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1.
Rev Assoc Med Bras (1992) ; 65(9): 1144-1150, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31618328

RESUMO

OBJECTIVE: In view of the high incidence of polycystic ovary syndrome (PCOS) and the unsatisfactory therapeutic effects of dimethyldiguanide or clomifene citrate alone, our study aimed to investigate the therapeutic effects of dimethyldiguanide combined with clomifene citrate in the treatment of PCOS. METHODS: A total of 79 patients with POCS and 35 healthy females were included, and endometrial biopsies were obtained. The sterol regulatory element-binding protein-1 (SREBP1) expression in endometrial tissues was detected by qRT-PCR. POC patients were randomly divided into group A (n=40) and group B (n=39). Patients in group A were treated with dimethyldiguanide combined with clomifene citrate, while patients in group B were treated with clomifene citrate alone. The number of mature follicles and cervical mucus score, follicular development rate and single follicle ovulation rate, cycle pregnancy rate, early miscarriage rate, ovulation rate, endometrial thickness, positive rate of three lines sign, follicle stimulating hormone level and luteinizing hormone level were compared between the two groups. RESULTS: The expression level of SREBP1 was higher in PCOS patients than that in the healthy control. SREBP1 expression was inhibited after treatment, while the inhibitory effects of combined treatment were stronger than those of clomifene citrate alone. Compared with clomifene citrate alone, the combined treatment improved cervical mucus score, follicle development rate, single follicle ovulation rate, endometrial thickness, positive rate of three lines sign, and follicle-stimulating hormone level. CONCLUSION: The therapeutic effect of combined treatment is better than clomifene citrate alone in the treatment of PCOS.


Assuntos
Clomifeno/uso terapêutico , Fármacos para a Fertilidade Feminina/uso terapêutico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Síndrome do Ovário Policístico/tratamento farmacológico , Adulto , Muco do Colo Uterino/efeitos dos fármacos , Clomifeno/farmacologia , Quimioterapia Combinada , Endométrio/fisiopatologia , Feminino , Fármacos para a Fertilidade Feminina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hipoglicemiantes/farmacologia , Metformina/farmacologia , Folículo Ovariano/efeitos dos fármacos , Indução da Ovulação , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Adulto Jovem
2.
Zhonghua Gan Zang Bing Za Zhi ; 26(6): 451-456, 2018 Jun 20.
Artigo em Chinês | MEDLINE | ID: mdl-30317760

RESUMO

Objective: To explore the effects of oleic acid and palmitic acid on lipid deposition and mTOR/S6K1/SREBP-1c pathways in HepG2 cells. Methods: The model of steatosis was established with induction of oleic acid and palmitic acid and was intervened by rapamycin. The changes in lipid droplets were observed after staining the cells with oil Red O. Intracellular triglyceride (TG) contents in cells were measured by TG kit. mTOR, S6K1, and SREBP-1c mRNA expression levels were detected using QRT-PCR. Western blot was used to determine protein expression levels of mTOR, S6K1 and SREBP-1c. Results: Both fatty acids increased lipid droplets in HepG2 cells. Fatty degeneration with elevated TG occurred with significant changes in oleic acid group lipids. Rapamycin alleviated lipid deposition caused by oleic acid and palmitic acid and inhibited their induction of increased expression of mTOR, S6K1, and SREBP-1c. QRT-PCR and Western blot results showed that mRNA and protein expressions of mTOR, S6K1, and SREBP-1c in oleic acid and palmitic acid group were significantly higher than the control group (P < 0.05). The increase was more pronounced in the palmitic acid group (P < 0.05); however, after rapamycin intervention, the expression of mRNA and protein in the three groups were significantly lower (P < 0.05), and the change in palmitic acid group was more pronounced (P < 0.05). Conclusion: Oleic acid and palmitic acid can induce lipid deposition in HepG2 cells and increase expression of every component of mTOR/S6K1/SREBP-1c pathway; however, Oleic acid-induced lipid deposition is more pronounced, and the mTOR, S6K1, and SREBP-1c pathway change is more obvious in palmitic acid. Rapamycin has high potent inhibitory effect on palmitic acid-induced lipid deposition. These results specify that lipid synthesis involved in the mTOR/S6K1/SREBP-1c pathways are mainly associated to palmitic acid in HepG2 cells, whereas other signaling pathway may mediate oleic acid-induced lipid synthesis.


Assuntos
Metabolismo dos Lipídeos/efeitos dos fármacos , Ácido Oleico/farmacologia , Ácido Palmítico/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Serina-Treonina Quinases TOR/efeitos dos fármacos , Células Hep G2 , Humanos
3.
Drug Discov Ther ; 11(5): 281-287, 2017 Nov 22.
Artigo em Inglês | MEDLINE | ID: mdl-29021504

RESUMO

The leaves of Aster yomena (Kitam.) Honda have long been used as a traditional herb for treating disorders including coughs, asthma, and insect bites. According to recent studies, A. yomena leaf extracts have several pharmacological properties, including anti-inflammatory, antioxidant, and anti-asthmatic activities. However, little information is available regarding their anti-obesity effect. In this study, we investigated the inhibitory effect of the ethanol extracts of A. yomena leaves (EEAY) on adipocyte differentiation and adipogenesis using 3T3-L1 preadipocytes. When 3T3-L1 preadipocytes were treated with various concentrations of EEAY (ranging from non-toxic), the number of lipid droplets, lipid content, and triglyceride production, the typical characteristics of adipocytes, were suppressed in a concentration-dependent manner. During this process, EEAY significantly reduced the expression of adipogenic transcription factors, including peroxisome proliferator-activated receptor-γ, CCAAT/enhancer-binding protein α and ß, and sterol regulatory element-binding protein-1c. In addition, EEAY was also found to potently inhibit the expression of adipocyte-specific genes, including adipocyte fatty acid-binding protein and leptin. In particular, EEAY treatment effectively enhanced the activation of the AMP-activated protein kinase (AMPK) signaling pathway; however, the co-treatment with compound C, an inhibitor of AMPK, significantly restored the EEAY-induced inhibition of pro-adipogenic transcription factors and adipocyte-specific genes. These results indicate that EEAY may exert an anti-obesity effect by controlling the AMPK signaling pathway, suggesting that the leaf extract of A. yomena may be a potential anti-obesity agent.


Assuntos
Adenilato Quinase/efeitos dos fármacos , Adipócitos/efeitos dos fármacos , Adipogenia/efeitos dos fármacos , Aster , Extratos Vegetais/farmacologia , Células 3T3-L1 , Adenilato Quinase/metabolismo , Adipócitos/metabolismo , Adipogenia/genética , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/efeitos dos fármacos , Proteína alfa Estimuladora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/efeitos dos fármacos , Proteína beta Intensificadora de Ligação a CCAAT/genética , Etanol , Proteínas de Ligação a Ácido Graxo/efeitos dos fármacos , Proteínas de Ligação a Ácido Graxo/genética , Expressão Gênica , Leptina/genética , Camundongos , PPAR gama/efeitos dos fármacos , PPAR gama/genética , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/genética
4.
World J Gastroenterol ; 22(26): 6016-26, 2016 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-27468193

RESUMO

AIM: To investigate in vitro the therapeutic effect and mechanisms of silybin in a cellular model of hepatic steatosis. METHODS: Rat hepatoma FaO cells were loaded with lipids by exposure to 0.75 mmol/L oleate/palmitate for 3 h to mimic liver steatosis. Then, the steatotic cells were incubated for 24 h with different concentrations (25 to 100 µmol/L) of silybin as phytosome complex with vitamin E. The effects of silybin on lipid accumulation and metabolism, and on indices of oxidative stress were evaluated by absorption and fluorescence microscopy, quantitative real-time PCR, Western blot, spectrophotometric and fluorimetric assays. RESULTS: Lipid-loading resulted in intracellular triglyceride (TG) accumulation inside lipid droplets, whose number and size increased. TG accumulation was mediated by increased levels of peroxisome proliferator-activated receptors (PPARs) and sterol regulatory element-binding protein-1c (SREBP-1c). The lipid imbalance was associated with higher production of reactive oxygen species (ROS) resulting in increased lipid peroxidation, stimulation of catalase activity and activation of nuclear factor kappa-B (NF-κB). Incubation of steatotic cells with silybin 50 µmol/L significantly reduced TG accumulation likely by promoting lipid catabolism and by inhibiting lipogenic pathways, as suggested by the changes in carnitine palmitoyltransferase 1 (CPT-1), PPAR and SREBP-1c levels. The reduction in fat accumulation exerted by silybin in the steatotic cells was associated with the improvement of the oxidative imbalance caused by lipid excess as demonstrated by the reduction in ROS content, lipid peroxidation, catalase activity and NF-κB activation. CONCLUSION: We demonstrated the direct anti-steatotic and anti-oxidant effects of silybin in steatotic cells, thus elucidating at a cellular level the encouraging results demonstrated in clinical and animal studies.


Assuntos
Antioxidantes/farmacologia , Fígado Gorduroso , Hepatócitos/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Silimarina/farmacologia , Vitamina E/farmacologia , Animais , Western Blotting , Carnitina O-Palmitoiltransferase/efeitos dos fármacos , Carnitina O-Palmitoiltransferase/metabolismo , Catalase/efeitos dos fármacos , Catalase/metabolismo , Linhagem Celular Tumoral , Células Cultivadas , Fluorometria , Hepatócitos/metabolismo , Hepatócitos/patologia , Gotículas Lipídicas/efeitos dos fármacos , Gotículas Lipídicas/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Microscopia de Fluorescência , NF-kappa B/efeitos dos fármacos , NF-kappa B/metabolismo , Ácido Oleico/farmacologia , Palmitatos/farmacologia , Receptores Ativados por Proliferador de Peroxissomo/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Silibina , Espectrofotometria , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/metabolismo
5.
J Nat Prod ; 79(5): 1423-8, 2016 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-27135143

RESUMO

Luteolin is a dietary flavonoid with medicinal properties including antioxidant, antimicrobial, anticancer, antiallergic, and anti-inflammatory. However, the effect of luteolin on liver X receptors (LXRs), oxysterol sensors that regulate cholesterol homeostasis, lipogenesis, and inflammation, has yet to be studied. To unveil the potential of luteolin as an LXRα/ß modulator, we investigated by real-time RT-PCR the expression of LXR-target genes, namely, sterol regulatory element binding protein 1c (SREBP-1c) in hepatocytes and ATP-binding cassette transporter (ABC)A1 in macrophages. The lipid content of hepatocytes was evaluated by Oil Red staining. The results demonstrated, for the first time, that luteolin abrogated the LXRα/ß agonist-induced LXRα/ß transcriptional activity and, consequently, inhibited SREBP-1c expression, lipid accumulation, and ABCA1 expression. Therefore, luteolin could abrogate hypertriglyceridemia associated with LXR activation, thus presenting putative therapeutic effects in diseases associated with deregulated lipid metabolism, such as hepatic steatosis, cardiovascular diseases, and diabetes.


Assuntos
Flavonas/farmacologia , Receptores X do Fígado/antagonistas & inibidores , Luteolina/farmacologia , Antioxidantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos , Fígado/efeitos dos fármacos , Luteolina/química , Estrutura Molecular , Reação em Cadeia da Polimerase , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos
6.
Am J Physiol Endocrinol Metab ; 310(7): E526-38, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-26786774

RESUMO

Recent epidemiological and animal studies have suggested that excess intake of phosphate (Pi) is a risk factor for the progression of chronic kidney disease and its cardiovascular complications. However, little is known about the impact of dietary high Pi intake on the development of metabolic disorders such as obesity and type 2 diabetes. In this study, we investigated the effects of dietary Pi on glucose and lipid metabolism in healthy rats. Male 8-wk-old Sprague-Dawley rats were divided into three groups and given experimental diets containing varying amounts of Pi, i.e., 0.2 [low Pi(LP)], 0.6 [control Pi(CP)], and 1.2% [high Pi(HP)]. After 4 wk, the HP group showed lower visceral fat accumulation compared with other groups, accompanied by a low respiratory exchange ratio (V̇CO2/V̇O2) without alteration of locomotive activity. The HP group had lower levels of plasma insulin and nonesterified fatty acids. In addition, the HP group also showed suppressed expression of hepatic lipogenic genes, including sterol regulatory element-binding protein-1c, fatty acid synthase, and acetyl-CoA carboxylase, whereas there was no difference in hepatic fat oxidation among the groups. On the other hand, uncoupling protein (UCP) 1 and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression were significantly increased in the brown adipose tissue (BAT) of the HP group. Our data demonstrated that a high-Pi diet can negatively regulate lipid synthesis in the liver and increase mRNA expression related to lipid oxidation and UCP1 in BAT, thereby preventing visceral fat accumulation. Thus, dietary Pi is a novel metabolic regulator.


Assuntos
Comportamento Animal/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Gordura Intra-Abdominal/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Fosfatos/farmacologia , Compostos de Potássio/farmacologia , Troca Gasosa Pulmonar/efeitos dos fármacos , Acetil-CoA Carboxilase/efeitos dos fármacos , Acetil-CoA Carboxilase/genética , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Animais , Glicemia/metabolismo , Ácido Graxo Sintase Tipo I/efeitos dos fármacos , Ácido Graxo Sintase Tipo I/genética , Ácidos Graxos não Esterificados/sangue , Insulina/sangue , Canais Iônicos/efeitos dos fármacos , Canais Iônicos/genética , Lipogênese/genética , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Proteínas Mitocondriais/efeitos dos fármacos , Proteínas Mitocondriais/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Ratos , Ratos Sprague-Dawley , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/genética , Proteína Desacopladora 1
7.
Alcohol ; 48(7): 707-15, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25262573

RESUMO

This study investigated the effects of umbelliferone (UF) on alcoholic fatty liver and its underlying mechanism. Rats were fed a Lieber-DeCarli liquid diet with 36% of calories as alcohol with or without UF (0.05 g/L) for 8 weeks. Pair-fed rats received an isocaloric carbohydrate liquid diet. UF significantly reduced the severity of alcohol-induced body weight loss, hepatic lipid accumulation and droplet formation, and dyslipidemia. UF decreased plasma AST, ALT, and γGTP activity. UF significantly reduced hepatic cytochrome P450 2E1 activities and increased alcohol dehydrogenase and aldehyde dehydrogenase 2 activities compared to the alcohol control group, which resulted in a lower plasma acetaldehyde level in the rats that received UF. Chronic alcohol exposure inhibited hepatic AMPK activation compared to the pair-fed rats, which was reversed by UF supplementation. UF also significantly suppressed the lipogenic gene expression (SREBP-1c, SREBP-2, FAS, CIDEA, and PPARγ) and elevated the fatty acid oxidation gene expression (PPARα, Acsl1, CPT, Acox, and Acaa1a) compared to the alcohol control group, which could lead to inhibition of FAS activity and stimulation of CPT and fatty acid ß-oxidation activities in the liver of chronic alcohol-fed rats. These results indicated that UF attenuated alcoholic steatosis through down-regulation of SREBP-1c-mediated lipogenesis and up-regulation of PPARα-mediated fatty acid oxidation. Therefore, UF may provide a promising natural therapeutic strategy against alcoholic fatty liver.


Assuntos
Fígado Gorduroso Alcoólico/tratamento farmacológico , PPAR alfa/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Umbeliferonas/uso terapêutico , Álcool Desidrogenase/metabolismo , Aldeído Desidrogenase/metabolismo , Aldeído-Desidrogenase Mitocondrial , Animais , Citocromo P-450 CYP2E1/metabolismo , Suplementos Nutricionais , Hipolipemiantes/uso terapêutico , Ifosfamida/análogos & derivados , Ifosfamida/sangue , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Proteínas Mitocondriais/metabolismo , PPAR alfa/fisiologia , Ratos , Ratos Sprague-Dawley , Proteína de Ligação a Elemento Regulador de Esterol 1/fisiologia
9.
Diabetes ; 63(6): 2097-113, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24458356

RESUMO

Decreased heart rate variability (HRV) is a major risk factor for sudden death and cardiovascular disease. We previously demonstrated that parasympathetic dysfunction in the heart of the Akita type 1 diabetic mouse was due to a decrease in the level of the sterol response element-binding protein (SREBP-1). Here we demonstrate that hyperactivity of glycogen synthase kinase-3ß (GSK3ß) in the atrium of the Akita mouse results in decreased SREBP-1, attenuation of parasympathetic modulation of heart rate, measured as a decrease in the high-frequency (HF) fraction of HRV in the presence of propranolol, and a decrease in expression of the G-protein coupled inward rectifying K(+) (GIRK4) subunit of the acetylcholine (ACh)-activated inward-rectifying K(+) channel (IKACh), the ion channel that mediates the heart rate response to parasympathetic stimulation. Treatment of atrial myocytes with the GSK3ß inhibitor Kenpaullone increased levels of SREBP-1 and expression of GIRK4 and IKACh, whereas a dominant-active GSK3ß mutant decreased SREBP-1 and GIRK4 expression. In Akita mice treated with GSK3ß inhibitors Li(+) and/or CHIR-99021, Li(+) increased IKACh, and Li(+) and CHIR-99021 both partially reversed the decrease in HF fraction while increasing GIRK4 and SREBP-1 expression. These data support the conclusion that increased GSK3ß activity in the type 1 diabetic heart plays a critical role in parasympathetic dysfunction through an effect on SREBP-1, supporting GSK3ß as a new therapeutic target for diabetic autonomic neuropathy.


Assuntos
Diabetes Mellitus Tipo 1/metabolismo , Neuropatias Diabéticas/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Quinase 3 da Glicogênio Sintase/metabolismo , Frequência Cardíaca , Miócitos Cardíacos/metabolismo , Sistema Nervoso Parassimpático/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Animais , Western Blotting , Células Cultivadas , Diabetes Mellitus Tipo 1/fisiopatologia , Neuropatias Diabéticas/fisiopatologia , Eletrocardiografia , Glicogênio Sintase Quinase 3 beta , Átrios do Coração/fisiopatologia , Camundongos , Camundongos Mutantes , Sistema Nervoso Parassimpático/fisiopatologia , Técnicas de Patch-Clamp , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
10.
Diabetologia ; 57(3): 592-602, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24362725

RESUMO

AIMS/HYPOTHESIS: Sterol regulatory element binding protein-1c (SREBP-1c) is a master regulator of fatty acid synthase and controls lipogenesis. IRS-1 is the key insulin signalling mediator in skeletal muscle. In the present study, we investigated the role of SREBP-1c in the regulation of IRS-1 in skeletal muscle cells. METHODS: L6 muscle cells were treated with palmitic acid (PA) or metformin. Adenovirus vectors expressing Srebp-1c (also known as Srebf1) and small interfering RNA (siRNA) against Srebp-1c were transfected into the L6 cells. Protein-DNA interactions were assessed by luciferase reporter analysis, electrophoretic mobility shift assay and chromatin immunoprecipitation assay. RESULTS: We found that both gene and protein expression of SREBP-1c was increased in contrast to IRS-1 expression in PA-treated L6 cells. SREBP-1c overproduction decreased Irs-1 mRNA and IRS-1 protein expression in a dose-dependent manner, and suppressed the resultant insulin signalling, whereas SERBP-1c knockdown by Serbp-1c siRNA blocked the downregulation of IRS-1 induced by PA. Protein-DNA interaction studies demonstrated that SREBP-1c was able to bind to the rat Irs-1 promoter region, thereby repressing its gene transcription. Of particular importance, we found that metformin treatment downregulated Srebp-1c promoter activity, decreased the specific binding of SREBP-1c to Irs-1 promoter and upregulated Irs-1 promoter activity in PA-cultured L6 cells. CONCLUSIONS/INTERPRETATION: Our data indicate for the first time that SREBP-1c activation participates in skeletal muscle insulin resistance through a direct effect of suppressing Irs-1 transcription. These findings imply that SREBP-1c could serve as an attractive therapeutic target for insulin resistance.


Assuntos
Hipoglicemiantes/farmacocinética , Proteínas Substratos do Receptor de Insulina/metabolismo , Resistência à Insulina , Metformina/farmacologia , Músculo Esquelético/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Adenoviridae , Animais , Western Blotting , Células Cultivadas , Dieta Hiperlipídica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Regiões Promotoras Genéticas , Ratos , Ratos Sprague-Dawley , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Ativação Transcricional
11.
J Cell Biochem ; 114(3): 558-69, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22991202

RESUMO

Diethyl hexyl phthalate (DEHP) is a plasticizer, commonly used in a variety of products, including lubricants, perfumes, hairsprays and cosmetics, construction materials, wood finishers, adhesives, floorings and paints. DEHP is an endocrine disruptor and it has a continuum of influence on various organ systems in human beings and experimental animals. However, specific effects of DEHP on insulin signaling in adipose tissue are not known. Adult male albino rats of Wistar strain were divided into four groups. Control, DEHP treated (dissolved in olive oil at a dose of 10, and 100 mg/kg body weight, respectively, once daily through gastric intubations for 30 days) and DEHP + vitamin E (50 mg/kg body weight) and C (100 mg/kg body weight) dissolved in olive oil and distilled water, respectively, once daily through gastric intubations for 30 days. After the completion of treatment, adipose tissue was dissected out to assess various parameters. DEHP treatment escalated H(2)O(2) and hydroxyl radical levels as well as lipid peroxidation in the adipose tissue. DEHP impaired the expression of insulin signaling molecules and their phosphorelay pathways leading to diminish plasma membrane GLUT4 level and thus decreased glucose uptake and oxidation. Blood glucose level was elevated as a result of these changes. Supplementation of vitamins (C & E) prevented the DEHP-induced changes. It is concluded that DEHP-induced ROS and lipid peroxidation disrupts the insulin signal transduction in adipose tissue and favors glucose intolerance. Antioxidant vitamins have a protective role against the adverse effect of DEHP.


Assuntos
Tecido Adiposo/metabolismo , Ácido Ascórbico/farmacologia , Dietilexilftalato/farmacologia , Resistência à Insulina , Vitamina E/farmacologia , Tecido Adiposo/efeitos dos fármacos , Animais , Antioxidantes , Arrestinas/biossíntese , Arrestinas/efeitos dos fármacos , Transporte Biológico/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Glucose/metabolismo , Intolerância à Glucose/prevenção & controle , Transportador de Glucose Tipo 4/biossíntese , Transportador de Glucose Tipo 4/efeitos dos fármacos , Peróxido de Hidrogênio/metabolismo , Insulina/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio , Transdução de Sinais/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/biossíntese , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , beta-Arrestinas
12.
Mol Nutr Food Res ; 55(12): 1809-18, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22038976

RESUMO

SCOPE: Mangiferin, a natural polyphenol, has been shown to have hypolipidemic effect in rat and mouse. However, the mechanism of action is not well understood. This study was conducted to determine the effect and mechanism of action of mangiferin on hyperlipidemia induced in hamsters by a high-fat diet. METHODS AND RESULTS: Forty male hamsters were randomly assigned to normal control, high-fat control, and high fat with mangiferin (50 and 150 mg/kg BW) groups. Mangiferin treatment significantly decreased final body weight, liver weight and visceral fat-pad weight, serum triglyceride (TG) and total free fatty acid (FFA) concentrations, hepatic TG levels and hepatic and muscle total FFA contents. Mangiferin upregulated mRNA expression of peroxisome proliferator-activated receptor-α (PPAR-α), fatty acid translocase (CD36) and carnitine palmitoyltransferase 1 (CPT-1), but downregulated mRNA expression of sterol regulatory element-binding protein 1c (SREBP-1c), acetyl CoA carboxylase (ACC), acyl-CoA:diacylglycerol acyltransferase 2 (DGAT-2) and microsomal triglyceride transfer protein (MTP) in liver. Mangiferin also stimulated mRNA expression of PPAR-α, CD36, CPT-1 and lipoprotein lipase (LPL) in muscle. CONCLUSIONS: The results suggest that mangiferin may ameliorate hypertriglyceridemia partly by modulating the expression levels of genes involved in lipid oxidation and lipogenesis.


Assuntos
Dieta Hiperlipídica , Gorduras na Dieta/administração & dosagem , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/farmacologia , Xantonas/farmacologia , Acetil-CoA Carboxilase/efeitos dos fármacos , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Tecido Adiposo/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Antígenos CD36/efeitos dos fármacos , Antígenos CD36/genética , Antígenos CD36/metabolismo , Carnitina O-Palmitoiltransferase/efeitos dos fármacos , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Proteínas de Transporte/efeitos dos fármacos , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Cricetinae , Diacilglicerol O-Aciltransferase/efeitos dos fármacos , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Regulação para Baixo , Ácidos Graxos não Esterificados/sangue , Hipertrigliceridemia/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Lipase Lipoproteica/efeitos dos fármacos , Lipase Lipoproteica/genética , Lipase Lipoproteica/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Tamanho do Órgão/efeitos dos fármacos , PPAR alfa/efeitos dos fármacos , PPAR alfa/genética , PPAR alfa/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Triglicerídeos/sangue , Regulação para Cima
13.
Can J Physiol Pharmacol ; 89(11): 793-9, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22017765

RESUMO

Resveratrol (Res) is a natural polyphenolic compound with anti-inflammatory and antioxidant properties. Also, Res can inhibit lipogenesis and adipocyte differentiation. However, the underlying mechanisms of Res's functions remain largely unknown. AMP-activated protein kinase (AMPK) is a key player in adipocyte differentiation. Therefore, the purpose of our study was to determine the role played by AMPK in the Res-mediated regulation of adipocyte differentiation. Incubation of 3T3-L1 cells with Res confirmed that Res inhibited adipocyte differentiation. The phosphorylation of AMPKα was increased by Res in a dose-dependent manner, while total AMPKα levels were unchanged, and peroxisome proliferator-activated receptor γ (PPARγ), CCAAT-enhancer-binding protein α (C/EBPα), and sterol regulatory element-binding protein 1c (SREBP-1c) levels were decreased. Interestingly, pretreatment with AMPKα siRNA and Res promoted adipocyte differentiation, while the decrease of p-AMPKα increased PPARγ, C/EBPα, and SREBP-1c protein expression. Our study shows that Res is capable of inhibiting lipogenesis and differentiation of 3T3-L1 adipocytes via activation of AMPK, suggesting its potential therapeutic application in the treatment or prevention of obesity.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Anti-Inflamatórios não Esteroides/farmacologia , Proteína alfa Estimuladora de Ligação a CCAAT/fisiologia , Diferenciação Celular/efeitos dos fármacos , PPAR gama/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/fisiologia , Estilbenos/farmacologia , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/efeitos dos fármacos , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Proteína alfa Estimuladora de Ligação a CCAAT/efeitos dos fármacos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Lipogênese/efeitos dos fármacos , Camundongos , Obesidade/fisiopatologia , PPAR gama/efeitos dos fármacos , Fosforilação , Resveratrol , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos
14.
Scand J Gastroenterol ; 46(11): 1381-8, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21936721

RESUMO

OBJECTIVE: The present study investigates the level of Sterol-regulatory element-binding proteins (SREBP-1c) and related proteins in obese mice (DIO) treated with SREBP-1c antisense oligonucleotide (ASO) to observe a reversal of steatosis. MATERIALS AND METHODS: Swiss mice were fed on chow containing 61 kJ% saturated fat for 8 weeks to develop obesity. After this period, one group of animals was used to assess the molecular effects of SREBP-1c antisense oligonucleotide treatment by immunoblot analysis in a dose-response curve (0; 1.0; 2.0; 3.0; 4.0 nmol/day). After the dose (3.0 nmol/day) was determined, another group was treated for 14 days. After a period of 24 h following the last injection mice were killed and plasma and hepatic tissue were obtained to evaluate plasma triglycerides and total liver fat. Western blot was performed to evaluate SREBP-1c, FAS, SCD-1, PPARγ and CPT1 expression and AMPK[Thr172] and ACC[Ser79] phosphorylation. Livers were stained using the hematoxylin and eosin method for histological analysis. RESULTS: Body weight, epididymal fat and glucose levels were not affected by one daily dose of ASO. However, total plasma triglycerides and total liver fat were significantly reduced. Also, this treatment inhibited SREBP-1c and reduced protein levels of a series of proteins involved in lipogenesis, including ACC, FAS and SCD-1. Moreover, mice treated with ASO presented a significant reduction in macroscopic and microscopic features of hepatic steatosis. CONCLUSION: Our results demonstrate that the inhibition of SREBP-1c decreased the expression of lipogenic enzymes, reducing the accumulation of triglycerides and, finally, reversing hepatic steatosis in mice.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/enzimologia , Oligonucleotídeos Antissenso/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteínas Quinases Ativadas por AMP/química , Acetil-CoA Carboxilase/química , Adiposidade , Animais , Ácido Graxo Sintases/metabolismo , Fígado Gorduroso/patologia , Camundongos , Camundongos Obesos , Hepatopatia Gordurosa não Alcoólica , Oligonucleotídeos Antissenso/uso terapêutico , PPAR gama/metabolismo , Fosforilação , Estearoil-CoA Dessaturase/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Triglicerídeos/sangue
15.
Jpn J Vet Res ; 58(3-4): 149-54, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21180254

RESUMO

Both retinoic acid (RA) and oxidative stress (H2O2) increased transcription and cleavage of membrane-bound sterol regulatory element-binding protein (SREBP)-1, leading to enhanced transcription of fatty acid synthase (FAS) in hepatoma cells. On the other hand, RA and H2O2 decreased and increased lipogenesis in adipocytes, respectively, although roles of SREBP-1 activation in these effects remain to be elucidated. To elucidate its involvement, we examined the activation of SREBP-la, expression of FAS genes and lipid accumulation in 3T3-L1 cells in the presence of RA and/or H2O2. RA (1 microM) treatment suppressed expression of SREBP-1a and FAS genes and lipid accumulation. H2O2 (2 microM) treatment induced increased cleavage of SREBP-1a, without affecting amounts of SREBP-1a mRNA and precursor protein, and enhanced expression of FAS gene and lipid accumulation. Increased cleavage of SREBP-1a by H2O2 was also observed even in the presence of RA. These results suggest that H2O2, enhances a cleavage of SREBP-1a precursor protein, which independently occurs with the RA suppression of SREBP-1a gene expression, and that RA itself has no role in the SREBP-1a activation in adipocytes.


Assuntos
Células 3T3-L1/citologia , Adipócitos/citologia , Diferenciação Celular/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Tretinoína/farmacologia , Células 3T3-L1/efeitos dos fármacos , Actinas/efeitos dos fármacos , Actinas/genética , Adipócitos/efeitos dos fármacos , Animais , Camundongos , Reação em Cadeia da Polimerase , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Receptor fas/efeitos dos fármacos , Receptor fas/genética
16.
Br J Nutr ; 104(2): 180-8, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20487577

RESUMO

The antioxidant activity of lemon balm (Melissa officinalis) essential oil (LBEO) on 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals and its hypoglycaemic effect in db/db mice were investigated. LBEO scavenged 97 % of DPPH radicals at a 270-fold dilution. Mice administered LBEO (0.015 mg/d) for 6 weeks showed significantly reduced blood glucose (65 %; P < 0.05) and TAG concentrations, improved glucose tolerance, as assessed by an oral glucose tolerance test, and significantly higher serum insulin levels, compared with the control group. The hypoglycaemic mechanism of LBEO was further explored via gene and protein expression analyses using RT-PCR and Western blotting, respectively. Among all glucose metabolism-related genes studied, hepatic glucokinase and GLUT4, as well as adipocyte GLUT4, PPAR-gamma, PPAR-alpha and SREBP-1c expression, were significantly up-regulated, whereas glucose-6-phosphatase and phosphoenolpyruvate carboxykinase expression was down-regulated in the livers of the LBEO group. The results further suggest that LBEO administered at low concentrations is an efficient hypoglycaemic agent, probably due to enhanced glucose uptake and metabolism in the liver and adipose tissue and the inhibition of gluconeogenesis in the liver.


Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/enzimologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Melissa/química , Óleos Voláteis/farmacologia , Óleos Vegetais/farmacologia , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Glucoquinase/efeitos dos fármacos , Glucoquinase/genética , Glucoquinase/metabolismo , Teste de Tolerância a Glucose , Proteínas Facilitadoras de Transporte de Glucose/efeitos dos fármacos , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Glucose-6-Fosfatase/efeitos dos fármacos , Glucose-6-Fosfatase/genética , Glucose-6-Fosfatase/metabolismo , Insulina/sangue , Camundongos , Óleos Voláteis/química , Óleos Voláteis/uso terapêutico , Receptores Ativados por Proliferador de Peroxissomo/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/genética , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Fosfoenolpiruvato Carboxiquinase (GTP)/efeitos dos fármacos , Fosfoenolpiruvato Carboxiquinase (GTP)/genética , Fosfoenolpiruvato Carboxiquinase (GTP)/metabolismo , Fitoterapia , Óleos Vegetais/química , Óleos Vegetais/uso terapêutico , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
17.
Naunyn Schmiedebergs Arch Pharmacol ; 381(4): 339-48, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20195573

RESUMO

In spite of their shared decrease of insulin resistance, oleoyl-estrone [OE], and rosiglitazone show diverging effects on body fat mass and distribution. In this study, we studied whether their effects on white adipose tissue [WAT] were due to a shared or synergistic mechanism of action. Combined effects of OE and rosiglitazone 10-day treatment on WAT lipid, cell mass/number, and the expression of key lipid metabolism and regulatory agents were studied using an adult male overweight rat model. OE decreased WAT cell mass and lipids, parameters not changed by rosiglitazone. The effects of OE and--specially--rosiglitazone were more marked in small-cell WAT (i.e., mesenteric and subcutaneous sites) than in larger cell WAT (retroperitoneal and perigonadal). OE decreased the expressions in WAT of lipogenic enzymes, lipoprotein lipase, PPARs, and SREBP1c, effects symmetrically reversed by rosiglitazone. OE showed no effects on hormone-sensitive lipase expression, which was increased by rosiglitazone. OE strongly inhibited WAT lipogenesis, leaving lipolysis unchanged, thus unbalancing (and helping mobilize) WAT lipid stores. Rosiglitazone acted practically only on small-cell WAT sites, where it favored lipogenesis, but also stimulated lipolysis, which resulted in limited changes in lipid stores. Combination of OE and rosiglitazone induced less fat loss than OE alone.


Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Estrona/análogos & derivados , Metabolismo dos Lipídeos/efeitos dos fármacos , Ácidos Oleicos/farmacologia , Tiazolidinedionas/farmacologia , Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/metabolismo , Animais , Fármacos Antiobesidade/farmacologia , Composição Corporal/efeitos dos fármacos , Interações de Medicamentos , Estrona/administração & dosagem , Estrona/farmacologia , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/farmacologia , Lipogênese/efeitos dos fármacos , Lipólise/efeitos dos fármacos , Lipase Lipoproteica/efeitos dos fármacos , Lipase Lipoproteica/metabolismo , Masculino , Ácidos Oleicos/administração & dosagem , Sobrepeso/tratamento farmacológico , Receptores Ativados por Proliferador de Peroxissomo/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Ratos , Ratos Wistar , Rosiglitazona , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Tiazolidinedionas/administração & dosagem
18.
Eur J Immunol ; 40(3): 803-12, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-20017192

RESUMO

We have shown previously that cytokines IL-4 and IL-13 induce protection in porcine vascular endothelial cells (EC) against killing by the membrane attack complex (MAC) of human complement. This protection is intrinsic, not due to changes in complement regulatory proteins, and requires activation of Akt and sterol receptor element binding protein-1 (SREBP-1), which regulates fatty acid and phospholipid synthesis. Here we report that, compared to EC incubated in medium, IL-4-treated EC had a profound reduction in complement-mediated ATP loss and in killing assessed by vital dye uptake, but only a slight reduction in permeability disruption measured by calcein release. While controls exposed to complement lost mitochondrial membrane potential and subsequently died, protected EC maintained mitochondrial morphology and membrane potential, and remained alive. SREBP-1 and fatty acid synthase activation were required for protection and fatty acid and phospholipid synthesis, including cardiolipin, were increased after IL-4 stimulation, without increase in cholesterol content or cell proliferation. IL-4 also induced protection of EC from killing by the channel forming protein melittin, similar to protection observed for the MAC. We conclude that IL-4 induced activation of Akt/SREBP-1/lipid biosynthesis in EC, resulting in protection against MAC and melittin, in association with mitochondrial protection.


Assuntos
Proteínas do Sistema Complemento/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Interleucina-4/farmacologia , Lipídeos/biossíntese , Meliteno/efeitos adversos , Transdução de Sinais/efeitos dos fármacos , Animais , Western Blotting , Permeabilidade da Membrana Celular , Separação Celular , Complexo de Ataque à Membrana do Sistema Complemento/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais/ultraestrutura , Citometria de Fluxo , Interleucina-4/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Microscopia Eletrônica de Transmissão , Mitocôndrias/patologia , Proteínas Proto-Oncogênicas c-akt/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Suínos
19.
J Hepatol ; 51(3): 535-47, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19556020

RESUMO

BACKGROUND/AIMS: The underlying mechanisms of steatosis, the first stage of non-alcoholic fatty liver disease (NAFLD) that is characterized by the accumulation of lipids in hepatocytes, remain unclear. Our study aimed to investigate the hypothesis that cigarette smoke is known to change circulating lipid profiles and thus may also contribute to the accumulation of lipids in the liver. METHODS: Mice and cultured hepatocytes were exposed to sidestream whole smoke (SSW), a major component of "second-hand" smoke and a variety of cellular and molecular approaches were used to study the effects of cigarette smoke on lipid metabolism. RESULTS: SSW increases lipid accumulation in hepatocytes by modulating the activity of 5'-AMP-activated protein kinase (AMPK) and sterol response element binding protein-1 (SREBP-1), two critical molecules involved in lipid synthesis. SSW causes dephosphorylation/ inactivation of AMPK, which contributes to increased activation of SREBP-1. These changes of activity lead to accumulation of triglycerides in hepatocytes. CONCLUSION: These novel findings are important because they point to another risk factor of smoking, i.e., that of contributing to NAFLD. In addition, our results showing that both AMPK and SREBP are critically involved in these effects of smoke point to the potential use of these molecules as targets for treatment of cigarette smoke-induced metabolic diseases.


Assuntos
Adenilato Quinase/metabolismo , Fígado Gorduroso/metabolismo , Lipogênese/fisiologia , Fígado/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Poluição por Fumaça de Tabaco/efeitos adversos , Adenilato Quinase/efeitos dos fármacos , Adiponectina/farmacologia , Animais , Apolipoproteínas B/genética , Apolipoproteínas B/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Fígado Gorduroso/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos , Triglicerídeos/metabolismo
20.
Hepatology ; 49(6): 1913-25, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19378344

RESUMO

UNLABELLED: Dithiolethiones, a novel class of adenosine monophosphate-activated protein kinase (AMPK) activators, prevent insulin resistance through AMPK-dependent p70 ribosomal S6 kinase-1 (S6K1) inhibition. There is no known effect of S6K1 for liver X receptor-alpha (LXRalpha)-mediated lipogenic gene expression and steatosis, a cause of chronic liver disease. This study investigated the role of S6K1 in LXRalpha activation and the effects of oltipraz (prototype) and other dithiolethiones on LXRalpha-dependent lipogenesis in hepatocytes and high-fat diet animal model. Oltipraz prevented the ability of LXRalpha agonist (T0901317) to activate sterol regulatory element binding protein-1c (SREBP-1c), inhibiting its own mRNA and protein induction. Impaired SREBP-1c activity by oltipraz caused inhibition of LXRalpha-induced transcription of the fatty acid synthase, LXRalpha, acetyl-CoA carboxylase, stearoyl-CoA desaturase-1, and adenosine triphosphate-binding cassette transporter A1 genes. S6K1 activation antagonized the inhibitory effect of oltipraz on SREBP-1c activation, whereas dominant negative (DN) mutant S6K1 and rapamycin inhibited the T0901317-induced SREBP-1c expression. Oltipraz impaired LXRalpha DNA binding activity and LXR agonist-induced CYP7A1-LXRE-luciferase (CYP7A1) transactivation. Moreover, in vitro S6K1 directly phosphorylated LXRalpha at serine residues for gene transactivation, which was antagonized by its DN mutant. S6K1 inhibition antagonized CYP7A1 induction promoted by AMPK inhibition, whereas AMPK activation abrogated S6K1-dependent CYP7A1 induction, supporting the opposing role of S6K1 and AMPK in LXR activity. Finally, oltipraz was found to inhibit hepatic triglyceride accumulation and lipogenic gene induction in mice fed a high-fat diet. Other dithiolethiones also inhibited SREBP-1c induction by T0901317. CONCLUSION: Our findings showing the role of AMPK-S6K1 pathway in LXR activity and S6K1-dependent inhibition of LXRalpha-induced lipogenic gene transactivation by a novel class of dithiolethiones led to the identification of S6K1 as a particularly attractive target for intervention in hepatic steatosis.


Assuntos
Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Proteínas de Ligação a DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Fígado Gorduroso/genética , Pirazinas/farmacologia , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/genética , Proteínas Quinases S6 Ribossômicas 70-kDa/fisiologia , Ativação Transcricional/efeitos dos fármacos , Animais , Proteínas de Ligação a DNA/fisiologia , Receptores X do Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Receptores Nucleares Órfãos , Receptores Citoplasmáticos e Nucleares/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/efeitos dos fármacos
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