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1.
Gastroenterology ; 165(1): 187-200.e7, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-36966941

RESUMEN

BACKGROUND & AIMS: Excess copper causes hepatocyte death in hereditary Wilson's disease (WD). Current WD treatments by copper-binding chelators may gradually reduce copper overload; they fail, however, to bring hepatic copper close to normal physiological levels. Consequently, lifelong daily dose regimens are required to hinder disease progression. This may result in severe issues due to nonadherence or unwanted adverse drug reactions and also due to drug switching and ultimate treatment failures. This study comparatively tested bacteria-derived copper binding agents-methanobactins (MBs)-for efficient liver copper depletion in WD rats as well as their safety and effect duration. METHODS: Copper chelators were tested in vitro and in vivo in WD rats. Metabolic cage housing allowed the accurate assessment of animal copper balances and long-term experiments related to the determination of minimal treatment phases. RESULTS: We found that copper-binding ARBM101 (previously known as MB-SB2) depletes WD rat liver copper dose dependently via fecal excretion down to normal physiological levels within 8 days, superseding the need for continuous treatment. Consequently, we developed a new treatment consisting of repetitive cycles, each of ∼1 week of ARBM101 applications, followed by months of in-between treatment pauses to ensure a healthy long-term survival in WD rats. CONCLUSIONS: ARBM101 safely and efficiently depletes excess liver copper from WD rats, thus allowing for short treatment periods as well as prolonged in-between rest periods.


Asunto(s)
Degeneración Hepatolenticular , Ratas , Animales , Degeneración Hepatolenticular/tratamiento farmacológico , Degeneración Hepatolenticular/metabolismo , Cobre , Eliminación Hepatobiliar , Hígado/metabolismo , Quelantes/farmacología , Quelantes/uso terapéutico
2.
Biol Pharm Bull ; 42(9): 1554-1561, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31474715

RESUMEN

Obesity, which is characterized by an excessive accumulation of body fat, is one of the critical factors causing metabolic syndrome. Many studies have been performed to identify appropriate agents to control obesity, but toxicity remains a problem. Herein, we identified that phenylbutyrate (PBA), which has been used to treat urea cycle disorder with very low toxicity for a long time, efficiently inhibited high fat-induced body weight gain in a diet-induced obesity mouse model (DIO model). PBA treatment decreased body fat mass and increased lean composition. Moreover, PBA increased brown adipose tissue (BAT) activity by increasing glucose uptake, thereby improving glucose tolerance and insulin tolerance. Interestingly, PBA could induce the expression of liver type phosphofructokinase (PFKL), a key enzyme in the glycolytic pathway, and knocking down PFKL dramatically repressed the expression level of Ucp1 as well as those of Prdm16, Cidea, Pgc1α, and Pparγ, which are marker genes for BAT activation. These results strongly suggested that PBA could increase energy expenditure by increasing BAT activity via the induction of PFKL. Taken together, PBA could be used as a therapeutic agent for people with obesity to prevent the development of metabolic syndrome.


Asunto(s)
Tejido Adiposo Pardo/efectos de los fármacos , Fármacos Antiobesidad/farmacología , Dieta Alta en Grasa , Obesidad/prevención & control , Fenilbutiratos/farmacología , Adipocitos/efectos de los fármacos , Adipocitos/metabolismo , Tejido Adiposo Pardo/diagnóstico por imagen , Tejido Adiposo Pardo/metabolismo , Animales , Modelos Animales de Enfermedad , Ingestión de Alimentos/efectos de los fármacos , Fluorodesoxiglucosa F18 , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Resistencia a la Insulina , Masculino , Ratones Endogámicos C57BL , Obesidad/metabolismo , Fenilbutiratos/uso terapéutico , Tomografía Computarizada por Tomografía de Emisión de Positrones , Aumento de Peso/efectos de los fármacos
3.
Cell Immunol ; 281(2): 122-8, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23603048

RESUMEN

Lysosome-associated membrane proteins (LAMPs), a family of highly glycosylated transmembrane proteins, are well known lysosomal markers. Recent investigations revealed the cell surface expression of LAMPs, especially after activation in various cell types. Although their role in lysosome function is under intense investigation, little is known about the function of this cell surface form of LAMPs. To investigate the role of cell surface LAMPs in macrophage activities, the human macrophage-like cell line THP-1 was stimulated with monoclonal antibodies specific to CD107a (LAMP-1) or CD107b (LAMP-2). Stimulation of CD107 enhanced LPS-induced IL-8 secretion and induced adhesion of THP-1 cells to culture plates coated with extracellular matrix proteins such as collagen, fibronectin, and laminin. Utilization of specific inhibitors of signaling adapters and Western blot analysis revealed that extracellular signal-regulated kinase (ERK) mediates the regulatory action of CD107. These results suggest that stimulation of THP-1 cells through CD107 affects macrophage-associated functions such as cytokine secretion and cellular adhesion through activation of ERK.


Asunto(s)
Interleucina-8/inmunología , Lipopolisacáridos/inmunología , Proteína 1 de la Membrana Asociada a los Lisosomas/inmunología , Proteína 2 de la Membrana Asociada a los Lisosomas/inmunología , Sistema de Señalización de MAP Quinasas/inmunología , Macrófagos/inmunología , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/farmacología , Western Blotting , Butadienos/farmacología , Adhesión Celular/efectos de los fármacos , Adhesión Celular/inmunología , Línea Celular , Activación Enzimática/efectos de los fármacos , Activación Enzimática/inmunología , Inhibidores Enzimáticos/farmacología , Ensayo de Inmunoadsorción Enzimática , Proteínas de la Matriz Extracelular/inmunología , Proteínas de la Matriz Extracelular/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Quinasas MAP Reguladas por Señal Extracelular/inmunología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Citometría de Flujo , Humanos , Interleucina-8/metabolismo , Lipopolisacáridos/farmacología , Proteína 1 de la Membrana Asociada a los Lisosomas/metabolismo , Proteína 2 de la Membrana Asociada a los Lisosomas/metabolismo , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Nitrilos/farmacología
4.
Exp Mol Med ; 53(9): 1390-1401, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-34552205

RESUMEN

Obesity is now recognized as a disease. This study revealed a novel role for pyruvate dehydrogenase kinase (PDK) in diet-induced hypertrophic obesity. Mice with global or adipose tissue-specific PDK2 deficiency were protected against diet-induced obesity. The weight of adipose tissues and the size of adipocytes were reduced. Adipocyte-specific PDK2 deficiency slightly increased insulin sensitivity in HFD-fed mice. In studies with 3T3-L1 preadipocytes, PDK2 and PDK1 expression was strongly increased during adipogenesis. Evidence was found for epigenetic induction of both PDK1 and PDK2. Gain- and loss-of-function studies with 3T3-L1 cells revealed a critical role for PDK1/2 in adipocyte differentiation and lipid accumulation. PDK1/2 induction during differentiation was also accompanied by increased expression of hypoxia-inducible factor-1α (HIF1α) and enhanced lactate production, both of which were absent in the context of PDK1/2 deficiency. Exogenous lactate supplementation increased the stability of HIF1α and promoted adipogenesis. PDK1/2 overexpression-mediated adipogenesis was abolished by HIF1α inhibition, suggesting a role for the PDK-lactate-HIF1α axis during adipogenesis. In human adipose tissue, the expression of PDK1/2 was positively correlated with that of the adipogenic marker PPARγ and inversely correlated with obesity. Similarly, PDK1/2 expression in mouse adipose tissue was decreased by chronic high-fat diet feeding. We conclude that PDK1 and 2 are novel regulators of adipogenesis that play critical roles in obesity.


Asunto(s)
Adipocitos/metabolismo , Adipogénesis/genética , Diferenciación Celular/genética , Dieta Alta en Grasa/efectos adversos , Obesidad/etiología , Obesidad/metabolismo , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/deficiencia , Células 3T3-L1 , Adipocitos/citología , Adiposidad/genética , Animales , Biomarcadores , Expresión Génica , Glucólisis , Resistencia a la Insulina , Ácido Láctico/metabolismo , Ratones , Ratones Noqueados , Obesidad/patología , Tamaño de los Órganos
5.
Exp Mol Med ; 51(10): 1-12, 2019 09 30.
Artículo en Inglés | MEDLINE | ID: mdl-31570705

RESUMEN

Dyslipidemia-induced atherosclerosis, which has a risk of high morbidity and mortality, can be alleviated by metabolic activation associated with mitochondrial function. The effect of dichloroacetate (DCA), a general pyruvate dehydrogenase kinase (PDK) inhibitor, on in vivo energy expenditure in ApoE-/- mice fed a western diet (WD) has not yet been investigated. WD-fed ApoE-/- mice developed atherosclerotic plaques and hyperlipidemia along with obesity, which were significantly ameliorated by DCA administration. Increased oxygen consumption was associated with heat production in the DCA-treated group, with no change in food intake or physical activity compared with those of the control. These processes were correlated with the increased gene expression of Dio2 and Ucp-1, which represents brown adipose tissue (BAT) activation, in both WD-induced atherosclerosis and high-fat-induced obesity models. In addition, we found that DCA stimulated hepatic fibroblast growth factor 21 (Fgf21) mRNA expression, which might be important for lowering lipid levels and insulin sensitization via BAT activation, in a dose- and time-dependent manner associated with serum FGF21 levels. Interestingly, Fgf21 mRNA expression was mediated in an AMP-activated protein kinase (AMPK)-dependent manner within several minutes after DCA treatment independent of peroxisome proliferator-activated receptor alpha (PPARα). Taken together, the results suggest that enhanced glucose oxidation by DCA protects against atherosclerosis by inducing hepatic FGF21 expression and BAT activation, resulting in augmented energy expenditure for heat generation.


Asunto(s)
Proteínas Quinasas Activadas por AMP/genética , Aterosclerosis/tratamiento farmacológico , Fármacos Cardiovasculares/farmacología , Ácido Dicloroacético/farmacología , Inhibidores Enzimáticos/farmacología , Factores de Crecimiento de Fibroblastos/genética , Placa Aterosclerótica/tratamiento farmacológico , Proteínas Quinasas Activadas por AMP/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/patología , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/etiología , Aterosclerosis/genética , Aterosclerosis/patología , Dieta Occidental/efectos adversos , Dislipidemias/tratamiento farmacológico , Dislipidemias/etiología , Dislipidemias/genética , Dislipidemias/patología , Metabolismo Energético/efectos de los fármacos , Factores de Crecimiento de Fibroblastos/agonistas , Factores de Crecimiento de Fibroblastos/metabolismo , Regulación de la Expresión Génica , Yoduro Peroxidasa/genética , Yoduro Peroxidasa/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Obesidad/tratamiento farmacológico , Obesidad/etiología , Obesidad/genética , Obesidad/patología , Consumo de Oxígeno/efectos de los fármacos , PPAR alfa/genética , PPAR alfa/metabolismo , Placa Aterosclerótica/etiología , Placa Aterosclerótica/genética , Placa Aterosclerótica/patología , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/antagonistas & inhibidores , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/genética , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Transducción de Señal , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Yodotironina Deyodinasa Tipo II
6.
Front Immunol ; 10: 944, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31134063

RESUMEN

Metabolic reprogramming during macrophage polarization supports the effector functions of these cells in health and disease. Here, we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the pyruvate dehydrogenase-mediated conversion of cytosolic pyruvate to mitochondrial acetyl-CoA, functions as a metabolic checkpoint in M1 macrophages. Polarization was not prevented by PDK2 or PDK4 deletion but was fully prevented by the combined deletion of PDK2 and PDK4; this lack of polarization was correlated with improved mitochondrial respiration and rewiring of metabolic breaks that are characterized by increased glycolytic intermediates and reduced metabolites in the TCA cycle. Genetic deletion or pharmacological inhibition of PDK2/4 prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus IFN-γ). Transplantation of PDK2/4-deficient bone marrow into irradiated wild-type mice to produce mice with PDK2/4-deficient myeloid cells prevented M1 polarization, reduced obesity-associated insulin resistance, and ameliorated adipose tissue inflammation. A novel, pharmacological PDK inhibitor, KPLH1130, improved high-fat diet-induced insulin resistance; this was correlated with a reduction in the levels of pro-inflammatory markers and improved mitochondrial function. These studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages, which could potentially be exploited as a novel therapeutic target for obesity-associated metabolic disorders and other inflammatory conditions.


Asunto(s)
Activación de Macrófagos/inmunología , Macrófagos/inmunología , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/inmunología , Complejo Piruvato Deshidrogenasa/inmunología , Acetilcoenzima A/inmunología , Acetilcoenzima A/metabolismo , Animales , Citosol/inmunología , Citosol/metabolismo , Dieta Alta en Grasa/efectos adversos , Resistencia a la Insulina/genética , Resistencia a la Insulina/inmunología , Macrófagos/clasificación , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/inmunología , Mitocondrias/metabolismo , Obesidad/etiología , Obesidad/genética , Obesidad/inmunología , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/deficiencia , Piruvato Deshidrogenasa Quinasa Acetil-Transferidora/genética , Complejo Piruvato Deshidrogenasa/metabolismo , Ácido Pirúvico/inmunología , Ácido Pirúvico/metabolismo
7.
Diabetes Metab J ; 42(4): 270-281, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-30136450

RESUMEN

Mitochondrial dysfunction is a hallmark of metabolic diseases such as obesity, type 2 diabetes mellitus, neurodegenerative diseases, and cancers. Dysfunction occurs in part because of altered regulation of the mitochondrial pyruvate dehydrogenase complex (PDC), which acts as a central metabolic node that mediates pyruvate oxidation after glycolysis and fuels the Krebs cycle to meet energy demands. Fine-tuning of PDC activity has been mainly attributed to post-translational modifications of its subunits, including the extensively studied phosphorylation and de-phosphorylation of the E1α subunit of pyruvate dehydrogenase (PDH), modulated by kinases (pyruvate dehydrogenase kinase [PDK] 1-4) and phosphatases (pyruvate dehydrogenase phosphatase [PDP] 1-2), respectively. In addition to phosphorylation, other covalent modifications, including acetylation and succinylation, and changes in metabolite levels via metabolic pathways linked to utilization of glucose, fatty acids, and amino acids, have been identified. In this review, we will summarize the roles of PDC in diverse tissues and how regulation of its activity is affected in various metabolic disorders.

8.
Diabetes Res Clin Pract ; 109(1): 64-70, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-25998917

RESUMEN

AIMS: Despite the absence of overt renal impairment and decreased erythropoietin (EPO) levels, patients are usually anemic. Hepcidin, which is induced by inflammatory stimuli, plays an important role in anemia in chronic disease. Growth differentiation factor 15 (GDF15) is a putative anti-inflammatory cytokine that is elevated in type 2 diabetes (T2DM). Hence, we investigated the relationship between hepcidin and GDF15 in anemic T2DM patients without overt renal impairment. METHODS: Among 1150 patients who visited Kyungpook National University Hospital for T2DM between June 2006 and June 2014, we selected 55 anemic patients without overt renal impairment (serum creatinine <1.5 mg/dL or estimated glomerular filtration rate >60 mL/min/1.73 m(2)) and other co-morbid diseases, including malignancy, thyroid disease, rheumatic arthritis, liver disease, iron-deficiency anemia and other endocrine disease. We measured anthropometric and metabolic parameters, as well as measured the serum iron, ferritin, interleukin-6 (IL-6), erythropoietin, hepcidin-25 and GDF15 levels. RESULTS: Anemic T2DM patients without overt renal impairment presented a greater inflammatory state, with increased serum hsCRP, ESR and IL-6 levels compared with non-anemic T2DM patients. Both hepcidin and GDF15 levels were increased and showed a positive correlation in anemic T2DM patients. CONCLUSION: In the absence of overt renal impairment, anemia in T2DM is associated with chronic inflammation, inducing elevation of hepcidin and GDF15 levels independently of the erythropoietin level.


Asunto(s)
Anemia/sangre , Diabetes Mellitus Tipo 2/sangre , Factor 15 de Diferenciación de Crecimiento/sangre , Hepcidinas/sangre , Adulto , Anciano , Anemia/etiología , Enfermedad Crónica , Comorbilidad , Diabetes Mellitus Tipo 2/complicaciones , Femenino , Ferritinas/sangre , Humanos , Inflamación/sangre , Inflamación/complicaciones , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Insuficiencia Renal/sangre , Insuficiencia Renal/complicaciones
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