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1.
Metabolism ; 59(4): 587-98, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19913854

RESUMO

We compared hepatic expression of genes that regulate lipid biosynthesis and metabolic signaling in liver biopsy specimens from women who were undergoing gastric bypass surgery (GBP) for morbid obesity with that in women undergoing ventral hernia repair who had experienced massive weight loss (MWL) after prior GBP. Comprehensive metabolic profiles of morbidly obese (MO) (22 subjects) and MWL (9 subjects) were also compared. Analyses of gene expression in liver biopsies from MO and MWL were accomplished by Affymetrix microarray, real-time polymerase chain reaction, and Western blotting techniques. After GBP, MWL subjects had lost on average 102 lb as compared with MO subjects. This was accompanied by effective reversal of the dyslipidemia and insulin resistance that were present in MO. As compared with MWL, livers of MO subjects exhibited increased expression of sterol regulatory element binding protein (SREBP)-1c and its downstream lipogenic targets, fatty acid synthase and acetyl-coenzyme A-carboxylase-1. Livers of MO subjects also exhibited enhanced expression of suppressor of cytokine signaling-3 protein and attenuated Janus kinase signal transducer and activator of transcription (JAK/STAT) signaling. Consistent with these findings, we found that the human SREBP-1c promoter was positively regulated by insulin and negatively regulated by STAT3. These data support the hypothesis that suppressor of cytokine signaling-3-mediated attenuation of the STAT signaling pathway and resulting enhanced expression of SREBP-1c, a key regulator of de novo lipid biosynthesis, are mechanistically related to the development of hepatic insulin resistance and dyslipidemia in MO women.


Assuntos
Regulação da Expressão Gênica , Fígado/metabolismo , Obesidade Mórbida/metabolismo , Fator de Transcrição STAT3/fisiologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteínas Supressoras da Sinalização de Citocina/fisiologia , Adulto , Ácidos Graxos/metabolismo , Feminino , Derivação Gástrica , Humanos , Hidrocarbonetos Fluorados/farmacologia , Insulina/farmacologia , Resistência à Insulina , Lipoproteínas VLDL/biossíntese , Reação em Cadeia da Polimerase , Regiões Promotoras Genéticas , Fator de Transcrição STAT1/fisiologia , Estearoil-CoA Dessaturase/fisiologia , Sulfonamidas/farmacologia , Proteína 3 Supressora da Sinalização de Citocinas , Triglicerídeos/biossíntese , Redução de Peso
2.
Biochim Biophys Acta ; 1791(12): 1190-6, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19716432

RESUMO

Insulin coordinately up-regulates lipogenic gene transcription via induction of sterol regulatory element binding protein-1c (SREBP-1c). Conversely, polyunsaturated fatty acids (PUFA) decrease lipogenic gene transcription via suppression of SREBP-1c. We therefore examined the ability of n-3 PUFA to mitigate induction of SREBP-1c and its downstream lipogenic targets by insulin in primary rat hepatocyte cultures. Insulin induced expression of SREBP-1c mRNA 5-6 fold as well as rat SREBP-1c promoter activity. These effects were prevented by the n-3 fatty acids eicosapentaenoic acid (20:5 n-3; EPA) and docosahexaenoic acid (22:6 n-3, DHA), but not by the monounsaturated fatty acid oleic acid (18:1 n-6, OLA). N-3 fatty acids also effectively prevented insulin induction of the downstream lipogenic enzyme targets fatty acid synthase (FAS) and acetyl carboxyl coenzyme acetyltransferase-1 (ACC-1), and reduced de novo lipogenesis. The SREBP-1c promoter contains an insulin response unit consisting of tandem LXRalpha response elements (LXREs) as well as sites for NF-Y, Sp1, and SREBP-1c itself. The LXREs were identified as a primary site mediating suppression of SREBP-1c transcription by n-3 PUFA. DHA effectively prevented LXRalpha-dependent activation of both the wild type SREBP-1c promoter and the synthetic LXRE-driven promoter, and significantly blunted LXRalpha-dependent activation of a Gal4-LXRalpha chimeric protein thus demonstrating that n-3 PUFA effectively mitigate induction of SREBP-1c by insulin via reduced trans-activation of LXRalpha.


Assuntos
Ácidos Graxos Ômega-3/farmacologia , Insulina/farmacologia , Receptores Nucleares Órfãos/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Transcrição Gênica/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos , Animais , Sítios de Ligação , Lipogênese/genética , Receptores X do Fígado , Luciferases/metabolismo , Mutação/genética , Receptores Nucleares Órfãos/agonistas , Receptores Nucleares Órfãos/antagonistas & inibidores , Ratos , Elementos de Resposta/genética
3.
Obesity (Silver Spring) ; 17(8): 1563-73, 2009 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19265796

RESUMO

The objective of this study was to determine the molecular bases of disordered hepatic function and disease susceptibility in obesity. We compared global gene expression in liver biopsies from morbidly obese (MO) women undergoing gastric bypass (GBP) surgery with that of women undergoing ventral hernia repair who had experienced massive weight loss (MWL) following prior GBP. Metabolic and hormonal profiles were examined in MO vs. MWL groups. Additionally, we analyzed individual profiles of hepatic gene expression in liver biopsy specimens obtained from MO and MWL subjects. All patients underwent preoperative metabolic profiling. RNAs were extracted from wedge biopsies of livers from MO and MWL subjects, and analysis of mRNA expression was carried out using Affymetrix HG-U133A microarray gene chips. Genes exhibiting greater than twofold differential expression between MO and MWL subjects were organized according to gene ontology and hierarchical clustering, and expression of key genes exhibiting differential regulation was quantified by real-time-polymerase chain reaction (RT-PCR). We discovered 154 genes to be differentially expressed in livers of MWL and MO subjects. A total of 28 candidate disease susceptibility genes were identified that encoded proteins regulating lipid and energy homeostasis (PLIN, ENO3, ELOVL2, APOF, LEPR, IGFBP1, DDIT4), signal transduction (MAP2K6, SOCS-2), postinflammatory tissue repair (HLA-DQB1, SPP1, P4HA1, LUM), bile acid transport (SULT2A, ABCB11), and metabolism of xenobiotics (GSTT2, CYP1A1). Using gene expression profiling, we have identified novel candidate disease susceptibility genes whose expression is altered in livers of MO subjects. The significance of altered expression of these genes to obesity-related disease is discussed.


Assuntos
Regulação da Expressão Gênica , Predisposição Genética para Doença , Fígado/metabolismo , Obesidade Mórbida/genética , Adulto , Biópsia , Proliferação de Células , Feminino , Perfilação da Expressão Gênica , Humanos , Inflamação , Metabolismo dos Lipídeos , Fígado/patologia , Obesidade Mórbida/patologia , Análise de Sequência com Séries de Oligonucleotídeos , RNA/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
4.
J Biol Chem ; 284(12): 7518-32, 2009 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-19158095

RESUMO

The regulation of lipid homeostasis by insulin is mediated in part by the enhanced transcription of the gene encoding SREBP-1c (sterol regulatory element-binding protein-1c). Nascent SREBP-1c is synthesized and embedded in the endoplasmic reticulum (ER) and must be transported to the Golgi in coatomer protein II (COPII) vesicles where two sequential cleavages generate the transcriptionally active NH(2)-terminal fragment, nSREBP-1c. There is limited indirect evidence to suggest that insulin may also regulate the posttranslational processing of the nascent SREBP-1c protein. Therefore, we designed experiments to directly assess the action of insulin on the post-translational processing of epitope-tagged full-length SREBP-1c and SREBP-2 proteins expressed in cultured hepatocytes. We demonstrate that insulin treatment led to enhanced post-translational processing of SREBP-1c, which was associated with phosphorylation of ER-bound nascent SREBP-1c protein that increased affinity of the SREBP-1c cleavage-activating protein (SCAP)-SREBP-1c complex for the Sec23/24 proteins of the COPII vesicles. Furthermore, chemical and molecular inhibitors of the phosphoinositide 3-kinase pathway and its downstream kinase protein kinase B (PKB)/Akt prevented both insulin-mediated phosphorylation of nascent SREBP-1c protein and its posttranslational processing. Insulin had no effect on the proteolysis of nascent SREBP-2 under identical conditions. We also show that in vitro incubation of an active PKB/Akt enzyme with recombinant full-length SREBP-1c led to its phosphorylation. Thus, insulin selectively stimulates the processing of SREBP-1c in rat hepatocytes by enhancing the association between the SCAP-SREBP-1c complex and COPII proteins and subsequent ER to Golgi transport and proteolytic cleavage. This effect of insulin is tightly linked to phosphoinositide 3-kinase and PKB/Akt-dependent serine phosphorylation of the precursor SREBP-1c protein.


Assuntos
Vesículas Revestidas pelo Complexo de Proteína do Envoltório/metabolismo , Hepatócitos/metabolismo , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Animais , Vesículas Revestidas pelo Complexo de Proteína do Envoltório/genética , Linhagem Celular , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Complexo de Golgi/genética , Complexo de Golgi/metabolismo , Hipoglicemiantes/metabolismo , Insulina/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologia , Processamento de Proteína Pós-Traducional/fisiologia , Transporte Proteico/efeitos dos fármacos , Transporte Proteico/fisiologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Proteína de Ligação a Elemento Regulador de Esterol 1/genética
5.
J Biol Chem ; 282(24): 17517-29, 2007 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-17449871

RESUMO

The induction of genes involved in lipid biosynthesis by insulin is mediated in part by the sterol regulatory element-binding protein-1c (SREBP-1c). SREBP-1c is directly regulated by insulin by transcriptional and post-transcriptional mechanisms. Previously, we have demonstrated that the insulin-responsive cis-acting unit of the rat SREBP-1c promoter is composed of several elements that include a sterol regulatory element, two liver X receptor elements, and a number of conserved GC boxes. Here we systematically dissected the role of these GC boxes and report that five bona fide Sp1-binding elements of the SREBP-1c promoter determine its basal and insulin-induced activation. Luciferase expression driven by the rat SREBP-1c promoter was accelerated by ectopic expression of Sp1, and insulin further enhanced the transactivation potential of Sp1. Introduction of a small interfering RNA against Sp1 reduced both basal and insulin-induced activation of the SREBP-1c promoter. We also found that Sp1 interacted with both SREBP-1c and LXRalpha proteins and that insulin promoted these interactions. Chromatin immunoprecipitation studies revealed that insulin facilitated the recruitment of the steroid receptor coactivator-1 to the SREBP-1c promoter. These studies identify a novel mechanism by which maximal activation of the rat SREBP-1c gene expression by insulin is mediated by Sp1 and its enhanced ability to interact with other transcriptional regulatory proteins.


Assuntos
Regulação da Expressão Gênica , Insulina/metabolismo , Fator de Transcrição Sp1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1 , Animais , Proteína de Ligação a CREB/metabolismo , Linhagem Celular , Proteínas de Ligação a DNA/metabolismo , Genes Reporter , Histona Acetiltransferases/metabolismo , Humanos , Receptores X do Fígado , Masculino , Coativador 1 de Receptor Nuclear , Receptores Nucleares Órfãos , Regiões Promotoras Genéticas , Interferência de RNA , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/metabolismo , Fator de Transcrição Sp1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Fatores de Transcrição/metabolismo , Ativação Transcricional
6.
Biochem Biophys Res Commun ; 332(1): 174-80, 2005 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-15896314

RESUMO

Insulin and cAMP have opposing effects on de novo fatty acid synthesis in liver and in cultured hepatocytes mediated by sterol-regulatory element binding protein (SREBP). To determine whether these agents regulate the cleavage of full-length SREBP to generate the transcriptionally active N-terminal fragment (nSREBP) in primary rat hepatocytes, an adenoviral vector (Ad-SREBP-1a) was constructed to constitutively express full-length SREBP-1a. Insulin increased, and dibutyryl (db)-cAMP inhibited, generation of nSREBP-1a from its full-length precursor. Insulin stimulated processing of SREBP-1a within 1h, and the effect was sustained for at least 24h. The initial stimulation of SREBP processing by insulin preceded measurable reduction in Insig-2 mRNA levels. Rat hepatocytes were also infected with an adenovirus expressing the nuclear form of SREBP-1c (Ad-nSREBP-1c). Insulin increased the half-life of constitutively expressed nSREBP-1c, and this effect of insulin was also inhibited by db-cAMP.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , AMP Cíclico/metabolismo , Proteínas de Ligação a DNA/metabolismo , Hepatócitos/metabolismo , Insulina/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Processamento de Proteína Pós-Traducional/fisiologia , Fatores de Transcrição/metabolismo , Animais , Células Cultivadas , Relação Dose-Resposta a Droga , Hepatócitos/efeitos dos fármacos , Insulina/farmacologia , Masculino , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Proteína de Ligação a Elemento Regulador de Esterol 1
7.
Biochem J ; 385(Pt 1): 207-16, 2005 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-15330762

RESUMO

The enhanced synthesis of fatty acids in the liver and adipose tissue in response to insulin is critically dependent on the transcription factor SREBP-1c (sterol-regulatory-element-binding protein 1c). Insulin increases the expression of the SREBP-1c gene in intact liver and in hepatocytes cultured in vitro. To learn the mechanism of this stimulation, we analysed the activation of the rat SREBP-1c promoter and its truncated or mutated congeners driving a luciferase reporter gene in transiently transfected rat hepatocytes. The rat SREBP-1c promoter contains binding sites for LXR (liver X receptor), Sp1, NF-Y (nuclear factor-Y) and SREBP itself. We have found that each of these sites is required for the full stimulatory response of the SREBP-1c promoter to insulin. Mutation of either the putative LXREs (LXR response elements) or the SRE (sterol response element) in the proximal SREBP-1c promoter reduced the stimulatory effect of insulin by about 50%. Insulin and the LXR agonist TO901317 increased the association of SREBP-1 with the SREBP-1c promoter. Ectopic expression of LXRalpha or SREBP-1c increased activity of the SREBP-1c promoter, and this effect is further enhanced by insulin. The Sp1 and NF-Y sites adjacent to the SRE are also required for full activation of the SREBP-1c promoter by insulin. We propose that the combined actions of the SRE, LXREs, Sp1 and NF-Y elements constitute an insulin-responsive cis-acting unit of the SREBP-1c gene in the liver.


Assuntos
Fator de Ligação a CCAAT/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Insulina/farmacologia , Regiões Promotoras Genéticas/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Elementos de Resposta/genética , Fator de Transcrição Sp1/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Anticolesterolemiantes/farmacologia , Células Cultivadas , Proteínas de Ligação a DNA/agonistas , Hidrocarbonetos Fluorados , Receptores X do Fígado , Masculino , Mutação/genética , Receptores Nucleares Órfãos , Ligação Proteica , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/agonistas , Receptores Citoplasmáticos e Nucleares/genética , Fator de Transcrição Sp3 , Proteína de Ligação a Elemento Regulador de Esterol 1 , Sulfonamidas , Regulação para Cima/efeitos dos fármacos
8.
Endocrinology ; 145(12): 5847-61, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15331573

RESUMO

In the corpulent James C. Russell corpulent (JCR:LA-cp) rat, hyperinsulinemia leads to induction of lipogenic enzymes via enhanced expression of sterol-regulatory-binding protein (SREBP)-1c. This results in increased hepatic lipid production and hypertriglyceridemia. Information regarding down-regulation of SREBP-1c and lipogenic enzymes by dietary fatty acids in this model is limited. We therefore assessed de novo hepatic lipogenesis and hepatic and plasma lipids in corpulent JCR rats fed diets enriched in olive oil or menhaden oil. Using microarray and Northern analysis, we determined the effect of these diets on expression of mRNA for lipogenic enzymes and other proteins related to lipid metabolism. In corpulent JCR:LA-cp rats, both the olive oil and menhaden oil diets reduced expression of SREBP-1c, with concomitant reductions in hepatic triglyceride content, lipogenesis, and expression of enzymes related to lipid synthesis. Unexpectedly, expression of many peroxisomal proliferator-activated receptor-dependent enzymes mediating fatty acid oxidation was increased in livers of corpulent JCR rats. The menhaden oil diet further increased expression of these enzymes. Induction of SREBP-1c by insulin is dependent on liver x receptor (LXR)alpha. Although hepatic expression of mRNA for LXR itself was not increased in corpulent rats, expression of Cyp7a1, an LXR-responsive gene, was increased, suggesting increased LXR activity. Expression of mRNA encoding fatty acid translocase and ATP-binding cassette subfamily DALD member 3 was also increased in livers of corpulent JCR rats, indicating a potential role for these fatty acid transporters in the pathogenesis of disordered lipid metabolism in obesity. This study clearly demonstrates that substitution of dietary polyunsaturated fatty acid for carbohydrate in the corpulent JCR:LA-cp rat reduces de novo lipogenesis, at least in part, by reducing hepatic expression of SREBP-1c and that strategies directed toward reducing SREBP-1c expression in the liver may mitigate the adverse effects of hyperinsulinemia on hepatic lipid production.


Assuntos
Óleos de Peixe/farmacologia , Insulina/sangue , Obesidade/dietoterapia , Obesidade/genética , Análise de Sequência com Séries de Oligonucleotídeos , Óleos de Plantas/farmacologia , Animais , Apoproteínas/genética , Ácidos e Sais Biliares/metabolismo , Northern Blotting , Peso Corporal , Colesterol/metabolismo , Gorduras na Dieta/farmacocinética , Ácidos Graxos/sangue , Expressão Gênica/efeitos dos fármacos , Hormônios/metabolismo , Insulina/genética , Fígado/metabolismo , Masculino , Mitocôndrias/metabolismo , Obesidade/fisiopatologia , Azeite de Oliva , Peroxissomos/metabolismo , RNA Mensageiro/análise , Ratos , Ratos Endogâmicos , Receptores de Superfície Celular/genética , Fatores de Transcrição/genética , Triglicerídeos/sangue
9.
Shock ; 18(2): 119-24, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12166773

RESUMO

Lack of enteral feeding increases P- and E-selectin and ICAM-1 expression on endothelial cells in organs, such as the small intestine and lung, and increases neutrophils in the intestine. These changes are associated with increased mortality after gut ischemia. We hypothesize that nutritional regimen affects endothelial ICAM-1 levels and leukocyte beta2 integrins after gut ischemia. Mice received chow, intravenous (IV) TPN, or intragastric (IG) TPN. In experiment 1, after 5 days of diet, 28 mice underwent 15 min of superior mesenteric artery (SMA) occlusion (I/R) for quantification of ICAM-1 expression in organs 3 h later. In experiment 2, after the same nutrient pretreatments of 38 mice, peripheral blood was obtained with or without gut I/R to measure CD11a and CD11b expression on myeloid cells. CD18 immunofluorescence staining was studied in the lung. Expression of ICAM-1 in the liver, kidney, and small intestine was significantly higher after IV-TPN than chow. IG-TPN reduced liver and kidney ICAM-1 levels midway between the chow and IV-TPN groups, but not intestinal expression. Expression of CD11b on the myeloid cell population in each group was similar before I/R, but CD11b levels increased after IV-TPN on circulating cells after I/R compared with all uninjured animals or injured chow or IG-TPN mice. Only IV-TPN mice had lung CD18-positive leukocytes after I/R. After I/R, lack of enteral feeding increases organ expression of ICAM-1, CD11b levels on myeloid cells, and lung of CD18 positive leukocytes. Through these changes, lack of enteral feeding may increase organ damage after gut ischemia.


Assuntos
Cadeias beta de Integrinas/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Intestino Delgado/irrigação sanguínea , Isquemia/diagnóstico , Insuficiência de Múltiplos Órgãos/prevenção & controle , Nutrição Parenteral , Análise de Variância , Animais , Biomarcadores/análise , Antígenos CD11/análise , Antígenos CD18/análise , Modelos Animais de Doenças , Citometria de Fluxo , Cadeias beta de Integrinas/análise , Molécula 1 de Adesão Intercelular/análise , Mucosa Intestinal/patologia , Intestino Delgado/patologia , Masculino , Camundongos , Camundongos Endogâmicos ICR , Probabilidade , Prognóstico , Valores de Referência , Sensibilidade e Especificidade
10.
Biochem Biophys Res Commun ; 290(1): 256-62, 2002 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-11779162

RESUMO

We have cloned 5 kb of genomic DNA encompassing 1.72 kb of 5'-regulatory sequence and exons 1-c and 2 of the rat SREBP-1c gene. A 1.5-kb segment upstream from the transcription start site was ligated ahead of the luciferase reporter gene and tested for promoter activity by transient transfection assays in primary rat hepatocytes. We discovered that insulin strongly activated the full-length promoter, regardless of whether 5 or 20 mM glucose was in the culture medium during treatment. Stimulation by insulin was blocked by dibutyryl-cAMP and by polyunsaturated fatty acids, such as alpha-linolenic acid, gamma-linolenic acid, or eicosapentaenoic acid; palmitic or oleic acids, however, had no inhibitory effect. A truncated promoter containing 149 bp of 5' flanking DNA, including proximal NF-Y, E-box, SRE, and Sp1 sites, retained most of the response. This is the first report that insulin, cAMP, and polyunsaturated fatty acids modulate the proximal SREBP-1c promoter in rat hepatocytes mirroring physiological regulation of SREBP-1c in vivo.


Assuntos
Proteínas Estimuladoras de Ligação a CCAAT/biossíntese , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Regulação da Expressão Gênica , Hepatócitos/metabolismo , Regiões Promotoras Genéticas , Fatores de Transcrição , Animais , Sequência de Bases , Bucladesina/metabolismo , Células Cultivadas , Clonagem Molecular , AMP Cíclico/metabolismo , Ácido Eicosapentaenoico/metabolismo , Inibidores Enzimáticos/farmacologia , Éxons , Genes Reporter , Glucose/farmacologia , Insulina/metabolismo , Fígado/metabolismo , Luciferases/metabolismo , Masculino , Dados de Sequência Molecular , Ácido Oleico/metabolismo , Ácido Palmítico/metabolismo , Plasmídeos/metabolismo , RNA/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Proteína de Ligação a Elemento Regulador de Esterol 1 , Fatores de Tempo , Transcrição Gênica , Transfecção , Ácido gama-Linolênico/metabolismo
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