RESUMEN
Extracellular acyl-coenzyme A binding protein [ACBP encoded by diazepam binding inhibitor (DBI)] is a phylogenetically ancient appetite stimulator that is secreted in a nonconventional, autophagy-dependent fashion. Here, we show that low ACBP/DBI plasma concentrations are associated with poor prognosis in patients with anorexia nervosa, a frequent and often intractable eating disorder. In mice, anorexia induced by chronic restraint stress (CRS) is accompanied by a reduction in circulating ACBP/DBI concentrations. We engineered a chemical-genetic system for the secretion of ACBP/DBI through a biotin-activatable, autophagy-independent pathway. In transgenic mice expressing this system in hepatocytes, biotin-induced elevations in plasma ACBP/DBI concentrations prevented anorexia induced by CRS or chemotherapeutic agents including cisplatin, doxorubicin, and paclitaxel. ACBP/DBI reversed the CRS or cisplatin-induced increase in plasma lipocalin-2 concentrations and the hypothalamic activation of anorexigenic melanocortin 4 receptors, for which lipocalin-2 is an agonist. Daily intravenous injections of recombinant ACBP/DBI protein or subcutaneous implantation of osmotic pumps releasing recombinant ACBP/DBI mimicked the orexigenic effects of the chemical-genetic system. In conclusion, the supplementation of extracellular and peripheral ACBP/DBI might constitute a viable strategy for treating anorexia.
Asunto(s)
Anorexia , Inhibidor de la Unión a Diazepam , Animales , Inhibidor de la Unión a Diazepam/metabolismo , Anorexia/tratamiento farmacológico , Anorexia/metabolismo , Humanos , Ratones Transgénicos , Ratones , Anorexia Nerviosa/metabolismo , Anorexia Nerviosa/tratamiento farmacológico , Lipocalina 2/metabolismo , Lipocalina 2/sangre , Hipotálamo/metabolismo , Masculino , Femenino , Ratones Endogámicos C57BL , Restricción Física , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacosRESUMEN
Astrocytes specifically synthesize and release endozepines, a family of regulatory peptides including octadecaneuropeptide (ODN). We have previously reported that ODN rescues neurons and astrocytes from 6-OHDA-induced oxidative stress and cell death. The purpose of this study was to examine the potential implication of miR-34b, miR-29a, and miR-21 in the protective activity of ODN on 6-OHDA-induced oxidative stress and cell death in cultured rat astrocytes. Flow cytometry analysis showed that 6-OHDA increased the number of early apoptotic and apoptotic dead cells while treatment with the subnanomolar dose of ODN significantly reduced the number of apoptotic cells induced by 6-OHDA. 6-OHDA-treated astrocytes exhibited the over-expression of miR-21 (+118%) associated with a knockdown of miR-34b (-61%) and miR-29a (-49%). Co-treatment of astrocytes with ODN blocked the 6-OHDA-stimulated production of ROS and NO and stimulation of Bax and caspase-3 gene transcription. Concomitantly, ODN down-regulated the expression of miR-34b and miR-29a and rescued the 6-OHDA-associated reduced expression of miR21, indicating that ODN regulates their expression during cell death. Transfection with miR-21-3p inhibitor prevented the effect of 6-OHDA against cell death. In conclusion, our study indicated that (i) the expression of miRNAs miR-34b, miR-29a, and miR-21 is modified in astrocytes under 6-OHDA injury and (ii) that ODN prevents this deregulation to induce its neuroprotective action. The present study identified miR-21 as an emerging candidate and as a promising pharmacological target that opens new neuroprotective therapeutic strategies in neurodegenerative diseases, especially in Parkinson's disease.
Asunto(s)
Apoptosis , Astrocitos , Supervivencia Celular , MicroARNs , Estrés Oxidativo , Oxidopamina , MicroARNs/genética , MicroARNs/metabolismo , Animales , Astrocitos/metabolismo , Astrocitos/efectos de los fármacos , Apoptosis/efectos de los fármacos , Apoptosis/genética , Estrés Oxidativo/efectos de los fármacos , Oxidopamina/farmacología , Ratas , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Células Cultivadas , Inhibidor de la Unión a Diazepam/metabolismo , Inhibidor de la Unión a Diazepam/genética , Especies Reactivas de Oxígeno/metabolismo , Neuropéptidos/metabolismo , Neuropéptidos/genética , Fragmentos de Péptidos , Ratas WistarRESUMEN
We report that diazepam binding inhibitor (DBI) is a glial messenger mediating crosstalk between satellite glial cells (SGCs) and sensory neurons in the dorsal root ganglion (DRG). DBI is highly expressed in SGCs of mice, rats, and humans, but not in sensory neurons or most other DRG-resident cells. Knockdown of DBI results in a robust mechanical hypersensitivity without major effects on other sensory modalities. In vivo overexpression of DBI in SGCs reduces sensitivity to mechanical stimulation and alleviates mechanical allodynia in neuropathic and inflammatory pain models. We further show that DBI acts as an unconventional agonist and positive allosteric modulator at the neuronal GABAA receptors, particularly strongly affecting those with a high-affinity benzodiazepine binding site. Such receptors are selectively expressed by a subpopulation of mechanosensitive DRG neurons, and these are also more enwrapped with DBI-expressing glia, as compared with other DRG neurons, suggesting a mechanism for a specific effect of DBI on mechanosensation. These findings identified a communication mechanism between peripheral neurons and SGCs. This communication modulates pain signaling and can be targeted therapeutically.
Asunto(s)
Inhibidor de la Unión a Diazepam , Ganglios Espinales , Neuroglía , Animales , Ganglios Espinales/metabolismo , Neuroglía/metabolismo , Ratones , Ratas , Humanos , Inhibidor de la Unión a Diazepam/metabolismo , Inhibidor de la Unión a Diazepam/genética , Masculino , Células Receptoras Sensoriales/metabolismo , Receptores de GABA-A/metabolismo , Receptores de GABA-A/genética , Hiperalgesia/metabolismo , Hiperalgesia/genética , Hiperalgesia/patología , Ratas Sprague-Dawley , Mecanotransducción Celular , Ratones Endogámicos C57BLRESUMEN
Acyl-CoA-Binding Proteins (ACBPs) bind acyl-CoA esters and function in lipid metabolism. Although acbp3-1, the ACBP3 mutant in Arabidopsis thaliana ecotype Col-0, displays normal floral development, the acbp3-2 mutant from ecotype Ler-0 characterized herein exhibits defective adaxial anther lobes and improper sporocyte formation. To understand these differences and identify the role of ERECTA in ACBP3 function, the acbp3 mutants and acbp3-erecta (er) lines were analyzed by microscopy for anther morphology and high-performance liquid chromatography for lipid composition. Defects in Landsberg anther development were related to the ERECTA-mediated pathway because the progenies of acbp3-2 × La-0 and acbp3-1 × er-1 in Col-0 showed normal anthers, contrasting to that of acbp3-2 in Ler-0. Polymorphism in the regulatory region of ACBP3 enabled its function in anther development in Ler-0 but not Col-0 which harbored an AT-repeat insertion. ACBP3 expression and anther development in acbp3-2 were restored using ACBP3pro (Ler)::ACBP3 not ACBP3pro (Col)::ACBP3. SPOROCYTELESS (SPL), a sporocyte formation regulator activated ACBP3 transcription in Ler-0 but not Col-0. For anther development, the ERECTA-related role of ACBP3 is required in Ler-0, but not Col-0. The disrupted promoter regulatory region for SPL binding in Col-0 eliminates the role of ACBP3 in anther development.
Asunto(s)
Alelos , Proteínas de Arabidopsis , Arabidopsis , Flores , Regulación de la Expresión Génica de las Plantas , Regiones Promotoras Genéticas , Arabidopsis/genética , Arabidopsis/crecimiento & desarrollo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Inhibidor de la Unión a Diazepam/metabolismo , Inhibidor de la Unión a Diazepam/genética , Ecotipo , Flores/genética , Flores/crecimiento & desarrollo , Mutación/genética , Fenotipo , Polimorfismo Genético , Regiones Promotoras Genéticas/genéticaRESUMEN
Acyl-CoA-binding proteins (ACBPs) are mainly involved in acyl-CoA ester binding and trafficking in eukaryotic cells, and they function in lipid metabolism, membrane biosynthesis, cellular signaling, stress response, disease resistance, and other biological activities in plants. However, the roles of ACBP family members in Medicago remain unclear. In this study, a total of eight ACBP genes were identified in the genome of Medicago truncatula and Medicago sativa, and they were clustered into four sub-families (Class I-IV). Many cis-acting elements related to abiotic response were identified in the promoter region of these ACBP genes, in particular light-responsive elements. These ACBP genes exhibited distinct expression pattern in various tissues, and the expression level of MtACBP1/MsACBP1 and MtACBP2/MsACBP2 gene pairs were significantly increased under NaCl treatment. Subcellular localization analysis showed that MtACBP1/MsACBP1 and MtACBP2/MsACBP2 were localized in the endoplasmic reticulum of tobacco epidermal cells. Arabidopsis seedlings over-expressing MtACBP2/MsACBP2 displayed increased root length than the wild type under short light, Cu2+, ABA, PEG, and NaCl treatments. Over-expression of MtACBP2/MsACBP2 also significantly enhanced Arabidopsis tolerance under NaCl and PEG treatments in mature plants. Collectively, our study identified salt and drought responsive ACBP genes in Medicago and verified their functions in increasing resistance against salt and drought stresses.
Asunto(s)
Arabidopsis , Resistencia a la Sequía , Regulación de la Expresión Génica de las Plantas , Tolerancia a la Sal , Arabidopsis/genética , Inhibidor de la Unión a Diazepam/genética , Inhibidor de la Unión a Diazepam/metabolismo , Medicago/genética , Medicago truncatula/genética , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Plantas Modificadas Genéticamente/genética , Tolerancia a la Sal/genética , Estrés Fisiológico/genéticaRESUMEN
BACKGROUND: Acyl-CoA-Binding proteins (ACBPs) function as coenzyme A transporters and play important roles in regulating plant growth and development in response to abiotic stress and phytohormones, as well as in membrane repair. To date, the ACBP family has not been a comprehensively characterized in barley (Hordeum vulgare L.). RESULTS: Eight ACBP genes were identified in the barley genome and named as HvACBP1-8. The analysis of the proteins structure and promoter elements of HvACBP suggested its potential functions in plant growth, development, and stress response. These HvACBPs are expressed in specific tissues and organs following induction by abiotic stressors such as drought, salinity, UV-B exposure, temperature extremes, and exposure to exogenous phytohormones. The HvACBP7 and HvACBP8 amino acid sequences were conserved during the domestication of Tibetan Qingke barley. CONCLUSIONS: Acyl-CoA-binding proteins may play important roles in barley growth and environmental adaptation. This study provides foundation for further analyses of the biological functions of HvACBPs in the barley stress response.
Asunto(s)
Hordeum , Hordeum/genética , Hordeum/metabolismo , Inhibidor de la Unión a Diazepam/metabolismo , Reguladores del Crecimiento de las Plantas , Hormonas , Estrés Fisiológico/genéticaRESUMEN
Nutrient availability is a major selective force in the evolution of metazoa, and thus plasticity in tissue function and morphology is shaped by adaptive responses to nutrient changes. Utilizing Drosophila, we reveal that distinct calibration of acyl-CoA metabolism, mediated by Acbp6 (Acyl-CoA binding-protein 6), is critical for nutrient-dependent tissue plasticity. Drosophila Acbp6, which arose by evolutionary duplication and binds acyl-CoA to tune acetyl-CoA metabolism, is required for intestinal resizing after nutrient deprivation through activating intestinal stem cell proliferation from quiescence. Disruption of acyl-CoA metabolism by Acbp6 attenuation drives aberrant 'switching' of metabolic networks in intestinal enterocytes during nutrient adaptation, impairing acetyl-CoA metabolism and acetylation amid intestinal resizing. We also identified STAT92e, whose function is influenced by acetyl-CoA levels, as a key regulator of acyl-CoA and nutrient-dependent changes in stem cell activation. These findings define a regulatory mechanism, shaped by acyl-CoA metabolism, that adjusts proliferative homeostasis to coordinately regulate tissue plasticity during nutrient adaptation.
Asunto(s)
Inhibidor de la Unión a Diazepam , Drosophila , Animales , Acetilcoenzima A/metabolismo , Inhibidor de la Unión a Diazepam/metabolismo , Drosophila/metabolismo , Acilcoenzima A/metabolismo , Unión ProteicaRESUMEN
Pharmacological stimulation/antagonism of astrocyte glio-peptide octadecaneuropeptide signaling alters ventromedial hypothalamic nucleus (VMN) counterregulatory γ-aminobutyric acid (GABA) and nitric oxide transmission. The current research used newly developed capillary zone electrophoresis-mass spectrometry methods to investigate hypoglycemia effects on VMN octadecaneuropeptide content, along with gene knockdown tools to determine if octadecaneuropeptide signaling regulates these transmitters during eu- and/or hypoglycemia. Hypoglycemia caused dissimilar adjustments in the octadecaneuropeptide precursor, i.e., diazepam-binding-inhibitor and octadecaneuropeptide levels in dorsomedial versus ventrolateral VMN. Intra-VMN diazepam-binding-inhibitor siRNA administration decreased baseline 67 and 65â kDa glutamate decarboxylase mRNA levels in GABAergic neurons laser-microdissected from each location, but only affected hypoglycemic transcript expression in ventrolateral VMN. This knockdown therapy imposed dissimilar effects on eu- and hypoglycemic glucokinase and 5'-AMP-activated protein kinase-alpha1 (AMPKα1) and -alpha2 (AMPKα2) gene profiles in dorsomedial versus ventrolateral GABAergic neurons. Diazepam-binding-inhibitor gene silencing up-regulated baseline (dorsomedial) or hypoglycemic (ventrolateral) nitrergic neuron neuronal nitric oxide synthase mRNA profiles. Baseline nitrergic cell glucokinase mRNA was up- (ventrolateral) or down- (dorsomedial) regulated by diazepam-binding-inhibitor siRNA, but knockdown enhanced hypoglycemic profiles in both sites. Nitrergic nerve cell AMPKα1 and -α2 transcripts exhibited division-specific responses to this genetic manipulation during eu- and hypoglycemia. Results document the utility of capillary zone electrophoresis-mass spectrometric tools for quantification of ODN in small-volume brain tissue samples. Data show that hypoglycemia has dissimilar effects on ODN signaling in the two major neuroanatomical divisions of the VMN and that this glio-peptide imposes differential control of glucose-regulatory neurotransmission in the VMNdm versus VMNvl during eu- and hypoglycemia.
Asunto(s)
Glucosa , Hipoglucemia , Ratas , Animales , Glucosa/metabolismo , Núcleo Hipotalámico Ventromedial , Hipoglucemiantes/farmacología , Hipoglucemiantes/metabolismo , Ratas Sprague-Dawley , Inhibidor de la Unión a Diazepam/metabolismo , Inhibidor de la Unión a Diazepam/farmacología , Glucoquinasa/metabolismo , Glucoquinasa/farmacología , Glucógeno/metabolismo , Hipoglucemia/genética , Hipoglucemia/metabolismo , ARN Mensajero/metabolismo , ARN Interferente Pequeño/metabolismo , Diazepam/metabolismo , Diazepam/farmacologíaRESUMEN
Paralogous proteins confer enhanced fitness to organisms via complex sequence-conformation codes that shape functional divergence, specialization, or promiscuity. Here, we dissect the underlying mechanism of promiscuous binding versus partial subfunctionalization in paralogues by studying structurally identical acyl-CoA binding proteins (ACBPs) from Plasmodium falciparum that serve as promising drug targets due to their high expression during the protozoan proliferative phase. Combining spectroscopic measurements, solution NMR, SPR, and simulations on two of the paralogues, A16 and A749, we show that minor sequence differences shape nearly every local and global conformational feature. A749 displays a broader and heterogeneous native ensemble, weaker thermodynamic coupling and cooperativity, enhanced fluctuations, and a larger binding pocket volume compared to A16. Site-specific tryptophan probes signal a graded reduction in the sampling of substates in the holo form, which is particularly apparent in A749. The paralogues exhibit a spectrum of binding affinities to different acyl-CoAs with A749, the more promiscuous and hence the likely ancestor, binding 1000-fold stronger to lauroyl-CoA under physiological conditions. We thus demonstrate how minor sequence changes modulate the extent of long-range interactions and dynamics, effectively contributing to the molecular evolution of contrasting functional repertoires in paralogues.
Asunto(s)
Inhibidor de la Unión a Diazepam , Proteínas , Inhibidor de la Unión a Diazepam/genética , Inhibidor de la Unión a Diazepam/química , Inhibidor de la Unión a Diazepam/metabolismo , Proteínas/metabolismo , Conformación Molecular , Acilcoenzima A/metabolismo , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismoRESUMEN
Acyl coenzyme A binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is a phylogenetically ancient protein present in some eubacteria and the entire eukaryotic radiation. In several eukaryotic phyla, ACBP/DBI transcends its intracellular function in fatty acid metabolism because it can be released into the extracellular space. This ACBP/DBI secretion usually occurs in response to nutrient scarcity through an autophagy-dependent pathway. ACBP/DBI and its peptide fragments then act on a range of distinct receptors that diverge among phyla, namely metabotropic G protein-coupled receptor in yeast (and likely in the mammalian central nervous system), a histidine receptor kinase in slime molds, and ionotropic gamma-aminobutyric acid (GABA)A receptors in mammals. Genetic or antibody-mediated inhibition of ACBP/DBI orthologs interferes with nutrient stress-induced adaptations such as sporulation or increased food intake in multiple species, as it enhances lifespan or healthspan in yeast, plant leaves, nematodes, and multiple mouse models. These lifespan and healthspan-extending effects of ACBP/DBI suppression are coupled to the induction of autophagy. Altogether, it appears that neutralization of extracellular ACBP/DBI results in "autophagy checkpoint inhibition" to unleash the anti-aging potential of autophagy. Of note, in humans, ACBP/DBI levels increase in various tissues, as well as in the plasma, in the context of aging, obesity, uncontrolled infection or cardiovascular, inflammatory, neurodegenerative, and malignant diseases.
Asunto(s)
Proteínas Portadoras , Inhibidor de la Unión a Diazepam , Animales , Humanos , Ratones , Acilcoenzima A/metabolismo , Envejecimiento , Autofagia , Inhibidor de la Unión a Diazepam/metabolismo , Mamíferos/metabolismo , Saccharomyces cerevisiae/metabolismoRESUMEN
Members of the acyl-CoA-binding protein (ACBP) gene family play vital roles in diverse processes related to lipid metabolism, growth and development, and environmental response. Plant ACBP genes have been well-studied in a variety of species including Arabidopsis, soybean, rice and maize. However, the identification and functions of ACBP genes in cotton remain to be elucidated. In this study, a total of 11 GaACBP, 12 GrACBP, 20 GbACBP, and 19 GhACBP genes were identified in the genomes of Gossypium arboreum, Gossypium raimondii, Gossypium babardense, and Gossypium hirsutum, respectively, and grouped into four clades. Forty-nine duplicated gene pairs were identified in Gossypium ACBP genes, and almost all of which have undergone purifying selection during the long evolutionary process. In addition, expression analyses showed that most of the GhACBP genes were highly expressed in the developing embryos. Furthermore, GhACBP1 and GhACBP2 were induced by salt and drought stress based on a real-time quantitative PCR (RT-qPCR) assay, indicating that these genes may play an important role in salt- and drought-stress tolerance. This study will provide a basic resource for further functional analysis of the ACBP gene family in cotton.
Asunto(s)
Inhibidor de la Unión a Diazepam , Gossypium , Gossypium/metabolismo , Inhibidor de la Unión a Diazepam/genética , Inhibidor de la Unión a Diazepam/metabolismo , Genes de Plantas , Estrés Fisiológico/genéticaRESUMEN
The diffuse nature of Glioblastoma (GBM) tumors poses a challenge to current therapeutic options. We have previously shown that Acyl-CoA Binding Protein (ACBP, also known as DBI) regulates lipid metabolism in GBM cells, favoring fatty acid oxidation (FAO). Here we show that ACBP downregulation results in wide transcriptional changes affecting invasion-related genes. In vivo experiments using patient-derived xenografts combined with in vitro models demonstrated that ACBP sustains GBM invasion via binding to fatty acyl-CoAs. Blocking FAO mimics ACBPKD-induced immobility, a cellular phenotype that can be rescued by increasing FAO rates. Further investigation into ACBP-downstream pathways served to identify Integrin beta-1, a gene downregulated upon inhibition of either ACBP expression or FAO rates, as a mediator for ACBP's role in GBM invasion. Altogether, our findings highlight a role for FAO in GBM invasion and reveal ACBP as a therapeutic vulnerability to stall FAO and subsequent cell invasion in GBM tumors.
Asunto(s)
Proteínas Portadoras , Glioblastoma , Humanos , Proteínas Portadoras/metabolismo , Glioblastoma/genética , Inhibidor de la Unión a Diazepam/metabolismo , Metabolismo de los Lípidos , Ácidos Grasos/metabolismoRESUMEN
Autophagy defects accelerate aging, while stimulation of autophagy decelerates aging. Acyl-coenzyme A binding protein (ACBP), which is encoded by a diazepam-binding inhibitor (DBI), acts as an extracellular feedback regulator of autophagy. As shown here, knockout of the gene coding for the yeast orthologue of ACBP/DBI (ACB1) improves chronological aging, and this effect is reversed by knockout of essential autophagy genes (ATG5, ATG7) but less so by knockout of an essential mitophagy gene (ATG32). In humans, ACBP/DBI levels independently correlate with body mass index (BMI) as well as with chronological age. In still-healthy individuals, we find that high ACBP/DBI levels correlate with future cardiovascular events (such as heart surgery, myocardial infarction, and stroke), an association that is independent of BMI and chronological age, suggesting that ACBP/DBI is indeed a biomarker of "biological" aging. Concurringly, ACBP/DBI plasma concentrations correlate with established cardiovascular risk factors (fasting glucose levels, systolic blood pressure, total free cholesterol, triglycerides), but are inversely correlated with atheroprotective high-density lipoprotein (HDL). In mice, neutralization of ACBP/DBI through a monoclonal antibody attenuates anthracycline-induced cardiotoxicity, which is a model of accelerated heart aging. In conclusion, plasma elevation of ACBP/DBI constitutes a novel biomarker of chronological aging and facets of biological aging with a prognostic value in cardiovascular disease.
Asunto(s)
Enfermedades Cardiovasculares , Proteínas Portadoras , Animales , Humanos , Ratones , Enfermedades Cardiovasculares/genética , Coenzima A/metabolismo , Inhibidor de la Unión a Diazepam/genética , Inhibidor de la Unión a Diazepam/metabolismo , Proteínas Nucleares/metabolismoRESUMEN
DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein) is a phylogenetically conserved paracrine inhibitor of macroautophagy/autophagy. As such, DBI/ACBP acts as a pro-aging molecule. Indeed, we observed that the knockout of ACB1 (the yeast equivalent of human DBI/ACBP) induces autophagy and prolongs lifespan in an autophagy-dependent fashion in chronological lifespan experiments. Intriguingly, circulating DBI/ACBP protein augments with age in humans, and this increase occurs independently from the known correlation of DBI/ACBP with body mass index (BMI). A supraphysiological DBI/ACBP level announces future cardiovascular disease (such as heart surgery, myocardial infarction and stroke) in still healthy individuals, suggesting that, beyond its correlation with chronological age, DBI/ACBP is a biomarker of biological age. Plasma DBI/ACBP concentrations correlate with triglycerides and anticorrelate with high-density lipoprotein. Of note, these associations with cardiovascular risk factors are independent from age and BMI in a multivariate regression model. In mice, we found that antibody-mediated neutralization of DBI/ACBP reduces signs of anthracycline-accelerated cardiac aging including the upregulation of the senescence marker CDKN2A/p16 (cyclin dependent kinase inhibitor 2A) and the functional decline of the heart. In conclusion, it appears that extracellular DBI/ACBP can be targeted to combat age-associated cardiovascular disease.Abbreviations: BMI: body mass index; CDKN2A/p16: cyclin dependent kinase inhibitor 2A; CVD: cardiovascular disease; DBI/ACBP: diazepam binding inhibitor, acyl-CoA binding protein; ELISA: enzyme-linked immunosorbent assay; GABA: gamma-aminobutyric acid; GABR: gamma-aminobutyric acid type A receptor.
Asunto(s)
Enfermedades Cardiovasculares , Inhibidor p16 de la Quinasa Dependiente de Ciclina , Humanos , Ratones , Animales , Secuencia de Bases , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Inhibidor de la Unión a Diazepam/metabolismo , Proteínas Portadoras/metabolismo , Autofagia , Envejecimiento , Ácido gamma-AminobutíricoRESUMEN
Acyl-CoA binding protein (ACBP), also known as diazepam binding inhibitor (DBI), has recently emerged as a hypothalamic and brainstem gliopeptide regulating energy balance. Previous work has shown that the ACBP-derived octadecaneuropeptide exerts strong anorectic action via proopiomelanocortin (POMC) neuron activation and the melanocortin-4 receptor. Importantly, targeted ACBP loss-of-function in astrocytes promotes hyperphagia and diet-induced obesity while its overexpression in arcuate astrocytes reduces feeding and body weight. Despite this knowledge, the role of astroglial ACBP in adaptive feeding and metabolic responses to acute metabolic challenges has not been investigated. Using different paradigms, we found that ACBP deletion in glial fibrillary acidic protein (GFAP)-positive astrocytes does not affect weight loss when obese male mice are transitioned from a high fat diet to a chow diet, nor metabolic parameters in mice fed with a normal chow diet (e.g., energy expenditure, body temperature) during fasting, cold exposure and at thermoneutrality. In contrast, astroglial ACBP deletion impairs meal pattern and feeding responses during refeeding after a fast and during cold exposure, thereby showing that ACBP is required to stimulate feeding in states of increased energy demand. These findings challenge the general view that astroglial ACBP exerts anorectic effects and suggest that regulation of feeding by ACBP is dependent on metabolic status.
Asunto(s)
Depresores del Apetito , Inhibidor de la Unión a Diazepam , Metabolismo Energético , Animales , Masculino , Ratones , Astrocitos/metabolismo , Inhibidor de la Unión a Diazepam/metabolismo , Metabolismo Energético/fisiología , Hiperfagia/metabolismoRESUMEN
Earlier work has implicated the neurotransmitter GABA in controlling forebrain progenitor proliferation. In this issue of Neuron, Everlien et al. (2022) demonstrate that diazepam binding inhibitor acts to keep the neurogenesis-promoting effect of GABA at bay.
Asunto(s)
Inhibidor de la Unión a Diazepam , Neurogénesis , Diazepam/metabolismo , Diazepam/farmacología , Inhibidor de la Unión a Diazepam/metabolismo , Neurogénesis/fisiología , Neuronas/metabolismo , Receptores de GABA-A/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Acyl-coenzyme A (CoA)-binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is an extracellular feedback regulator of autophagy. Here, we report that injection of a monoclonal antibody neutralizing ACBP/DBI (α-DBI) protects the murine liver against ischemia/reperfusion damage, intoxication by acetaminophen and concanavalin A, and nonalcoholic steatohepatitis caused by methionine/choline-deficient diet as well as against liver fibrosis induced by bile duct ligation or carbon tetrachloride. α-DBI downregulated proinflammatory and profibrotic genes and upregulated antioxidant defenses and fatty acid oxidation in the liver. The hepatoprotective effects of α-DBI were mimicked by the induction of ACBP/DBI-specific autoantibodies, an inducible Acbp/Dbi knockout or a constitutive Gabrg2F77I mutation that abolishes ACBP/DBI binding to the GABAA receptor. Liver-protective α-DBI effects were lost when autophagy was pharmacologically blocked or genetically inhibited by knockout of Atg4b. Of note, α-DBI also reduced myocardium infarction and lung fibrosis, supporting the contention that it mediates broad organ-protective effects against multiple insults.
Asunto(s)
Inhibidor de la Unión a Diazepam , Receptores de GABA-A , Animales , Ratones , Acetaminofén , Anticuerpos Monoclonales/metabolismo , Antioxidantes , Autoanticuerpos/metabolismo , Autofagia , Tetracloruro de Carbono , Proteínas Portadoras/genética , Colina , Coenzima A/metabolismo , Concanavalina A/metabolismo , Diazepam , Inhibidor de la Unión a Diazepam/metabolismo , Ácidos Grasos/metabolismo , Fibrosis , Inflamación , MetioninaRESUMEN
Of the neurotransmitters that influence neurogenesis, gamma-aminobutyric acid (GABA) plays an outstanding role, and GABA receptors support non-synaptic signaling in progenitors and migrating neurons. Here, we report that expression levels of diazepam binding inhibitor (DBI), an endozepine that modulates GABA signaling, regulate embryonic neurogenesis, affecting the long-term outcome regarding the number of neurons in the postnatal mouse brain. We demonstrate that DBI is highly expressed in radial glia and intermediate progenitor cells in the germinal zones of the embryonic mouse brain that give rise to excitatory and inhibitory cells. The mechanism by which DBI controls neurogenesis involves its action as a negative allosteric modulator of GABA-induced currents on progenitor cells that express GABAA receptors containing γ2 subunits. DBI's modulatory effect parallels that of GABAA-receptor-mediating signaling in these cells in the proliferative areas, reflecting the tight control that DBI exerts on embryonic neurogenesis.
Asunto(s)
Inhibidor de la Unión a Diazepam , Receptores de GABA-A , Animales , Diazepam/farmacología , Inhibidor de la Unión a Diazepam/metabolismo , Desarrollo Embrionario , Ratones , Neurogénesis , Neuronas/fisiología , Receptores de GABA-A/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Mitochondria are involved in many cellular activities, including energy metabolism and biosynthesis of nucleotides, fatty acids and amino acids. Mitochondrial morphology is a key factor in dictating mitochondrial functions. Here, we report that the acyl-CoA-binding protein (ACBP) Acb1 in the fission yeast Schizosaccharomyces pombe is required for the maintenance of tubular mitochondrial morphology and proper mitochondrial respiration. The absence of Acb1 causes severe mitochondrial fragmentation in a dynamin-related protein Dnm1-dependent manner and impairs mitochondrial respiration. Moreover, Acb1 regulates the remodelling of lipid droplets in nutrient-rich conditions. Importantly, Acb1 promotes cell survival when cells are cultured in nutrient-rich medium. Hence, our findings establish roles of ACBP in regulating mitochondria, lipid droplets and cell viability.
Asunto(s)
Inhibidor de la Unión a Diazepam , Proteínas de Schizosaccharomyces pombe , Schizosaccharomyces , Proliferación Celular/genética , Proliferación Celular/fisiología , Inhibidor de la Unión a Diazepam/metabolismo , Dinaminas/metabolismo , Gotas Lipídicas/metabolismo , Mitocondrias/metabolismo , Schizosaccharomyces/metabolismo , Proteínas de Schizosaccharomyces pombe/genética , Proteínas de Schizosaccharomyces pombe/metabolismoRESUMEN
Acyl-CoA-binding proteins (ACBPs) constitute a well-conserved family of proteins in eukaryotes that are important in stress responses and development. Past studies have shown that ACBPs are involved in maintaining, transporting and protecting acyl-CoA esters during lipid biosynthesis in plants, mammals, and yeast. ACBPs show differential expression and various binding affinities for acyl-CoA esters. Hence, ACBPs can play a crucial part in maintaining lipid homeostasis. This review summarizes the functions of ACBPs during the stages of reproduction in plants and other organisms. A comprehensive understanding on the roles of ACBPs during plant reproduction may lead to opportunities in crop improvement in agriculture.