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1.
Dalton Trans ; 53(6): 2534-2540, 2024 Feb 06.
Artículo en Inglés | MEDLINE | ID: mdl-38234156

RESUMEN

Designing photocatalysts with efficient charge separation and electron transport capabilities to achieve efficient visible-driven hydrogen production remains a challenge. Herein, 2D-2D conductive metal-organic framework/g-C3N4 heterojunctions were successfully prepared by an in situ assembly. Compared to pristine g-C3N4, the ratio-optimized Ni-CAT-1/g-C3N4 exhibits approximately 3.6 times higher visible-light H2 production activity, reaching 14 mmol g-1. Through investigations using time-resolved photoluminescence, surface photovoltage, and wavelength-dependent photocurrent action spectroscopies, it is determined that the improved photocatalytic performance is attributed to enhanced charge transfer and separation, specifically the efficient transfer of excited high-energy-level electrons from g-C3N4 to Ni-CAT in the heterojunctions. Furthermore, the high electrical conductivity of Ni-CAT enables rapid electron transport, contributing to the overall enhanced performance. This work provides a feasible strategy to construct efficient dimension-matched g-C3N4-based heterojunction photocatalysts with high-efficiency charge separation for solar-driven H2 production.

2.
Nat Metab ; 5(3): 481-494, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36879120

RESUMEN

Sympathetic neurons activate thermogenic adipocytes through release of catecholamine; however, the regulation of sympathetic innervation by thermogenic adipocytes is unclear. Here, we identify primary zinc ion (Zn) as a thermogenic adipocyte-secreted factor that promotes sympathetic innervation and thermogenesis in brown adipose tissue and subcutaneous white adipose tissue in male mice. Depleting thermogenic adipocytes or antagonizing ß3-adrenergic receptor on adipocytes impairs sympathetic innervation. In obesity, inflammation-induced upregulation of Zn chaperone protein metallothionein-2 decreases Zn secretion from thermogenic adipocytes and leads to decreased energy expenditure. Furthermore, Zn supplementation ameliorates obesity by promoting sympathetic neuron-induced thermogenesis, while sympathetic denervation abrogates this antiobesity effect. Thus, we have identified a positive feedback mechanism for the reciprocal regulation of thermogenic adipocytes and sympathetic neurons. This mechanism is important for adaptive thermogenesis and could serve as a potential target for the treatment of obesity.


Asunto(s)
Adipocitos , Zinc , Masculino , Ratones , Animales , Zinc/metabolismo , Zinc/farmacología , Adipocitos/metabolismo , Tejido Adiposo Pardo/metabolismo , Termogénesis , Obesidad/metabolismo
3.
Diabetes ; 72(3): 326-335, 2023 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-36473059

RESUMEN

The imbalance between energy intake and energy expenditure leads to the prevalence of obesity worldwide. A strategy to simultaneously limit energy intake and promote energy expenditure would be an important new obesity treatment. Here, we identified rhamnose as a nonnutritive sweetener to promote adipose thermogenesis and energy expenditure. Rhamnose promotes cAMP production and PKA activation through dopamine receptor D1 in adipose tissue. As a result, rhamnose administration promotes UCP1-dependent thermogenesis and ameliorates obesity in mice. Thus, we have demonstrated a rhamnose-dopamine receptor D1-PKA axis critical for thermogenesis, and that rhamnose may have a role in therapeutic molecular diets against obesity.


Asunto(s)
Tejido Adiposo Pardo , Ramnosa , Ratones , Animales , Ramnosa/metabolismo , Tejido Adiposo Pardo/metabolismo , Obesidad/metabolismo , Metabolismo Energético/fisiología , Receptores Dopaminérgicos/metabolismo , Termogénesis/fisiología , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Tejido Adiposo Blanco/metabolismo , Ratones Endogámicos C57BL
4.
Cell Rep ; 40(13): 111422, 2022 09 27.
Artículo en Inglés | MEDLINE | ID: mdl-36170814

RESUMEN

Hepatic endoplasmic reticulum (ER) stress is a hallmark of obesity-induced liver steatosis and contributes to the progress of steatosis and insulin resistance in liver. However, its influence on adipose function is still unclear. Here, we identify a hepatic ER stress-induced activating transcription factor 4 (ATF4)-cold-inducible RNA-binding protein (CIRP)-angiopoietin-related protein3 (ANGPTL3) cascade critical for the regulation of adipose browning. We find that obesity increases CIRP expression in liver through ER stress-induced ATF4. CIRP in turn binds to the 3' UTR and increases mRNA stability of ANGPTL3. ANGPTL3 secreted from liver suppresses uncoupling protein 1 expression through integrin αvß3 and c-Jun N-terminal kinase in adipose tissue. While hepatic expression of either ATF4, CIRP, or ANGPTL3 suppresses adipose browning, knockdown of CIRP and ANGPTL3 in liver or administration of integrin αvß3 inhibitor cilengitide increases adipose browning process. Taken together, we identify a communication mechanism to link hepatic ER stress and adipose browning that may imply a reciprocal regulation of obesity and liver steatosis.


Asunto(s)
Factor de Transcripción Activador 4 , Hígado Graso , Regiones no Traducidas 3' , Factor de Transcripción Activador 4/metabolismo , Tejido Adiposo/metabolismo , Proteína 3 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina/genética , Proteínas Similares a la Angiopoyetina/metabolismo , Angiopoyetinas/genética , Angiopoyetinas/metabolismo , Estrés del Retículo Endoplásmico/genética , Hígado Graso/metabolismo , Humanos , Integrinas/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Hígado/metabolismo , Obesidad/metabolismo , Proteínas de Unión al ARN/metabolismo , Proteína Desacopladora 1/metabolismo
5.
Nat Commun ; 13(1): 3301, 2022 06 08.
Artículo en Inglés | MEDLINE | ID: mdl-35676256

RESUMEN

Exercise benefits M2 macrophage polarization, energy homeostasis and protects against obesity partially through exercise-induced circulating factors. Here, by unbiased quantitative proteomics on serum samples from sedentary and exercised mice, we identify parvalbumin as a circulating factor suppressed by exercise. Parvalbumin functions as a non-competitive CSF1R antagonist to inhibit M2 macrophage activation and energy expenditure in adipose tissue. More importantly, serum concentrations of parvalbumin positively correlate with obesity in mouse and human, while treating mice with a recombinant parvalbumin blocker prevents its interaction with CSF1R and promotes M2 macrophage polarization and ameliorates diet-induced obesity. Thus, although further studies are required to assess the significance of parvalbumin in mediating the effects of exercise, our results implicate parvalbumin as a potential therapeutic strategy against obesity in mice.


Asunto(s)
Activación de Macrófagos , Parvalbúminas , Tejido Adiposo/metabolismo , Animales , Dieta Alta en Grasa , Metabolismo Energético , Inflamación/metabolismo , Macrófagos , Ratones , Ratones Endogámicos C57BL , Obesidad/metabolismo , Parvalbúminas/metabolismo
6.
Zhongguo Zhong Yao Za Zhi ; 47(3): 737-744, 2022 Feb.
Artículo en Chino | MEDLINE | ID: mdl-35178957

RESUMEN

The present study investigated the mechanism of components in stasis-resolving and collateral-dredging Chinese herbal medicines, including scutellarin(Scu), paeonol(Pae), and hydroxy safflower yellow A(HSYA), in the treatment of psoriasis by regulating angiogenesis and inflammation. The human umbilical vein endothelial cells(HUVECs) cultured in vitro were divided into a normal group, a model group, a VEGFR tyrosine kinase inhibitor Ⅱ(VRI) group, and Scu, Pae, and HSYA groups with low, me-dium, and high doses. Cell viability was detected by the CCK-8 assay. Cell migration was detected by wound healing assay. Tube formation assay was used to measure the tube formation ability. Western blot was used to detect the protein expression of the VEGFR2/Akt/ERK1/2 signaling pathway. The secretion levels of inflammatory cytokines IFN-γ, IL-1ß, IL-6, and TNF-α were detected by ELISA. The results showed that compared with the model group, all the Scu, Pae, and HSYA groups could reduce cell viability, inhibit cell migration and tube formation(P<0.05, P<0.01), and down-regulated the protein expression of VEGFR2, p-VEGFR2, Akt, p-Akt, ERK1/2, and p-ERK1/2. Scu and Pae could down-regulate VEGFR2 expression(P<0.05, P<0.01), while other groups only showed a downward trend. Scu and Pae significantly reduced IFN-γ and IL-6 levels(P<0.01), and HSYA significantly reduced the levels of IFN-γ, IL-1ß, and IL-6(P<0.01). Scu, Pae, and HSYA had no significant effect on TNF-α. The results suggested that Scu, Pae, and HSYA may exert a therapeutic role in psoriasis-related angiogenesis and inflammation by inhibiting VEGFR2/Akt/ERK1/2 signaling pathway and inhibiting the secretion of IFN-γ, IL-1ß, and IL-6.


Asunto(s)
Neovascularización Patológica , Factor A de Crecimiento Endotelial Vascular , Inhibidores de la Angiogénesis/farmacología , China , Células Endoteliales de la Vena Umbilical Humana , Humanos , Neovascularización Patológica/tratamiento farmacológico , Factor A de Crecimiento Endotelial Vascular/metabolismo
7.
Cancer Res ; 81(20): 5217-5229, 2021 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-34385181

RESUMEN

Ferroptosis is a lipid peroxidation-dependent cell death caused by metabolic dysfunction. Ferroptosis-associated enzymes are promising therapeutic targets for cancer treatment. However, such therapeutic strategies show limited efficacy due to drug resistance and other largely unknown underlying mechanisms. Here we report that cystine transporter SLC7A11 is upregulated in lung cancer stem-like cells (CSLC) and can be activated by stem cell transcriptional factor SOX2. Mutation of SOX2 binding site in SLC7A11 promoter reduced SLC7A11 expression and increased sensitivity to ferroptosis in cancer cells. Oxidation at Cys265 of SOX2 inhibited its activity and decreased the self-renewal capacity of CSLCs. Moreover, tumors with high SOX2 expression were more resistant to ferroptosis, and SLC7A11 expression was positively correlated with SOX2 in both mouse and human lung cancer tissue. Together, our study provides a mechanism by which cancer cells evade ferroptosis and suggests that oxidation of SOX2 can be a potential therapeutic target for cancer treatment. SIGNIFICANCE: This study uncovers a SOX2-SLC7A11 regulatory axis that confers resistance to ferroptosis in lung cancer stem-like cells.


Asunto(s)
Sistema de Transporte de Aminoácidos y+/metabolismo , Biomarcadores de Tumor/metabolismo , Ferroptosis , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/patología , Células Madre Neoplásicas/patología , Factores de Transcripción SOXB1/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Animales , Apoptosis , Biomarcadores de Tumor/genética , Proliferación Celular , Humanos , Peroxidación de Lípido , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Ratones , Mutación , Células Madre Neoplásicas/metabolismo , Pronóstico , Factores de Transcripción SOXB1/genética , Tasa de Supervivencia , Activación Transcripcional , Células Tumorales Cultivadas
9.
Nucleic Acids Res ; 49(7): 4171-4185, 2021 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-33751124

RESUMEN

CRISPR-mediated gene activation (CRISPRa) is a promising therapeutic gene editing strategy without inducing DNA double-strand breaks (DSBs). However, in vivo implementation of these CRISPRa systems remains a challenge. Here, we report a compact and robust miniCas9 activator (termed miniCAFE) for in vivo activation of endogenous target genes. The system relies on recruitment of an engineered minimal nuclease-null Cas9 from Campylobacter jejuni and potent transcriptional activators to a target locus by a single guide RNA. It enables robust gene activation in human cells even with a single DNA copy and is able to promote lifespan of Caenorhabditis elegans through activation of longevity-regulating genes. As proof-of-concept, delivered within an all-in-one adeno-associated virus (AAV), miniCAFE can activate Fgf21 expression in the liver and regulate energy metabolism in adult mice. Thus, miniCAFE holds great therapeutic potential against human diseases.


Asunto(s)
Proteína 9 Asociada a CRISPR/metabolismo , Sistemas CRISPR-Cas , Factores de Crecimiento de Fibroblastos/metabolismo , Edición Génica , ARN Guía de Kinetoplastida/metabolismo , Animales , Caenorhabditis elegans , Campylobacter jejuni , Células HEK293 , Humanos , Melanoma Experimental , Ratones , Ratones Endogámicos C57BL
10.
J Plant Physiol ; 253: 153260, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32846310

RESUMEN

The endophytic Bacillus amyloliquefaciens YTB1407 was previously reported to promote the growth of sweet potato (Ipomoea batatas cv. Yanshu 25). Here, we demonstrate in both in vitro and pot trial assays that pre-treatment with YTB1407 suspension could enhance resistance against root rot disease and black rot disease, caused by Fusarium solani Mart. Sacc. f. sp. batatas McClure and Ceratocystis fimbriata Ell. & Halst on sweet potato, respectively. When seedlings were infected with fungal pathogens at 10 days post irrigation, pre-treatment with YTB1407 suspension decreased these pathogens and YTB1407 bacterial biomass in sweet potato roots. The pre-treatment activated the expression of salicylic acid (SA)-responsive PR-1 gene, raised SA content, and reduced hydrogen peroxide (H2O2) in the host to resist F. solani, while it enhanced the expression levels of SA-responsive NPR1 and PR1 genes and increased SA content to resist C. fimbriata. The disease resistance control effect initiated by pre-treatment with YTB1407 for root rot pathogen (F. solani) was better than for black rot pathogen (C. fimbriata). The results indicated that Bacillus amyloliquefaciens YTB1407 played a pivotal role in enhancing resistance to two fungi pathogens in sweet potato, through production of some antifungal metabolites to decrease infection in the early stage as well as induction of SA-dependent systemic resistance.


Asunto(s)
Bacillus amyloliquefaciens/fisiología , Resistencia a la Enfermedad , Fusarium/fisiología , Peróxido de Hidrógeno/metabolismo , Ipomoea batatas/microbiología , Enfermedades de las Plantas/microbiología , Antifúngicos/metabolismo , Endófitos , Ipomoea batatas/inmunología , Enfermedades de las Plantas/inmunología , Raíces de Plantas/inmunología , Raíces de Plantas/microbiología , Ácido Salicílico/metabolismo , Plantones/inmunología , Plantones/microbiología
11.
Mol Med Rep ; 19(4): 3123-3131, 2019 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30816539

RESUMEN

The present study aimed to identify the disease­causing gene of a four­generation Chinese family affected with congenital posterior subcapsular cataracts (CPSC), to additionally investigate the frequency of paired like homeodomain 3 (PITX3) mutations in Chinese patients with autosomal dominant congenital cataract (ADCC) and to analyze the pathogenesis of the mutations identified in the present study. Whole exome sequencing (WES) was utilized to identify the genetic cause of CPSC in the four­generation family. Sanger sequencing was performed to verify the WES results and to screen for mutations of the PITX3 gene in probands of an additional 194 Chinese ADCC families. Co­segregation analysis was performed in the family members with available DNA. Subcellular localization analyses and transactivation assays were performed for the PITX3 mutations identified. From the WES data, the c.608delC (p.A203GfsX106) mutation of PITX3 was identified in the four­generation family with CPSC. A second PITX3 mutation c.640_656del (p.A214RfsX42) was detected in two of the additional 194 ADCC families and one of these two families exhibited incomplete penetrance. Functional studies indicated that these 2 PITX3 mutant proteins retained a nuclear localization pattern, but resulted in decreased transactivation activity, similar to other previously identified PITX3 mutations. In the present study, 2 different mutations (p.A203GfsX106 and p.A214RfsX42) in PITX3 were identified as the causative defect in a four­generation family with CPSC and two ADCC families, respectively. The prevalence of PITX3 gene­associated cataract was 1.54% (3/195) in the Chinese congenital cataract (CC) family cohort. In vitro functional analyses of these 2 PITX3 mutations were performed, in order to enhance understanding of the pathogenesis of CC caused by PITX3 mutations.


Asunto(s)
Pueblo Asiatico/genética , Catarata/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Proteínas de Homeodominio/genética , Mutación , Factores de Transcripción/genética , Catarata/epidemiología , Biología Computacional/métodos , Femenino , Técnica del Anticuerpo Fluorescente , Regulación de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Humanos , Espacio Intracelular/metabolismo , Masculino , Unión Proteica , Transporte de Proteínas , Factores de Transcripción/metabolismo , Secuenciación del Exoma
12.
Methods Mol Biol ; 1957: 365-384, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30919366

RESUMEN

Type II diabetes is one of the most serious worldwide public health problems, and its hallmark is insulin resistance, obesity associated with chronic inflammation, and defective islet ß-cell function. ß-Arrestins play important roles in diabetes pathogenesis through scaffolding insulin-induced AKT activation in the liver, suppressing peroxisome proliferator-activated receptor-γ-mediated adipogenesis and inflammatory responses in adipose tissue and through promoting GLP-1-induced insulin secretion in the islet. The current chapter provides detailed protocols for both in vitro and in vivo studies of the function of ß-arrestins associated with type II diabetes.


Asunto(s)
Biología Molecular/métodos , beta-Arrestinas/metabolismo , Adipocitos/metabolismo , Animales , Células de la Médula Ósea/citología , Células Cultivadas , Regulación de la Expresión Génica , Glucosa/biosíntesis , Hepatocitos/metabolismo , Resistencia a la Insulina , Secreción de Insulina , Células Secretoras de Insulina/metabolismo , Macrófagos/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal , Coloración y Etiquetado
13.
Ying Yong Sheng Tai Xue Bao ; 29(11): 3819-3828, 2018 Nov.
Artículo en Chino | MEDLINE | ID: mdl-30460829

RESUMEN

We isolated the endophytic Bacillus amyloliquefaciens YTB1407 from the root of Panax quinquefolium, which has both biological control and growth promoting effects. To investigate its potential applications, a pot experiment of sweet potato was tested to assess the capacity of endophytic colonization of YTB1407 and the selection of its optimum concentration by investigating the performance of root characteristics on three time points in the whole early growth phase after irrigating with different concentrations of bacterial suspensions with treatment of sterile water as control. The activities of endogenous hormone IAA, ZR, t-ZR and IAA oxidase (IAAO, PPO, POD) were analyzed. The results showed that YTB1407 promoted the specific colonization of root system, the elongation of adventitious root and branch roots, and root activity in the early growth stage of sweet potato. At later growth stage, it formed greater fresh mass of absorption root and lower aboveground/root system mass ratio. YTB1407 suspensions with OD600 of 0.50 (T0.50) had more significant effect, which induced the highest fresh tuber mass and the largest effective tuber numbers of per plant at top cover stage. YTB1407 promoted the differentiation of adventitious roots into tubers at initial point of tuberization by increasing IAA content and the ratio of (t-ZR+ZR)/IAA, decreasing IAAO activity and enhancing PPO activity. Moreover, it promoted the differentiated roots into tubers at tuberization stage by keeping the higher content of IAA, lower ratio of (t-ZR+ZR)/IAA, and decreasing IAAO and PPO activities.


Asunto(s)
Bacillus amyloliquefaciens/fisiología , Ácidos Indolacéticos/metabolismo , Ipomoea batatas/microbiología , Ipomoea batatas/fisiología , Raíces de Plantas/microbiología
14.
Endocrine ; 61(1): 94-104, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29704154

RESUMEN

PURPOSE: Melanocortin-3 receptor (MC3R), melanocortin-4 receptor (MC4R), and a recently identified melanocortin-2 receptor accessory protein 2 (MRAP2), are highly expressed in hypothalamus and coordinately regulate energy homeostasis, but the single cellular transcriptome of melanocortin system remains unknown. Several infrequent MRAP2 variants are reported from severe obese human patients but the mechanisms on how they affect melanocortin signaling are unclear. METHODS: First, we performed in silico analysis of mouse hypothalamus RNA sequencing datasets at single-cell resolution from two independent studies. Next, we inspected the three-dimensional conformational alteration of three mutations on MRAP2 protein. Finally, the influence of MRAP2 variants on MC3R and MC4R signaling was analyzed in vitro. RESULTS: (1) We confirmed the actual co-expression of Mrap2 with Mc3r and Mc4r, and demonstrated more broad distribution of Mrap2-positive neuronal populations than Mc3r or Mc4r in mouse hypothalamus. (2) Compared with wild-type MRAP2, MRAP2N88Y, and MRAP2R125C showed impaired α-MSH-induced MC4R or MC3R stimulation. (3) MRAP2N88Yexhibited enhanced interaction with MC4R protein and its own. CONCLUSIONS: This is the first dedicated description of single-cell transcriptome signature of Mrap2, Mc3r, and Mc4r in the central nerve system and the first evidence describing the unique dimer formation, conformational change, and pharmacological effect of MRAP2 mutations on MC3R signaling.


Asunto(s)
Proteínas Portadoras/farmacología , Hipotálamo/metabolismo , Receptores de Melanocortina/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales , Animales , Simulación por Computador , Variación Genética , Humanos , Hipotálamo/efectos de los fármacos , Ratones , Mutación/genética , Neuronas/metabolismo , Conformación de Ácido Nucleico , Plásmidos , ARN/genética , Receptor de Melanocortina Tipo 3/genética , Receptor de Melanocortina Tipo 3/metabolismo , Receptor de Melanocortina Tipo 4/genética , Receptor de Melanocortina Tipo 4/metabolismo , Transducción de Señal/genética , alfa-MSH/farmacología
16.
J Lipid Res ; 59(2): 330-338, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-29229738

RESUMEN

Disregulation of fatty acid oxidation, one of the major mechanisms for maintaining hepatic lipid homeostasis under fasting conditions, leads to hepatic steatosis. Although obesity and type 2 diabetes-induced endoplasmic reticulum (ER) stress contribute to hepatic steatosis, it is largely unknown how ER stress regulates fatty acid oxidation. Here we show that fasting glucagon stimulates the dephosphorylation and nuclear translocation of histone deacetylase 5 (HDAC5), where it interacts with PPARα and promotes transcriptional activity of PPARα. As a result, overexpression of HDAC5 but not PPARα binding-deficient HDAC5 in liver improves lipid homeostasis, whereas RNAi-mediated knockdown of HDAC5 deteriorates hepatic steatosis. ER stress inhibits fatty acid oxidation gene expression via calcium/calmodulin-dependent protein kinase II-mediated phosphorylation of HDAC5. Most important, hepatic overexpression of a phosphorylation-deficient mutant HDAC5 2SA promotes hepatic fatty acid oxidation gene expression and protects against hepatic steatosis in mice fed a high-fat diet. We have identified HDAC5 as a novel mediator of hepatic fatty acid oxidation by fasting and ER stress signals, and strategies to promote HDAC5 dephosphorylation could serve as new tools for the treatment of obesity-associated hepatic steatosis.


Asunto(s)
Estrés del Retículo Endoplásmico , Ayuno/metabolismo , Ácidos Grasos/metabolismo , Histona Desacetilasas/metabolismo , Hígado/metabolismo , Animales , Masculino , Ratones , Ratones Endogámicos C57BL , Oxidación-Reducción
17.
J Endocrinol ; 234(2): 73-87, 2017 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-28515141

RESUMEN

Hormonal signals help to maintain glucose and lipid homeostasis in the liver during the periods of fasting. Glucagon, a pancreas-derived hormone induced by fasting, promotes gluconeogenesis through induction of intracellular cAMP production. Glucagon also stimulates hepatic fatty acid oxidation but the underlying mechanism is poorly characterized. Here we report that following the acute induction of gluconeogenic genes Glucose 6 phosphatase (G6Pase) and Phosphoenolpyruvate carboxykinase (Pepck) expression through cAMP-response element-binding protein (CREB), glucagon triggers a second delayed phase of fatty acid oxidation genes Acyl-coenzyme A oxidase (Aox) and Carnitine palmitoyltransferase 1a (Cpt1a) expression via extracellular cAMP. Increase in extracellular cAMP promotes PPARα activity through direct phosphorylation by AMP-activated protein kinase (AMPK), while inhibition of cAMP efflux greatly attenuates Aox and Cpt1a expression. Importantly, cAMP injection improves lipid homeostasis in fasted mice and obese mice, while inhibition of cAMP efflux deteriorates hepatic steatosis in fasted mice. Collectively, our results demonstrate the vital role of glucagon-stimulated extracellular cAMP in the regulation of hepatic lipid metabolism through AMPK-mediated PPARα activation. Therefore, strategies to improve cAMP efflux could serve as potential new tools to prevent obesity-associated hepatic steatosis.


Asunto(s)
AMP Cíclico/metabolismo , Glucagón/farmacología , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Animales , Células Cultivadas , Ácidos Grasos/metabolismo , Hígado Graso/tratamiento farmacológico , Hígado Graso/etiología , Regulación de la Expresión Génica/fisiología , Metabolismo de los Lípidos/fisiología , Ratones , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Obesidad/complicaciones , Oxidación-Reducción
18.
Cell Death Differ ; 24(3): 492-499, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28009352

RESUMEN

The NF-κB pathway has important roles in innate immune responses and its regulation is critical to maintain immune homeostasis. Here, we report a newly discovered feedback mechanism for the regulation of this pathway by TLR ligands in macrophages. Lipopolysaccharide (LPS) induced the expression of ICER via p38-mediated activation of CREB in macrophages. ICER, in turn, inhibited the transcriptional activity of NF-κB by direct interaction with the p65 subunit of NF-κB. Deficiency in ICER elevated binding of NF-κB to promoters of pro-inflammatory genes and their subsequent gene expression. Mice deficient in ICER were hypersensitive to LPS-induced endotoxic shock and showed propagated inflammation. Whereas ICER expression in ICER KO bone marrow transplanted mice rescued the ultra-inflammation phenotype, expression of a p65 binding-deficient ICER mutant failed to do so. Our results thus establish p38-CREB-ICER as key components of a negative feedback mechanism necessary to regulate TLR-driven inflammation.


Asunto(s)
Modulador del Elemento de Respuesta al AMP Cíclico/genética , Inmunidad Innata , FN-kappa B/metabolismo , Receptores Toll-Like/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Trasplante de Médula Ósea , Células Cultivadas , Modulador del Elemento de Respuesta al AMP Cíclico/deficiencia , Modulador del Elemento de Respuesta al AMP Cíclico/metabolismo , Inflamación/metabolismo , Inflamación/patología , Interleucina-6/sangre , Interleucina-6/metabolismo , Lipopolisacáridos/toxicidad , Hígado/metabolismo , Macrófagos Peritoneales/citología , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Regiones Promotoras Genéticas , Transducción de Señal/efectos de los fármacos , Bazo/metabolismo , Factor de Transcripción ReIA/metabolismo , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismo
19.
Cell Discov ; 2: 16046, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27990298

RESUMEN

Although hypoglycemia has been documented as a major cause of high mortality in the setting of septic shock, the mechanism of hypoglycemia in infection has not been clearly determined. Hepatic gluconeogenesis serves as an important mechanism to maintain glucose levels under physiological conditions and CREB coactivator CRTC2 plays an important role in regulating gluconeogenic gene expression. Here, we show that triggering of the Toll-like receptor 4 pathway in response to endotoxin lipopolysaccharide (LPS) inhibits gluconeogenic gene expression and hepatic glucose output by blocking CRTC2 activation. Interleukin-1ß (IL-1ß) is found to disrupt gluconeogenic gene expression via the activation of the E3 ubiquitin ligase TRAF6, a key component of the Toll-like receptor 4 signaling pathway that associates with and ubiquitinates CRTC2. TRAF6 promotes the K63-linked ubiquitination of CRTC2, a modification that blocks binding of calcineurin at an adjacent calcineurin-binding site, thereby disrupting CRTC2 dephosphorylation in response to glucagon signals. Mutation of TRAF6-binding sites or ubiquitination site in CRTC2 rescues hepatic gluconeogenesis in LPS-challenged mice. These results suggest that pro-inflammatory signals intersect with the CRTC2 pathway in liver, thus contributing to hypoglycemia caused by infection.

20.
Anat Rec (Hoboken) ; 299(10): 1402-8, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27507762

RESUMEN

The myodural bridge was proposed initially in 1995. The myodural bridge is a connective tissue bridge that connects a pair of deep muscles at the suboccipital region to the dura mater. There have been numerous studies concerning the morphology and function of the myodural bridge. To determine whether a myodural bridge exists in reptiles, six Siamese crocodiles were investigated using gross anatomy dissection and P45 sheet plastination technologies. As a result, we demonstrated that the posterior occipital muscles of the Siamese crocodile are directly or indirectly connected to the proatlas, atlas, and intermembrane between them. Multiple trabeculae existing in the posterior epidural space extended from the ventral surface of the proatlas, atlas, and intermembrane between them to the dorsal surface of the spinal dura mater. This study showed that the posterior occipital muscle in the suboccipital region of the Siamese crocodile is connected to the spinal dura mater through the proatlas, atlas, and the trabeculae. In conclusion, a myodural bridge-like structure exists in reptiles. This connection may act as a pump to provide cerebrospinal fluid (CSF) circulation at the occipitocervical junction. We hypothesize that a physiologic role of the Siamese crocodile's myodural bridge may be analogous to the human myodural bridge. Anat Rec, 299:1402-1408, 2016. © 2016 Wiley Periodicals, Inc.


Asunto(s)
Caimanes y Cocodrilos/anatomía & histología , Atlas Cervical/anatomía & histología , Duramadre/anatomía & histología , Músculos del Cuello/anatomía & histología , Cuello/anatomía & histología , Animales , Disección
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