RESUMO
Tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist, has, in clinical trials, demonstrated greater reductions in glucose, body weight, and triglyceride levels compared with selective GLP-1R agonists in people with type 2 diabetes (T2D). However, cellular mechanisms by which GIPR agonism may contribute to these improved efficacy outcomes have not been fully defined. Using human adipocyte and mouse models, we investigated how long-acting GIPR agonists regulate fasted and fed adipocyte functions. In functional assays, GIPR agonism enhanced insulin signaling, augmented glucose uptake, and increased the conversion of glucose to glycerol in a cooperative manner with insulin; however, in the absence of insulin, GIPR agonists increased lipolysis. In diet-induced obese mice treated with a long-acting GIPR agonist, circulating triglyceride levels were reduced during oral lipid challenge, and lipoprotein-derived fatty acid uptake into adipose tissue was increased. Our findings support a model for long-acting GIPR agonists to modulate both fasted and fed adipose tissue function differentially by cooperating with insulin to augment glucose and lipid clearance in the fed state while enhancing lipid release when insulin levels are reduced in the fasted state.
Assuntos
Adipócitos , Polipeptídeo Inibidor Gástrico , Receptores dos Hormônios Gastrointestinais , Animais , Humanos , Masculino , Camundongos , Adipócitos/metabolismo , Adipócitos/efeitos dos fármacos , Polipeptídeo Inibidor Gástrico/metabolismo , Polipeptídeo Inibidor Gástrico/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Receptor do Peptídeo Semelhante ao Glucagon 2 , Glucose/metabolismo , Insulina/metabolismo , Lipólise/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Nutrientes/metabolismo , Obesidade/metabolismo , Obesidade/tratamento farmacológico , Receptores dos Hormônios Gastrointestinais/metabolismo , Receptores dos Hormônios Gastrointestinais/agonistas , Transdução de Sinais/efeitos dos fármacos , Triglicerídeos/metabolismoRESUMO
Recent studies have found that glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism can enhance the metabolic efficacy of glucagon-like peptide-1 receptor agonist treatment by promoting both weight-dependent and -independent improvements on systemic insulin sensitivity. These findings have prompted new investigations aimed at better understanding the broad metabolic benefit of GIPR activation. Herein, we determined whether GIPR agonism favorably influenced the pharmacologic efficacy of the insulin-sensitizing thiazolidinedione (TZD) rosiglitazone in obese insulin-resistant (IR) mice. Genetic and pharmacological approaches were used to examine the role of GIPR signaling on rosiglitazone-induced weight gain, hyperphagia, and glycemic control. RNA sequencing was conducted to uncover potential mechanisms by which GIPR activation influences energy balance and insulin sensitivity. In line with previous findings, treatment with rosiglitazone induced the mRNA expression of the GIPR in white and brown fat. However, obese GIPR-null mice dosed with rosiglitazone had equivalent weight gain to that of wild-type (WT) animals. Strikingly, chronic treatment of obese IR WT animals with a long-acting GIPR agonist prevented rosiglitazone-induced weight-gain and hyperphagia, and it enhanced the insulin-sensitivity effect of this TZD. The systemic insulin sensitization was accompanied by increased glucose disposal in brown adipose tissue, which was underlined by the recruitment of metabolic and thermogenic genes. These findings suggest that GIPR agonism can counter the negative consequences of rosiglitazone treatment on body weight and adiposity, while improving its insulin-sensitizing efficacy at the same time.
Assuntos
Resistência à Insulina , Receptores dos Hormônios Gastrointestinais , Tiazolidinedionas , Camundongos , Animais , Insulina/metabolismo , Resistência à Insulina/fisiologia , Rosiglitazona/uso terapêutico , Obesidade/metabolismo , Tiazolidinedionas/uso terapêutico , Receptores dos Hormônios Gastrointestinais/metabolismo , Aumento de Peso , Insulina Regular Humana/uso terapêutico , Hiperfagia , Polipeptídeo Inibidor Gástrico/farmacologiaRESUMO
Tirzepatide (LY3298176), a dual GIP and GLP-1 receptor (GLP-1R) agonist, delivered superior glycemic control and weight loss compared with GLP-1R agonism in patients with type 2 diabetes. However, the mechanism by which tirzepatide improves efficacy and how GIP receptor (GIPR) agonism contributes is not fully understood. Here, we show that tirzepatide is an effective insulin sensitizer, improving insulin sensitivity in obese mice to a greater extent than GLP-1R agonism. To determine whether GIPR agonism contributes, we compared the effect of tirzepatide in obese WT and Glp-1r-null mice. In the absence of GLP-1R-induced weight loss, tirzepatide improved insulin sensitivity by enhancing glucose disposal in white adipose tissue (WAT). In support of this, a long-acting GIPR agonist (LAGIPRA) was found to enhance insulin sensitivity by augmenting glucose disposal in WAT. Interestingly, the effect of tirzepatide and LAGIPRA on insulin sensitivity was associated with reduced branched-chain amino acids (BCAAs) and ketoacids in the circulation. Insulin sensitization was associated with upregulation of genes associated with the catabolism of glucose, lipid, and BCAAs in brown adipose tissue. Together, our studies show that tirzepatide improved insulin sensitivity in a weight-dependent and -independent manner. These results highlight how GIPR agonism contributes to the therapeutic profile of dual-receptor agonism, offering mechanistic insights into the clinical efficacy of tirzepatide.
Assuntos
Tecido Adiposo Branco/metabolismo , Polipeptídeo Inibidor Gástrico/farmacologia , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Resistência à Insulina , Obesidade/metabolismo , Tecido Adiposo Branco/patologia , Aminoácidos de Cadeia Ramificada/genética , Aminoácidos de Cadeia Ramificada/metabolismo , Animais , Peso Corporal/efeitos dos fármacos , Peso Corporal/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/genética , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Camundongos , Camundongos Knockout , Obesidade/tratamento farmacológico , Obesidade/genética , Obesidade/patologiaRESUMO
This study tested the hypothesis that (pyr)apelin-13 dose-dependently augments myocardial contractility and coronary blood flow, irrespective of changes in systemic hemodynamics. Acute effects of intravenous (pyr)apelin-13 administration (10 to 1,000 nM) on blood pressure, heart rate, left ventricular pressure and volume, and coronary parameters were measured in dogs and pigs. Administration of (pyr)apelin-13 did not influence blood pressure (P = 0.59), dP/dtmax (P = 0.26), or dP/dtmin (P = 0.85) in dogs. However, heart rate dose-dependently increased > 70% (P < 0.01), which was accompanied by a significant increase in coronary blood flow (P < 0.05) and reductions in left ventricular end-diastolic volume and stroke volume (P < 0.001). In contrast, (pyr)apelin-13 did not significantly affect hemodynamics, coronary blood flow, or indexes of contractile function in pigs. Furthermore, swine studies found no effect of intracoronary (pyr)apelin-13 administration on coronary blood flow (P = 0.83) or vasorelaxation in isolated, endothelium-intact (P = 0.89) or denuded (P = 0.38) coronary artery rings. Examination of all data across (pyr)apelin-13 concentrations revealed an exponential increase in cardiac output as peripheral resistance decreased across pigs and dogs (P < 0.001; R2 = 0.78). Assessment of the Frank-Starling relationship demonstrated a significant linear relationship between left ventricular end-diastolic volume and stroke volume across species (P < 0.001; R2 = 0.70). Taken together, these findings demonstrate that (pyr)apelin-13 does not directly influence myocardial contractility or coronary blood flow in either dogs or pigs.NEW & NOTEWORTHY Our findings provide much needed insight regarding the pharmacological cardiac and coronary effects of (pyr)apelin-13 in larger animal preparations. In particular, data highlight distinct hemodynamic responses of apelin across species, which are independent of any direct effect on myocardial contractility or perfusion.
Assuntos
Circulação Coronária/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Contração Miocárdica/efeitos dos fármacos , Animais , Pressão Sanguínea , Vasos Coronários/efeitos dos fármacos , Cães , Frequência Cardíaca , Masculino , Volume Sistólico , Suínos , VasodilataçãoRESUMO
Class B G-protein-coupled receptors are major targets for the treatment of chronic diseases, including diabetes and obesity1. Structures of active receptors reveal peptide agonists engage deep within the receptor core, leading to an outward movement of extracellular loop 3 and the tops of transmembrane helices 6 and 7, an inward movement of transmembrane helix 1, reorganization of extracellular loop 2 and outward movement of the intracellular side of transmembrane helix 6, resulting in G-protein interaction and activation2-6. Here we solved the structure of a non-peptide agonist, TT-OAD2, bound to the glucagon-like peptide-1 (GLP-1) receptor. Our structure identified an unpredicted non-peptide agonist-binding pocket in which reorganization of extracellular loop 3 and transmembrane helices 6 and 7 manifests independently of direct ligand interaction within the deep transmembrane domain pocket. TT-OAD2 exhibits biased agonism, and kinetics of G-protein activation and signalling that are distinct from peptide agonists. Within the structure, TT-OAD2 protrudes beyond the receptor core to interact with the lipid or detergent, providing an explanation for the distinct activation kinetics that may contribute to the clinical efficacy of this compound series. This work alters our understanding of the events that drive the activation of class B receptors.
Assuntos
Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Isoquinolinas/farmacologia , Fenilalanina/análogos & derivados , Piridinas/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Receptor do Peptídeo Semelhante ao Glucagon 1/química , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Isoquinolinas/química , Cinética , Modelos Moleculares , Fenilalanina/química , Fenilalanina/farmacologia , Estrutura Quaternária de Proteína , Estrutura Terciária de Proteína , Piridinas/química , Homologia Estrutural de ProteínaRESUMO
Insulin-degrading enzyme (IDE, insulysin) is the best characterized catabolic enzyme implicated in proteolysis of insulin. Recently, a peptide inhibitor of IDE has been shown to affect levels of insulin, amylin, and glucagon in vivo. However, IDE(-/-) mice display variable phenotypes relating to fasting plasma insulin levels, glucose tolerance, and insulin sensitivity depending on the cohort and age of animals. Here, we interrogated the importance of IDE-mediated catabolism on insulin clearance in vivo. Using a structure-based design, we linked two newly identified ligands binding at unique IDE exosites together to construct a potent series of novel inhibitors. These compounds do not interact with the catalytic zinc of the protease. Because one of these inhibitors (NTE-1) was determined to have pharmacokinetic properties sufficient to sustain plasma levels >50 times its IDE IC50 value, studies in rodents were conducted. In oral glucose tolerance tests with diet-induced obese mice, NTE-1 treatment improved the glucose excursion. Yet in insulin tolerance tests and euglycemic clamp experiments, NTE-1 did not enhance insulin action or increase plasma insulin levels. Importantly, IDE inhibition with NTE-1 did result in elevated plasma amylin levels, suggesting the in vivo role of IDE action on amylin may be more significant than an effect on insulin. Furthermore, using the inhibitors described in this report, we demonstrate that in HEK cells IDE has little impact on insulin clearance. In total, evidence from our studies supports a minimal role for IDE in insulin metabolism in vivo and suggests IDE may be more important in helping regulate amylin clearance.
Assuntos
Inibidores Enzimáticos/farmacologia , Insulina/metabolismo , Insulisina/antagonistas & inibidores , Animais , Sítios de Ligação , Cristalografia por Raios X , Inibidores Enzimáticos/farmacocinética , Células HEK293 , Humanos , Insulisina/química , Modelos Moleculares , ProteóliseRESUMO
The design, synthesis, and structure activity relationships for a novel series of indoles as potent, selective, thyroid hormone receptor ß (TRß) agonists is described. Compounds with >50× binding selectivity for TRß over TRα were generated and evaluation of compound 1c from this series in a model of dyslipidemia demonstrated positive effects on plasma lipid endpoints in vivo.
Assuntos
Acetatos/farmacologia , Desenho de Fármacos , Indóis/farmacologia , Receptores beta dos Hormônios Tireóideos/agonistas , Acetatos/síntese química , Acetatos/química , Relação Dose-Resposta a Droga , Humanos , Indóis/síntese química , Indóis/química , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
The absence of insulin results in oscillating hyperglycemia and ketoacidosis in type 1 diabetes. Remarkably, mice genetically deficient in the glucagon receptor (Gcgr) are refractory to the pathophysiological symptoms of insulin deficiency, and therefore, studies interrogating this unique model may uncover metabolic regulatory mechanisms that are independent of insulin. A significant feature of Gcgr-null mice is the high circulating concentrations of GLP-1. Hence, the objective of this report was to investigate potential noninsulinotropic roles of GLP-1 in mice where GCGR signaling is inactivated. For these studies, pancreatic ß-cells were chemically destroyed by streptozotocin (STZ) in Gcgr(-/-):Glp-1r(-/-) mice and in Glp-1r(-/-) animals that were subsequently treated with a high-affinity GCGR antagonist antibody that recapitulates the physiological state of Gcgr ablation. Loss of GLP-1 action substantially worsened nonfasting glucose concentrations and glucose tolerance in mice deficient in, and undergoing pharmacological inhibition of, the GCGR. Further, lack of the Glp-1r in STZ-treated Gcgr(-/-) mice elevated rates of endogenous glucose production, likely accounting for the differences in glucose homeostasis. These results support the emerging hypothesis that non-ß-cell actions of GLP-1 analogs may improve metabolic control in patients with insulinopenic diabetes.
Assuntos
Glucagon/metabolismo , Glucose/metabolismo , Insulina/metabolismo , Receptores de Glucagon/deficiência , Animais , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1 , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Receptores de Glucagon/antagonistas & inibidores , Receptores de Glucagon/genética , Receptores de Glucagon/metabolismo , Estreptozocina/farmacologiaRESUMO
Muscarinic receptor-mediated cardiac parasympathetic activity is essential for regulating heart rate and heart rate variability (HRV). It has not been clear which G(i)/G(o) protein is responsible for these effects. We addressed this question using knockout mice that lack G protein alpha(i2), alpha(i3), or alpha(o) specifically. Unlike previously reported, our alpha(o)-null mice had significantly more survivors with normal life span. Isolated hearts from alpha(o)-null mice demonstrated much less sensitivity to the negative chronotropic effects of the muscarinic agonist carbachol to lower heart rate at baseline and a more profound effect under the stimulation of the beta-adrenergic agonist isoproterenol. In the presence of parasympathetic activation indirectly produced by methoxamine, an alpha(1)-adrenergic agonist, alpha(o)-null mice showed markedly decreased HRV compared with wild-type control mice. These differences in heart rate and HRV were not observed in alpha(i2)-null or alpha(i3)-null mice. Our findings establish an essential role for alpha(o) G protein in the anti-adrenergic effect of carbachol on heart rate regulation.
Assuntos
Proteínas de Ligação ao GTP/metabolismo , Frequência Cardíaca/fisiologia , Coração/fisiologia , Receptores Muscarínicos/metabolismo , Animais , Subunidade alfa Gi2 de Proteína de Ligação ao GTP/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Camundongos , Camundongos KnockoutRESUMO
The role of the Frank-Starling mechanism in the regulation of cardiac systolic function in the ischemic failing heart was examined in conscious dogs. Left ventricular (LV) dimension, pressure and systolic function were assessed using surgically implanted instrumentations and non-invasive echocardiogram. Heart failure was induced by daily intra-coronary injections of microspheres for 3-4 weeks via implanted coronary catheters. Chronic coronary embolization resulted in a progressive dilation of the left ventricle (12+/-3%), increase in LV end-diastolic pressure (118+/-19%), depression of LV dP/dt(max) (-19+/-4%), fractional shortening (-36+/-7%), and cardiac work (-60+/-9%), and development of heart failure, while the LV contractile response to dobutamine was depressed. A brief inferior vena caval occlusion in dogs with heart failure decreased LV preload to match the levels attained in their control state and caused a further reduction of LV dP/dt(max), fractional shortening, stroke work and cardiac work. Moreover, in response to acute volume loading, the change in the LV end-diastolic dimension-pressure (DeltaLVEDD-DeltaLVEDP) curve in the failing heart became steeper and shifted significantly to the left, while the increases in LV stroke work and cardiac work were blunted. Thus, our results suggest that the Frank-Starling mechanism is exhausted in heart failure and unable to further respond to increasing volume while it plays an important compensatory role in adaptation to LV dysfunction in heart failure.
Assuntos
Baixo Débito Cardíaco/etiologia , Vasos Coronários/fisiopatologia , Embolia/complicações , Volume Sistólico/fisiologia , Função Ventricular Esquerda/fisiologia , Animais , Baixo Débito Cardíaco/patologia , Baixo Débito Cardíaco/fisiopatologia , Modelos Animais de Doenças , Cães , Ecocardiografia sob Estresse , Embolia/patologia , Ventrículos do Coração/patologia , Masculino , Veia Cava Inferior/fisiopatologia , Função VentricularRESUMO
Peroxisomes are the exclusive site for the beta-oxidation of very-long-chain fatty acids of more than 20 carbons in length (VLCFAs). Although the bulk of dietary long-chain fatty acids are oxidized in the mitochondria, VLCFAs cannot be catabolized in mitochondria and must be shortened first by peroxisomal beta-oxidation. The regulation of peroxisomal, mitochondrial, and microsomal fatty acid oxidation systems in liver is mediated principally by peroxisome proliferator-activated receptor alpha (PPARalpha). In this study we provide evidence that the liver X receptor (LXR) regulates the expression of the genetic program for peroxisomal beta-oxidation in liver. The genes encoding the three enzymes of the classic peroxisomal beta-oxidation cycle, acyl-coenzyme A (acyl-CoA) oxidase, enoyl-CoA hydratase/L-3-hydroxyacyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase, are activated by the LXR ligand, T0901317. Accordingly, administration of T0901317 in mice promoted a dose-dependent and greater than 2-fold increase in the rate of peroxisomal beta-oxidation in the liver. The LXR effect is independent of PPARalpha, because T0901317-induced peroxisomal beta-oxidation in the liver of PPARalpha-null mice. Interestingly, T0901317-induced peroxisomal beta-oxidation is dependent on the LXRalpha isoform, but not the LXRbeta isoform. We propose that induction of peroxisomal beta-oxidation by LXR agonists may serve as a counterregulatory mechanism for responding to the hypertriglyceridemia and liver steatosis that is promoted by potent LXR agonists in vivo; however, additional studies are warranted.
Assuntos
Proteínas de Ligação a DNA/fisiologia , Ácidos Graxos/metabolismo , Fígado/metabolismo , Peroxissomos/metabolismo , Receptores Citoplasmáticos e Nucleares/fisiologia , Acetil-CoA C-Aciltransferase/genética , Acil Coenzima A/genética , Animais , Relação Dose-Resposta a Droga , Enoil-CoA Hidratase/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Hidrocarbonetos Fluorados , Ligantes , Receptores X do Fígado , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Nucleares Órfãos , Oxirredução/efeitos dos fármacos , PPAR alfa/deficiência , PPAR alfa/fisiologia , Sulfonamidas/administração & dosagem , Sulfonamidas/farmacologiaRESUMO
Mixed lineage kinase 7 (MLK7) is a mitogen-activated protein kinase kinase kinase (MAPKKK) that activates the pro-apoptotic signaling pathways p38 and JNK. A library of potential kinase inhibitors was screened, and a series of dihydropyrrolopyrazole quinolines was identified as highly potent inhibitors of MLK7 in vitro catalytic activity. Of this series, an aryl-substituted dihydropyrrolopyrazole quinoline (DHP-2) demonstrated an IC50 of 70 nM for inhibition of pJNK formation in COS-7 cell MLK7/JNK co-transfection assays. In stimulated cells, DHP-2 at 200 nM or MLK7 small interfering RNA completely blocked anisomycin and UV induced but had no effect on interleukin-1beta or tumor necrosis factor-alpha-induced p38 and JNK activation. Additionally, the compound blocked anisomycin and UV-induced apoptosis in COS-7 cells. Heart tissue homogenates from MLK7 transgenic mice treated with DHP-2 at 30 mg/kg had reduced JNK and p38 activation with no apparent effect on ERK activation, demonstrating that this compound can be used to block MLK7-driven MAPK pathway activation in vivo. Taken together, these data demonstrate that MLK7 is the MAPKKK required for modulation of the stress-activated MAPKs downstream of anisomycin and UV stimulation and that DHP-2 can be used to block MLK7 pathway activation in cells as well as in vivo.
Assuntos
Anisomicina/antagonistas & inibidores , Anisomicina/química , Citocinas/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Proteínas Musculares/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Pirazóis/farmacologia , Quinolinas/farmacologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Anisomicina/farmacologia , Apoptose , Western Blotting , Células COS , Catálise , Fragmentação do DNA , Relação Dose-Resposta a Droga , Eletroforese em Gel de Poliacrilamida , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Glutationa Transferase/metabolismo , Humanos , Concentração Inibidora 50 , Interleucina-1/metabolismo , MAP Quinase Quinase 4 , MAP Quinase Quinase Quinases/metabolismo , Camundongos , Modelos Químicos , Proteínas Musculares/metabolismo , Miocárdio/metabolismo , Inibidores da Síntese de Ácido Nucleico/química , Inibidores da Síntese de Ácido Nucleico/farmacologia , Plasmídeos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Pirazóis/química , Quinolinas/química , RNA Interferente Pequeno/metabolismo , Transdução de Sinais , Fatores de Tempo , Transfecção , Transgenes , Fator de Necrose Tumoral alfa/metabolismo , Raios UltravioletaRESUMO
The farnesoid X receptor (FXR; NR1H4) is a nuclear hormone receptor that functions as the bile acid receptor. In addition to the critical role FXR plays in bile acid metabolism and transport, it regulates a variety of genes important in lipoprotein metabolism. We demonstrate that FXR also plays a role in carbohydrate metabolism via regulation of phosphoenolpyruvate carboxykinase (PEPCK) gene expression. Treatment of either H4IIE or MH1C1 rat hepatoma cell lines as well as primary rat or human hepatocytes with FXR agonists led to stimulation of PEPCK mRNA expression to levels comparable to those obtained with glucocorticoid receptor agonists. We examined the physiological significance of FXR agonist-induced enhancement of PEPCK expression in primary rat hepatocytes. In addition to inducing PEPCK expression in primary hepatocytes, FXR agonists stimulated glucose output to levels comparable to those observed with a glucocorticoid receptor agonist. Consistent with these observations, treatment of C57BL6 mice with GW4064 significantly increased hepatic PEPCK expression. Activation of FXR initiated a cascade involving induction of peroxisome proliferator-activated receptor alpha and TRB3 expression that is consistent with stimulation of PEPCK gene expression via interference with a pathway that may involve Akt-dependent phosphorylation of Forkhead/winged helix transcription factor (FOXO1). The FXR-peroxisome proliferator-activated receptor alpha-TRB3 pathway was conserved in rat hepatoma cell lines, mice, as well as primary human hepatocytes. Thus, in addition to its role in the regulation of lipid metabolism, FXR regulates carbohydrate metabolism.
Assuntos
Carboidratos/química , Proteínas de Ligação a DNA/fisiologia , Fatores de Transcrição/fisiologia , Animais , Ácidos e Sais Biliares/metabolismo , Metabolismo dos Carboidratos , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/metabolismo , Relação Dose-Resposta a Droga , Glucocorticoides/metabolismo , Glucose/metabolismo , Hepatócitos/metabolismo , Humanos , Immunoblotting , Isoxazóis/farmacologia , Metabolismo dos Lipídeos , Lipoproteínas/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , PPAR alfa/metabolismo , Fosfoenolpiruvato Carboxiquinase (GTP)/fisiologia , Fosforilação , Pregnenodionas/farmacologia , RNA Mensageiro/metabolismo , Ratos , Receptores Citoplasmáticos e Nucleares , Fatores de Transcrição/metabolismoRESUMO
Mixed lineage kinase 7 (MLK7) is a recently identified mitogen-activated protein kinase kinase kinase with enriched expression in skeletal muscle and heart. When over-expressed in cardiac myocytes, MLK7 activates both the p38 and c-Jun N-terminal kinase (JNK) stress-activated pathways and induces a cellular phenotype characteristic of cardiac hypertrophy, including a fetal gene expression pattern and increased protein synthesis. We sought to determine the effect of MLK7 on cardiac function in vivo by generating transgenic (Tg) mice with cardiac restricted over-expression of the enzyme. The mice were viable and demonstrated no visible signs of distress at rest. Microscopic examination of the hearts showed myocardial fibrosis and hypertrophy. Hemodynamic analysis of the Tg mice revealed impaired systolic function and significant diastolic dysfunction. Furthermore, significant mortality was observed in MLK7 Tg mice following 24-48 h of isoproterenol administration. Isoproterenol activation of JNK and p38, but not extracellular signal-regulated kinase, was significantly greater in the MLK7 Tg mice compared to littermate controls. These data indicate that MLK7 is an important signal transducer in cardiac compensation. Simultaneous activation of JNK and p38 by MLK7 may contribute to cardiac decompensation during the periods of acute cardiac stress.