mTORC1-SREBP1 axes. Based on these results, ILF-RE is suggested to be a potential therapeutic strategy for hepatic steatosis and may represent a promising novel agent for the prevention and treatment of NAFLD.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Eucommiaceae/química , Fígado Gorduroso/etiologia , Fígado Gorduroso/prevenção & controle , Fitoterapia , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Antioxidantes , Modelos Animais de Doenças , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/metabolismo , Glucosídeos Iridoides/isolamento & purificação , Glucosídeos Iridoides/farmacologia , Glucosídeos Iridoides/uso terapêutico , Iridoides/isolamento & purificação , Iridoides/farmacologia , Iridoides/uso terapêutico , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificação , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo
3.
PLoS One ; 14(8): e0214903, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31390361

RESUMO

This study aimed to evaluate the effects of a high dose of conjugated linoleic acid (CLA) on lactating mice. In one experiment, Kunming mice were separated into four groups (n = 6 per group); the control (CON) group received 3.0% linoleic acid (LA) oil, the L-CLA group received a mixture of 2.0% LA and 1.0% CLA, the M-CLA group received a mixture of 1.0% LA and a 2.0% CLA, and the H-CLA group received 3.0% CLA. Feeding proceeded from day 4 to day 10 of lactation. In a second experiment, a CON group received 3.0% LA, and an H-CLA group received 3.0% CLA. Plasma parameters were analyzed for all groups, and insulin tolerance tests (ITTs) were conducted. CLA treatment did not affect dam weight but significantly decreased the food intake of dams during lactation. Furthermore, CLA decreased the weight of pups on day 10 of lactation; this effect was attributed to lower milk fat of dams in the CLA group than in those of the other groups. Relative to mice in the CON group, the mice in the H-CLA group displayed increased liver weight and liver triglyceride (TG) content as well as higher TG content and γ-glutamyl transferase (γ-GT) activity in the plasma. Moreover, high-dose CLA resulted in insulin resistance, possibly affecting the red blood cell (RBC) and hemoglobin (HCB) levels in the plasma. In conclusion, lactating mice receiving a high dose of CLA exhibited fatty liver, insulin resistance, and impaired lactation performance.


Assuntos
Fígado Gorduroso/prevenção & controle , Resistência à Insulina , Lactação , Ácidos Linoleicos Conjugados/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Suplementos Nutricionais/análise , Relação Dose-Resposta a Droga , Ingestão de Alimentos/efeitos dos fármacos , Fígado Gorduroso/metabolismo , Ácidos Linoleicos Conjugados/análise , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Leite/efeitos dos fármacos , Leite/metabolismo
4.
Toxicol Lett ; 316: 183-193, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31437515

RESUMO

Olanzapine, a representative of antipsychotics, is a first-line drug for treatment of schizophrenia. However, olanzapine-induced liver steatosis limits its clinical utilization. This study is to explore the mechanism of liver steatosis induced by olanzapine based on the regulation of transporters involved in uptake and oxidation of fatty acids. Our results revealed that 12-week oral administration of olanzapine increased hepatic triglyceride(TG), caused liver steatosis. Our further studies showed that the expression of fatty acid transporter 2(FATP2) and fatty acid binding protein 1(FABP1) were up-regulated in liver of female mice after 12-week olanzapine exposure, as well as in primary mouse hepatocytes treated with olanzapine. Olanzapine treatment also reduced hepatic ß-hydroxybutyrate level (indicator of fatty acid ß-oxidation), meanwhile, the L-carnitine (L-Car) concentration in liver of olanzapine group was significantly lower than that in control group. Further study demonstrated that both mRNA and protein expression of hepatic OCTN2 (carnitine/organic cation transporter 2) were obviously down-regulated in male mice after 12-week olanzapine treatment. Also, olanzapine markedly inhibited L-Car uptake in MDCK-hOCTN2 cells (1.06 µM of IC50), HepG2 cells and primary mouse hepatocytes. Supplementation of L-Car attenuated hepatic TG rise and improved simple steatosis in olanzapine treatment mice. Taken together, up-regulation of FATP2/FABP1 and down-regulation/inhibition of hepatic OCTN2 probably contribute to olanzapine-induced liver steatosis. Supplementation of L-Car is a promising strategy to attenuate olanzapine-induced simple steatosis.


Assuntos
Antipsicóticos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Coenzima A Ligases/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Fígado Gorduroso/induzido quimicamente , Hepatócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Olanzapina/toxicidade , Membro 5 da Família 22 de Carreadores de Soluto/antagonistas & inibidores , Adulto , Animais , Carnitina/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Coenzima A Ligases/genética , Cães , Proteínas de Ligação a Ácido Graxo/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Fígado Gorduroso/prevenção & controle , Feminino , Células Hep G2 , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Fígado/metabolismo , Fígado/patologia , Células Madin Darby de Rim Canino , Masculino , Camundongos Endogâmicos C57BL , Membro 5 da Família 22 de Carreadores de Soluto/genética , Membro 5 da Família 22 de Carreadores de Soluto/metabolismo , Regulação para Cima
5.
PLoS One ; 14(7): e0217155, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31295333

RESUMO

Intestinal failure-associated liver disease (IFALD) is a risk of parenteral nutrition (PN)-dependence. Intravenous soybean oil-based parenteral fat can exacerbate the risk of IFALD while intravenous fish oil can minimize its progression, yet the mechanisms by which soybean oil harms and fish oil protects the liver are uncertain. Properties that differentiate soybean and fish oils include α-tocopherol and phytosterol content. Soybean oil is rich in phytosterols and contains little α-tocopherol. Fish oil contains abundant α-tocopherol and little phytosterols. This study tested whether α-tocopherol confers hepatoprotective properties while phytosterols confer hepatotoxicity to intravenous fat emulsions. Utilizing emulsions formulated in the laboratory, a soybean oil emulsion (SO) failed to protect from hepatosteatosis in mice administered a PN solution enterally. An emulsion of soybean oil containing α-tocopherol (SO+AT) preserved normal hepatic architecture. A fish oil emulsion (FO) and an emulsion of fish oil containing phytosterols (FO+P) protected from steatosis in this model. Expression of hepatic acetyl CoA carboxylase (ACC) and peroxisome proliferator-activated receptor gamma (PPARγ), was increased in animals administered SO. ACC and PPARγ levels were comparable to chow-fed controls in animals receiving SO+AT, FO, and FO+P. This study suggests a hepatoprotective role for α-tocopherol in liver injury induced by the enteral administration of a parenteral nutrition solution. Phytosterols do not appear to compromise the hepatoprotective effects of fish oil.


Assuntos
Emulsões Gordurosas Intravenosas/uso terapêutico , Fígado Gorduroso/etiologia , Fígado Gorduroso/prevenção & controle , Substâncias Protetoras/uso terapêutico , alfa-Tocoferol/uso terapêutico , Animais , Modelos Animais de Doenças , Emulsões Gordurosas Intravenosas/administração & dosagem , Emulsões Gordurosas Intravenosas/efeitos adversos , Fígado Gorduroso/patologia , Óleos de Peixe/administração & dosagem , Óleos de Peixe/efeitos adversos , Óleos de Peixe/uso terapêutico , Camundongos Endogâmicos C57BL , Nutrição Parenteral/efeitos adversos , Fitosteróis/administração & dosagem , Fitosteróis/efeitos adversos , Fitosteróis/uso terapêutico , Substâncias Protetoras/administração & dosagem , Substâncias Protetoras/efeitos adversos , Óleo de Soja/administração & dosagem , Óleo de Soja/efeitos adversos , Óleo de Soja/uso terapêutico , alfa-Tocoferol/administração & dosagem , alfa-Tocoferol/efeitos adversos
6.
Food Chem Toxicol ; 131: 110558, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31175915

RESUMO

Effects of Spirulina platensis 55% ethanol extract (SPL55) on lipid metabolism in high-fat diet-induced hyperlipidaemic rats were investigated. Ultra performance liquid chromatography-quadrupole time-of-flight mass spectrometry indicated that SPL55 was enriched with polyunsaturated fatty acids. Meanwhile, serum and liver lipid levels, including total triglyceride, total cholesterol, and low-density-lipoprotein cholesterol, were significantly decreased in hyperlipidaemic rats of SPL55. Analysis of tissue sections showed that SPL55 treatment could markedly inhibit hepatic lipid accumulation and steatosis. Moreover, SPL55 regulated the mRNA and protein expression levels of SREBP-1c, HMG-CoA, PEPCK, ACC, and AMPK genes involved in lipid metabolism. Furthermore, SPL55 led to decrease the abundances of Turicibacter, Clostridium_XlVa, and Romboutsia, which were positive correlation with lipid metabolism indicators, and has also enriched Alloprevotella, Prevotella, Porphyromonadaceae, and Barnesiella. These results provided evidence that SPL55 might be developed as a functional food to ameliorate lipid metabolic disorders and hyperlipidaemia.


Assuntos
Ácidos Graxos Insaturados/farmacologia , Fígado Gorduroso/prevenção & controle , Microbioma Gastrointestinal/efeitos dos fármacos , Spirulina/química , Animais , Peso Corporal/efeitos dos fármacos , HDL-Colesterol/sangue , HDL-Colesterol/metabolismo , LDL-Colesterol/sangue , LDL-Colesterol/metabolismo , Dieta Hiperlipídica , Ácidos Graxos Insaturados/metabolismo , Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Fígado/patologia , Microalgas/química , Ratos , Ratos Wistar , Triglicerídeos/sangue , Triglicerídeos/metabolismo
7.
J Steroid Biochem Mol Biol ; 192: 105399, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31175967

RESUMO

The fructose added to soft drinks and processed food, as well as frequent detection of vitamin D deficiency in the body, are two insults increasingly considered to cause lesions in target organs. We studied the liver after a chronic high-fructose diet deficient and supplemented with vitamin D. Sixty C57BL/6 mature male mice were allocated into six groups (n = 10) for ten weeks: control (C), control deficient in vitamin D (CDD), control supplemented with vitamin D (CDS), fructose (F), fructose deficient in vitamin D (FDD), and fructose supplemented with vitamin D (FDS). The gene expressions of vitamin D receptor and CYP27B1 and 25 hydroxyvitamin D plasma level ensured that the diets caused vitamin D deficiency or supplementation. Body mass did not change, but blood pressure (BP) increased in CDD, F, and FDD, whereas BP was controlled in FDS. Insulinemia, insulin tolerance and resistance were seen in both vitamin D deficiency and fructose groups but improved with vitamin D supplementation. The steatosis and fibrosis were observed in the CDD, F and FDD groups. Also, F and FDD showed activation of stellate cells (HSC). Lipogenesis and inflammation gene expressions were enhanced in the CDD, F and FDD groups, but diminished with vitamin D supplementation. In conclusion, we demonstrated the adverse effects of vitamin D deficiency on metabolism, liver steatosis and, combined with fructose intake, liver interstitial fibrosis with hepatic stellate cell activation, and alteration of the lipogenesis, beta-oxidation, and liver inflammation. All these data improved when vitamin D was supplemented in the animals.


Assuntos
Suplementos Nutricionais , Fígado Gorduroso/prevenção & controle , Frutose/farmacologia , Resistência à Insulina , Lipogênese , Deficiência de Vitamina D/complicações , Vitamina D/administração & dosagem , Animais , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Frutose/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vitaminas/administração & dosagem
8.
Nutrients ; 11(5)2019 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-31035507

RESUMO

Excessive fat accumulation within the liver is known as "simple hepatic steatosis", which is the most benign form of non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to determine whether pterostilbene improves this hepatic alteration in Zucker (fa/fa) rats. Animals were distributed in two experimental groups (n = 10) and fed a standard laboratory diet. Rats in the pterostilbene group were given a dose of 30 mg/kg body weight/d for six weeks. After sacrifice, serum glucose, transaminase, and insulin concentrations were quantified and the liver triacylglycerol content and fatty acid profile was analyzed. Different pathways of triacylglycerol metabolism in liver were studied, including fatty acid synthesis and oxidation, triglyceride assembly, fatty acid uptake, and glucose uptake. With pterostilbene administration, a reduction in insulin concentrations (consequently in the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)) and hepatic triacylglycerol content were observed. No effects were observed in pterostilbene-treated rats in the activity of de novo lipogenesis enzymes. An improvement in the fatty acid profile was observed in pterostilbene-treated rats. In conclusion, pterostilbene is a useful molecule to reduce liver steatosis. Its delipidating effect is due, at least in part, to reduced fatty acid availability and triacylglycerol synthesis, as well as to an increased very low-density lipoprotein assembly and fatty acid oxidation.


Assuntos
Fígado Gorduroso/prevenção & controle , Fígado/metabolismo , Obesidade/metabolismo , Estilbenos/uso terapêutico , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/enzimologia , RNA/genética , RNA/metabolismo , Distribuição Aleatória , Ratos , Ratos Zucker , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estilbenos/administração & dosagem
9.
Nutrients ; 11(5)2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31075850

RESUMO

4-Hydroxy-3-methoxycinnamic acid (HMCA), a hydroxycinnamic acid derivative, is abundant in fruits and vegetables, including oranges, carrots, rice bran, and coffee beans. Several beneficial effects of HMCA have been reported, including improvement of metabolic abnormalities in animal models and human studies. However, its mitigating effects on high-fat diet (HFD)-induced obesity, and the mechanism underlying these effects, remain to be elucidated. In this study, we demonstrated that dietary HMCA was efficacious against HFD-induced weight gain and hepatic steatosis, and that it improved insulin sensitivity. These metabolic benefits of HMCA were ascribable to 3-(4-hydroxy-3-methoxyphenyl)propionic acid (HMPA) produced by gut microbiota. Moreover, conversion of HMCA into HMPA was attributable to a wide variety of microbes belonging to the phylum Bacteroidetes. We further showed that HMPA modulated gut microbes associated with host metabolic homeostasis by increasing the abundance of organisms belonging to the phylum Bacteroidetes and reducing the abundance of the phylum Firmicutes. Collectively, these results suggest that HMPA derived from HMCA is metabolically beneficial, and regulates hepatic lipid metabolism, insulin sensitivity, and the gut microbial community. Our results provide insights for the development of functional foods and preventive medicines, based on the microbiota of the intestinal environment, for the prevention of metabolic disorders.


Assuntos
Ácidos Cumáricos/farmacologia , Dieta , Microbioma Gastrointestinal/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Obesidade/metabolismo , Propionatos/farmacologia , Animais , Bacteroidetes/efeitos dos fármacos , Bacteroidetes/crescimento & desenvolvimento , Bacteroidetes/metabolismo , Citrus sinensis/química , Coffea/química , Ácidos Cumáricos/metabolismo , Daucus carota/química , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/etiologia , Fígado Gorduroso/prevenção & controle , Firmicutes/crescimento & desenvolvimento , Firmicutes/metabolismo , Trato Gastrointestinal/metabolismo , Trato Gastrointestinal/microbiologia , Resistência à Insulina , Fígado/metabolismo , Fígado/patologia , Masculino , Doenças Metabólicas/etiologia , Doenças Metabólicas/metabolismo , Doenças Metabólicas/patologia , Doenças Metabólicas/prevenção & controle , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/complicações , Obesidade/etiologia , Oryza/química , Plantas Comestíveis/química , Propionatos/metabolismo , Ganho de Peso/efeitos dos fármacos
10.
Int J Mol Sci ; 20(10)2019 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-31126043

RESUMO

Phytochemicals are known to benefit human health by modulating various cellular processes, including cell proliferation, apoptosis, and inflammation. Due to the potential use of phytochemicals as therapeutic agents against human diseases such as cancer, studies are ongoing to elucidate the molecular mechanisms by which phytochemicals affect cellular functions. It has recently been shown that phytochemicals may regulate the expression of microRNAs (miRNAs). MiRNAs are responsible for the fine-tuning of gene expression by controlling the expression of their target mRNAs in both normal and pathological cells. This review summarizes the recent findings regarding phytochemicals that modulate miRNA expression and promote human health by exerting anticancer, photoprotective, and anti-hepatosteatosis effects. Identifying miRNAs modulated by phytochemicals and understanding the regulatory mechanisms mediated by their target mRNAs will facilitate the efforts to maximize the therapeutic benefits of phytochemicals.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Fígado Gorduroso/tratamento farmacológico , MicroRNAs/genética , Neoplasias/tratamento farmacológico , Compostos Fitoquímicos/uso terapêutico , Substâncias Protetoras/uso terapêutico , Animais , Antineoplásicos Fitogênicos/farmacologia , Fígado Gorduroso/genética , Fígado Gorduroso/prevenção & controle , Regulação da Expressão Gênica/efeitos dos fármacos , Promoção da Saúde , Humanos , Neoplasias/genética , Neoplasias/prevenção & controle , Compostos Fitoquímicos/farmacologia , Substâncias Protetoras/farmacologia
11.
Nutrients ; 11(5)2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31064103

RESUMO

Nonalcoholic fatty liver diseases (NAFLD) is characterized by accumulation of lipid droplets in the liver. The objective of this study was to evaluate protective effects of fermented Cordyceps militaris extract by Pediococcus pentosaceus ON188 (ONE) against hepatosteatosis and obesity in mice fed a high-fat diet (HFD). Eight-week-old male C57BL/6J mice were fed HFD mixed with ONE for four weeks and its effects on hepatosteatosis and obesity were examined. Although ONE did not change food intake, it reduced body weights of mice at administration dose of 200 mg/kg/day. Activities of lactate dehydrogenase (LDH), aspartate transaminase (AST), and alanine transaminase (ALT) as plasma parameters were reduced by ONE in a dose-dependent manner. Hepatic lipid droplets and triglyceride (TG) levels were also reduced by ONE due to upregulation of fatty acid oxidizing genes such as carnithine palmitoyltransferase (CPT1) and peroxisomal proliferator activated receptor α(PPARα) mediated by induction of sphingosine kinase 2 (SPHK2). In epididymal fat tissue, sizes of adipocytes were significantly reduced by ONE in a dose-dependent manner. This is mainly due to suppression of lipogenesis and upregulation of adipocyte browning genes. Collectively, these results suggest that fermented ONE can activate fatty acid oxidation via SPHK2 in the liver. It can also suppress lipogenesis and activate browning in adipose tissue. Thus, ONE might have potential to be used for the development of functional foods against liver dysfunction and obesity.


Assuntos
Adipócitos/efeitos dos fármacos , Produtos Biológicos/farmacologia , Cordyceps/química , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/prevenção & controle , Adenosina/química , Tecido Adiposo Branco/citologia , Animais , Produtos Biológicos/química , Desoxiadenosinas/química , Fígado Gorduroso/induzido quimicamente , Fermentação , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Regulação para Cima
12.
Nutrients ; 11(4)2019 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-31022865

RESUMO

Hepatic steatosis, an early stage of non-alcoholic fatty liver disease, is commonly present in obesity and type 2 diabetes, and is associated with reduced hepatic omega-3 polyunsaturated fatty acid (n3-PUFA) status that impacts on the anti-inflammatory and insulin sensitizing functions of n3-PUFA. Our objective was to directly compare plant- and marine-based n3-PUFA (α-linoleic acid (ALA)), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)) for their effects on hepatic steatosis, markers of hepatic inflammation and fibrosis, and insulinemia in obese rats. Fa/fa Zucker rats were provided diets containing ALA, EPA, DHA, or linoleic acid (LA, n6-PUFA) for eight weeks and compared to baseline fa/fa rats and lean Zucker rats fed LA-rich diet for eight weeks. Both DHA and EPA groups had liver lipid similar to baseline, however, DHA was more effective than EPA for reducing hepatic fatty acid synthase (FAS), increasing the proportion of smaller lipid droplets, reversing early fibrotic damage, and reducing fasting hyperinsulinemia. EPA was more effective for reducing FoxO1. Dietary ALA did not attenuate hepatic steatosis, most inflammatory markers or FAS. In summary, amongst the n3-PUFA, DHA was the most effective for elevating hepatic DHA levels, and preventing progression of hepatic steatosis via reductions in FAS and a marker of fibrosis.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Fígado Gorduroso/prevenção & controle , Hiperinsulinismo/prevenção & controle , Ração Animal/análise , Animais , Biomarcadores , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Comportamento Alimentar , Fígado/química , Fígado/metabolismo , Masculino , Fosfolipídeos/química , Fosfolipídeos/metabolismo , Ratos , Ratos Zucker , Triglicerídeos/química , Triglicerídeos/metabolismo
13.
Nutrients ; 11(4)2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995745

RESUMO

Accumulation of reactive oxygen species (ROS) in response to excess alcohol exposure is a major cause of gut barrier disruption and lipopolysaccharide (LPS)-induced hepatic inflammation, as well as liver steatosis and apoptosis. This study was designed to investigate protective effects of the cricket Gryllus bimaculatus, an edible insect recognized by the Korea Food and Drug Administration, against acute alcoholic liver damage in mice. Administration of G. bimaculatus extracts (GBE) attenuated alcohol-induced steatosis and apoptotic responses in the liver and intestinal permeability to bacterial endotoxin. These protective effects were associated with suppression of ROS-mediated oxidative stress in both the liver and small intestine. Furthermore, in vivo and in vitro studies revealed that GBE inhibits LPS-induced Kupffer cell activation and subsequent inflammatory signaling. Importantly, the protective effects of GBE were more potent than those of silymarin, a known therapeutic agent for alcoholic liver diseases.


Assuntos
Produtos Biológicos/uso terapêutico , Gryllidae , Inflamação/prevenção & controle , Enteropatias/prevenção & controle , Intestino Delgado/efeitos dos fármacos , Hepatopatias Alcoólicas/prevenção & controle , Fígado/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Apoptose , Produtos Biológicos/farmacologia , Etanol/efeitos adversos , Fígado Gorduroso/prevenção & controle , Comportamento Alimentar , Feminino , Inflamação/metabolismo , Enteropatias/patologia , Intestino Delgado/patologia , Macrófagos do Fígado/efeitos dos fármacos , Lipopolissacarídeos , Fígado/metabolismo , Fígado/patologia , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Permeabilidade , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico
14.
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
15.
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
16.
Diabetes Care ; 42(5): 931-937, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30885955

RESUMO

OBJECTIVE: The aim of this study was to investigate tissue-specific effects of dapagliflozin on insulin sensitivity and liver and body fat in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This randomized, double-blind, parallel group, placebo-controlled study recruited 32 patients with type 2 diabetes. Enrolled patients were to have HbA1c 6.5-10.5% (48-91 mmol/mol) and ≥3 months of stable treatment with metformin, dipeptidyl peptidase 4 inhibitor, or their combination. Patients were randomized 1:1 to receive 10 mg dapagliflozin or placebo daily for 8 weeks. Before and after the intervention, tissue insulin sensitivity was measured using [18F]-fluorodeoxyglucose and positron emission tomography during hyperinsulinemic-euglycemic clamp. Liver proton density fat fraction (PDFF) and adipose tissue volumes were assessed using MRI, and blood biomarkers were analyzed. RESULTS: After 8 weeks, glycemic control was improved by dapagliflozin (placebo-corrected change in HbA1c -0.39%, P < 0.01), but whole-body glucose uptake was not increased (P = 0.90). Tissue-specific insulin-stimulated glucose uptake did not change in skeletal muscle, liver, myocardium, or white and brown adipose tissue, and endogenous glucose production remained unaffected. However, there were significant placebo-corrected decreases in liver PDFF (-3.74%, P < 0.01), liver volume (-0.10 L, P < 0.05), visceral adipose tissue volume (-0.35 L, P < 0.01), interleukin-6 (-1.87 pg/mL, P < 0.05), and N-terminal prohormone of brain natriuretic peptide (-96 ng/L, P = 0.03). CONCLUSIONS: In this study, 8 weeks of treatment with dapagliflozin reduced liver PDFF and the volume of visceral adipose tissue in obese patients with type 2 diabetes. Although glycemic control was improved, no effect on tissue-level insulin sensitivity was observed.


Assuntos
Compostos Benzidrílicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucosídeos/uso terapêutico , Resistência à Insulina , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Adulto , Idoso , Compostos Benzidrílicos/farmacologia , Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/metabolismo , Método Duplo-Cego , Fígado Gorduroso/prevenção & controle , Feminino , Glucosídeos/farmacologia , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Resistência à Insulina/fisiologia , Fígado/metabolismo , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Placebos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
17.
Food Chem ; 287: 107-114, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-30857678

RESUMO

The purpose of this study was to investigate if quinoa (Chenopodium quinoa Willd.), a good source of nutrients, fibre, and phytochemicals, can modulate risk disease biomarkers on obese-diabetic (db/db) mice. The db/db mice fed quinoa-supplemented (quinoa) or AIN-93G diet (obese) were compared to lean control fed AIN-93G diet. Quinoa intake reduced at significant level plasma total-cholesterol (total-c), LDL-c, and oxidized-LDL to levels similar to lean; lessened protein carbonyls and interleukin (IL)-6. The hepatic steatosis and total-c accumulation in liver were also similar between lean and quinoa and lower than obese. Quinoa fibre and phytochemicals may have contributed to these health benefits. However, quinoa intake increased plasma insulin and did not protect from other pathophysiological manifestations of the db/db research model. More studies are needed with other research models and quinoa doses achievable by human diet to validate the clinical relevance of this study.


Assuntos
Chenopodium quinoa , Colesterol/análise , Dieta , Fígado Gorduroso , Inflamação , Obesidade/metabolismo , Animais , Colesterol/sangue , Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Inflamação/metabolismo , Inflamação/prevenção & controle , Camundongos , Camundongos Obesos , Sementes
18.
Am J Clin Nutr ; 109(2): 288-296, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30721948

RESUMO

Background: Epidemiological studies suggest that an increased red meat intake is associated with a higher risk of type 2 diabetes, whereas an increased fiber intake is associated with a lower risk. Objectives: We conducted an intervention study to investigate the effects of these nutritional factors on glucose and lipid metabolism, body-fat distribution, and liver fat content in subjects at increased risk of type 2 diabetes. Methods: This prospective, randomized, and controlled dietary intervention study was performed over 6 mo. All groups decreased their daily caloric intake by 400 kcal. The "control" group (N = 40) only had this requirement. The "no red meat" group (N = 48) in addition aimed to avoid the intake of red meat, and the "fiber" group (N = 44) increased intake of fibers to 40 g/d. Anthropometric parameters and frequently sampled oral glucose tolerance tests were performed before and after intervention. Body-fat mass and distribution, liver fat, and liver iron content were assessed by MRI and single voxel proton magnetic resonance spectroscopy. Results: Participants in all groups lost weight (mean 3.3 ± 0.5 kg, P < 0.0001). Glucose tolerance and insulin sensitivity improved (P < 0.001), and body and visceral fat mass decreased in all groups (P < 0.001). These changes did not differ between groups. Liver fat content decreased significantly (P < 0.001) with no differences between the groups. The decrease in liver fat correlated with the decrease in ferritin during intervention (r2 = 0.08, P = 0.0021). This association was confirmed in an independent lifestyle intervention study (Tuebingen Lifestyle Intervention Program, N = 229, P = 0.0084). Conclusions: Our data indicate that caloric restriction leads to a marked improvement in glucose metabolism and body-fat composition, including liver-fat content. The marked reduction in liver fat might be mediated via changes in ferritin levels. In the context of caloric restriction, there seems to be no additional beneficial impact of reduced red meat intake and increased fiber intake on the improvement in cardiometabolic risk parameters. This trial was registered at clinicaltrials.gov as NCT03231839.


Assuntos
Tecido Adiposo/metabolismo , Glicemia/metabolismo , Restrição Calórica , Fibras na Dieta/farmacologia , Ingestão de Energia , Fígado/metabolismo , Carne Vermelha , Adulto , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/prevenção & controle , Dieta , Fibras na Dieta/administração & dosagem , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Comportamento Alimentar , Feminino , Ferritinas/metabolismo , Teste de Tolerância a Glucose , Humanos , Resistência à Insulina , Gordura Intra-Abdominal/metabolismo , Ferro/metabolismo , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Carne Vermelha/efeitos adversos , Perda de Peso
19.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1402-1409, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30776415

RESUMO

The nuclear receptor liver X receptor (LXR) impacts on cholesterol metabolism as well as hepatic lipogenesis via transcriptional regulation. It is proposed that inhibition of the protein arginine methyltransferase 3 (PRMT3) uncouples these two transcriptional pathways in vivo by acting as a specific lipogenic coactivator of LXR. Here we validated the hypothesis that treatment with the allosteric PRMT3 inhibitor SGC707 will diminish the hepatic steatosis extent, while leaving global cholesterol metabolism, important in cholesterol-driven pathologies like atherosclerosis, untouched. For this purpose, 12-week old hyperlipidemic apolipoprotein E knockout mice were fed a Western-type diet for six weeks to induce both hepatic steatosis and atherosclerosis. The mice received 3 intraperitoneal injections with SGC707 or solvent control per week. Mice chronically treated with SGC707 developed less severe hepatic steatosis as exemplified by the 51% reduced (P < 0.05) liver triglyceride levels. In contrast, the extent of in vivo macrophage foam cell formation and aortic root atherosclerosis was not affected by SGC707 treatment. Interestingly, SGC707-treated mice gained 94% less body weight (P < 0.05), which was paralleled by changes in white adipose tissue morphology, i.e. reduction in adipocyte size and browning. In conclusion, we have shown that through PRMT3 inhibitor treatment specific functions of LXR involved in respectively the development of fatty liver disease and atherosclerosis can be uncoupled, resulting in an overall diminished hepatic steatosis extent without a negative impact on atherosclerosis susceptibility. As such, our studies highlight that PRMT3 inhibition may constitute a novel therapeutic approach to limit the development of fatty liver disease in humans.


Assuntos
Apolipoproteínas E/genética , Aterosclerose/genética , Inibidores Enzimáticos/farmacologia , Fígado Gorduroso/prevenção & controle , Isoquinolinas/farmacologia , Proteína-Arginina N-Metiltransferases/genética , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/enzimologia , Tecido Adiposo Branco/patologia , Regulação Alostérica/efeitos dos fármacos , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Aorta/patologia , Apolipoproteínas E/deficiência , Aterosclerose/enzimologia , Aterosclerose/etiologia , Aterosclerose/patologia , Colesterol/metabolismo , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Suscetibilidade a Doenças , Fígado Gorduroso/etiologia , Fígado Gorduroso/genética , Fígado Gorduroso/patologia , Células Espumosas/efeitos dos fármacos , Células Espumosas/metabolismo , Células Espumosas/patologia , Regulação da Expressão Gênica , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Masculino , Camundongos , Camundongos Knockout para ApoE , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Proteína-Arginina N-Metiltransferases/metabolismo , Transdução de Sinais , Triglicerídeos/metabolismo
20.
Comput Methods Programs Biomed ; 170: 23-29, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30712601

RESUMO

BACKGROUND AND OBJECTIVE: Fatty liver disease (FLD) is a common clinical complication; it is associated with high morbidity and mortality. However, an early prediction of FLD patients provides an opportunity to make an appropriate strategy for prevention, early diagnosis and treatment. We aimed to develop a machine learning model to predict FLD that could assist physicians in classifying high-risk patients and make a novel diagnosis, prevent and manage FLD. METHODS: We included all patients who had an initial fatty liver screening at the New Taipei City Hospital between 1st and 31st December 2009. Classification models such as random forest (RF), Naïve Bayes (NB), artificial neural networks (ANN), and logistic regression (LR) were developed to predict FLD. The area under the receiver operating characteristic curve (ROC) was used to evaluate performances among the four models. RESULTS: A total of 577 patients were included in this study; of those 377 patients had fatty liver. The area under the receiver operating characteristic (AUROC) of RF, NB, ANN, and LR with 10 fold-cross validation was 0.925, 0.888, 0.895, and 0.854 respectively. Additionally, The accuracy of RF, NB, ANN, and LR 87.48, 82.65, 81.85, and 76.96%. CONCLUSION: In this study, we developed and compared the four classification models to predict fatty liver disease accurately. However, the random forest model showed higher performance than other classification models. Implementation of a random forest model in the clinical setting could help physicians to stratify fatty liver patients for primary prevention, surveillance, early treatment, and management.


Assuntos
Algoritmos , Fígado Gorduroso , Aprendizado de Máquina , Adulto , Idoso , Diagnóstico Precoce , Registros Eletrônicos de Saúde , Fígado Gorduroso/diagnóstico , Fígado Gorduroso/prevenção & controle , Feminino , Previsões , Humanos , Masculino , Pessoa de Meia-Idade , Curva ROC , Taiwan
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA