Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 223
Filtrar
Más filtros

Bases de datos
Tipo del documento
Intervalo de año de publicación
1.
Cell ; 173(1): 74-89.e20, 2018 03 22.
Artículo en Inglés | MEDLINE | ID: mdl-29570999

RESUMEN

A decline in capillary density and blood flow with age is a major cause of mortality and morbidity. Understanding why this occurs is key to future gains in human health. NAD precursors reverse aspects of aging, in part, by activating sirtuin deacylases (SIRT1-SIRT7) that mediate the benefits of exercise and dietary restriction (DR). We show that SIRT1 in endothelial cells is a key mediator of pro-angiogenic signals secreted from myocytes. Treatment of mice with the NAD+ booster nicotinamide mononucleotide (NMN) improves blood flow and increases endurance in elderly mice by promoting SIRT1-dependent increases in capillary density, an effect augmented by exercise or increasing the levels of hydrogen sulfide (H2S), a DR mimetic and regulator of endothelial NAD+ levels. These findings have implications for improving blood flow to organs and tissues, increasing human performance, and reestablishing a virtuous cycle of mobility in the elderly.


Asunto(s)
Envejecimiento , Sulfuro de Hidrógeno/metabolismo , NAD/metabolismo , Animales , Células Endoteliales/citología , Células Endoteliales/metabolismo , Humanos , Ratones , Ratones Noqueados , Microvasos/metabolismo , Mitocondrias/metabolismo , Músculo Esquelético/metabolismo , Neovascularización Fisiológica , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Condicionamiento Físico Animal , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Receptores Notch/metabolismo , Transducción de Señal , Sirtuina 1/antagonistas & inhibidores , Sirtuina 1/genética , Sirtuina 1/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo
3.
Cell ; 155(7): 1624-38, 2013 Dec 19.
Artículo en Inglés | MEDLINE | ID: mdl-24360282

RESUMEN

Ever since eukaryotes subsumed the bacterial ancestor of mitochondria, the nuclear and mitochondrial genomes have had to closely coordinate their activities, as each encode different subunits of the oxidative phosphorylation (OXPHOS) system. Mitochondrial dysfunction is a hallmark of aging, but its causes are debated. We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1α/ß-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD(+) and the accumulation of HIF-1α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD(+) levels in old mice restores mitochondrial function to that of a young mouse in a SIRT1-dependent manner. Thus, a pseudohypoxic state that disrupts PGC-1α/ß-independent nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age, a process that is apparently reversible.


Asunto(s)
Envejecimiento/patología , Núcleo Celular/metabolismo , Mitocondrias/metabolismo , NAD/metabolismo , Fosforilación Oxidativa , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones , Músculo Esquelético/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Especies Reactivas de Oxígeno/metabolismo , Sirtuina 1/metabolismo , Factores de Transcripción/metabolismo
4.
Clin Sci (Lond) ; 138(4): 173-187, 2024 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-38315575

RESUMEN

Semaglutide is an anti-diabetes and weight loss drug that decreases food intake, slows gastric emptying, and increases insulin secretion. Patients begin treatment with low-dose semaglutide and increase dosage over time as efficacy plateaus. With increasing dosage, there is also greater incidence of gastrointestinal side effects. One reason for the plateau in semaglutide efficacy despite continued low food intake is due to compensatory actions whereby the body becomes more metabolically efficient to defend against further weight loss. Mitochondrial uncoupler drugs decrease metabolic efficiency, therefore we sought to investigate the combination therapy of semaglutide with the mitochondrial uncoupler BAM15 in diet-induced obese mice. Mice were fed high-fat western diet (WD) and stratified into six treatment groups including WD control, BAM15, low-dose semaglutide without or with BAM15, and high-dose semaglutide without or with BAM15. Combining BAM15 with either semaglutide dose decreased body fat and liver triglycerides, which was not achieved by any monotherapy, while high-dose semaglutide with BAM15 had the greatest effect on glucose homeostasis. This study demonstrates a novel approach to improve weight loss without loss of lean mass and improve glucose control by simultaneously targeting energy intake and energy efficiency. Such a combination may decrease the need for semaglutide dose escalation and hence minimize potential gastrointestinal side effects.


Asunto(s)
Ingestión de Energía , Pérdida de Peso , Humanos , Animales , Ratones , Ratones Obesos , Dieta Alta en Grasa/efectos adversos , Tejido Adiposo
5.
Int J Health Plann Manage ; 39(4): 980-992, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-38192113

RESUMEN

BACKGROUND: The aim of this paper is to provide a system-level snapshot of the operational status of mental health, substance use, and problem gambling services 2 years into the pandemic in Ontario, Canada, with a specific focus on services that target individuals experiencing vulnerable circumstances (e.g., homelessness and legal issues). METHODS: We examined data from 6038 publicly funded community services that provide mental health, substance use, and problem gambling services in Ontario. We used descriptive statistics to describe counts and percentages by service type and specialisation of service delivery. We generated cross-tabulations to analyse the relationship between the service status and service type for each target population group. RESULTS: As of March 2022, 38.4% (n = 2321) of services were fully operational, including 36.0% (n = 1492) of mental health, 44.1% (n = 1037) of substance use, and 23.4% (n = 78) of problem gambling services. These service disruptions were also apparent among services tailored to sexual/gender identity (women/girls, men/boys, 2SLGBTQQIA + individuals), individuals with legal issues, with acquired brain injury, and those experiencing homelessness. CONCLUSION: Accessible community-based mental health, substance use and problem gambling services are critical supports, particularly for communities that have historically contended with higher needs and greater barriers to care relative to the general population. We discuss the public health implications of the findings for the ongoing pandemic response and future emergency preparedness planning for community-based mental health, substance use and problem gambling services.


Asunto(s)
COVID-19 , Juego de Azar , Pandemias , Trastornos Relacionados con Sustancias , Humanos , COVID-19/epidemiología , Ontario/epidemiología , Juego de Azar/epidemiología , Juego de Azar/terapia , Trastornos Relacionados con Sustancias/epidemiología , Trastornos Relacionados con Sustancias/terapia , Femenino , Masculino , Servicios de Salud Mental/organización & administración , Adulto , SARS-CoV-2
6.
Int J Mol Sci ; 25(2)2024 Jan 12.
Artículo en Inglés | MEDLINE | ID: mdl-38256063

RESUMEN

'Inner mitochondrial membrane peptidase 2 like' (IMMP2L) is a nuclear-encoded mitochondrial peptidase that has been conserved through evolutionary history, as has its target enzyme, 'mitochondrial glycerol phosphate dehydrogenase 2' (GPD2). IMMP2L is known to cleave the mitochondrial transit peptide from GPD2 and another nuclear-encoded mitochondrial respiratory-related protein, cytochrome C1 (CYC1). However, it is not known whether IMMP2L peptidase activates or alters the activity or respiratory-related functions of GPD2 or CYC1. Previous investigations found compelling evidence of behavioural change in the Immp2lKD-/- KO mouse, and in this study, EchoMRI analysis found that the organs of the Immp2lKD-/- KO mouse were smaller and that the KO mouse had significantly less lean mass and overall body weight compared with wildtype littermates (p < 0.05). Moreover, all organs analysed from the Immp2lKD-/- KO had lower relative levels of mitochondrial reactive oxygen species (mitoROS). The kidneys of the Immp2lKD-/- KO mouse displayed the greatest decrease in mitoROS levels that were over 50% less compared with wildtype litter mates. Mitochondrial respiration was also lowest in the kidney of the Immp2lKD-/- KO mouse compared with other tissues when using succinate as the respiratory substrate, whereas respiration was similar to the wildtype when glutamate was used as the substrate. When glycerol-3-phosphate (G3P) was used as the substrate for Gpd2, we observed ~20% and ~7% respective decreases in respiration in female and male Immp2lKD-/- KO mice over time. Together, these findings indicate that the respiratory-related functions of mGpd2 and Cyc1 have been compromised to different degrees in different tissues and genders of the Immp2lKD-/- KO mouse. Structural analyses using AlphaFold2-Multimer further predicted that the interaction between Cyc1 and mitochondrial-encoded cytochrome b (Cyb) in Complex III had been altered, as had the homodimeric structure of the mGpd2 enzyme within the inner mitochondrial membrane of the Immp2lKD-/- KO mouse. mGpd2 functions as an integral component of the glycerol phosphate shuttle (GPS), which positively regulates both mitochondrial respiration and glycolysis. Interestingly, we found that nonmitochondrial respiration (NMR) was also dramatically lowered in the Immp2lKD-/- KO mouse. Primary mouse embryonic fibroblast (MEF) cell lines derived from the Immp2lKD-/- KO mouse displayed a ~27% decrease in total respiration, comprising a ~50% decrease in NMR and a ~12% decrease in total mitochondrial respiration, where the latter was consistent with the cumulative decreases in substrate-specific mediated mitochondrial respiration reported here. This study is the first to report the role of Immp2l in enhancing Gpd2 structure and function, mitochondrial respiration, nonmitochondrial respiration, organ size and homeostasis.


Asunto(s)
Atrofia Bulboespinal Ligada al X , Glicerol , Glicerofosfatos , Femenino , Masculino , Animales , Ratones , Fibroblastos , Ácido Glutámico , Glicerolfosfato Deshidrogenasa/genética , Péptido Hidrolasas , Fosfatos
7.
J Lipid Res ; 64(3): 100341, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36740022

RESUMEN

Recent advances in single-cell genomics and transcriptomics technologies have transformed our understanding of cellular heterogeneity in growth, development, ageing, and disease; however, methods for single-cell lipidomics have comparatively lagged behind in development. We have developed a method for the detection and quantification of a wide range of phosphatidylcholine and sphingomyelin species from single cells that combines fluorescence-assisted cell sorting with automated chip-based nanoESI and shotgun lipidomics. We show herein that our method is capable of quantifying more than 50 different phosphatidylcholine and sphingomyelin species from single cells and can easily distinguish between cells of different lineages or cells treated with exogenous fatty acids. Moreover, our method can detect more subtle differences in the lipidome between cell lines of the same cancer type. Our approach can be run in parallel with other single-cell technologies to deliver near-complete, high-throughput multi-omics data on cells with a similar phenotype and has the capacity to significantly advance our current knowledge on cellular heterogeneity.


Asunto(s)
Fosfatidilcolinas , Esfingomielinas , Fosfatidilcolinas/metabolismo , Lipidómica , Ácidos Grasos
8.
J Gambl Stud ; 2023 Dec 13.
Artículo en Inglés | MEDLINE | ID: mdl-38087132

RESUMEN

In this paper we examine the nature of calls for the Ontario Problem Gambling Helpline from June 2021 to Jan 2023 to determine if the increased marketing of online and sports gambling has changed the nature of calls to the helpline. An interrupted time series model comparing the monthly calls before and after the expansion of online gambling and advertising (April 2023), found a significant effect. Calls related to the other games examined did not have a significant interrupted time series effect of from the expansion and advertising of online gambling. The results of this analysis clearly indicate an association between the expansion of legalized gambling and gambling advertising with the number of people who call the helpline for problem related to online gambling.

9.
Biochem Biophys Res Commun ; 607: 131-137, 2022 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-35367825

RESUMEN

The mitochondrial enzyme SIRT3 is an NAD+-dependent deacetylase important in cell metabolism, and a decline in its protein expression or activity has been linked with insulin resistance in obesity, ageing and type 2 diabetes. While studies in SIRT3 knockout mice have dramatically improved our understanding of the function of SIRT3, the impact of increasing SIRT3 levels remains under-examined. In this study we investigated the effects of liver-specific SIRT3 overexpression in mice on mitochondrial function and metabolic profile in both isolated hepatocytes and in vivo. Primary hepatocytes overexpressing SIRT3 displayed increased oxygen consumption and a reduction in triglyceride accumulation. In mice with hepatic SIRT3 overexpression, increased fasting ß-hydroxybutyrate levels were observed, coupled with an increase in oxygen consumption in isolated mitochondria and increased substrate utilization in liver homogenates. However, metabolic profiling of mice exposed to either chow or high-fat diet revealed no effect of hepatic SIRT3 overexpression on glucose tolerance, body composition or tissue triglyceride accumulation. These findings suggest limited whole-body benefit of increasing hepatic SIRT3 during the development of diet-induced insulin resistance.


Asunto(s)
Resistencia a la Insulina , Hígado , Sirtuina 3 , Animales , Hígado/metabolismo , Ratones , Ratones Noqueados , Estrés Oxidativo , Sirtuina 3/genética , Sirtuina 3/metabolismo , Triglicéridos/metabolismo
10.
Am J Public Health ; 112(8): 1134-1137, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35709410

RESUMEN

During fall 2020 in rural Pierce County, Washington, school districts and the county health department offered weekly rapid antigen screening to students and staff. Asymptomatic screening identified 42.5% of confirmed cases from the population. Parents reported it was a positive experience for their children. The program supported decisions to return to in-person learning, but screening ended because of resource and technical limitations. When planning in-school screening, stakeholder engagement and resource sustainability are important factors to consider. (Am J Public Health. 2022;112(8):1134-1137. https://doi.org/10.2105/AJPH.2022.306875).


Asunto(s)
COVID-19 , SARS-CoV-2 , COVID-19/diagnóstico , Niño , Humanos , Instituciones Académicas , Estudiantes , Washingtón/epidemiología
11.
J Pathol ; 254(2): 135-146, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33768538

RESUMEN

Glutamine is a critical nutrient in cancer; however, its contribution to purine metabolism in prostate cancer has not previously been determined. Guanosine monophosphate synthetase (GMPS) acts in the de novo purine biosynthesis pathway, utilizing a glutamine amide to synthesize the guanine nucleotide. This study demonstrates that GMPS mRNA expression correlates with Gleason score in prostate cancer samples, while high GMPS expression was associated with decreased rates of overall and disease/progression-free survival. Pharmacological inhibition or knockdown of GMPS significantly decreased cell growth in both LNCaP and PC-3 prostate cancer cells. We utilized [15 N-(amide)]glutamine and [U-13 C5 ]glutamine metabolomics to dissect the pathways involved and despite similar growth inhibition by GMPS knockdown, we show unique metabolic effects across each cell line. Using a PC-3 xenograft mouse model, tumor growth was also significantly decreased after GMPS knockdown, highlighting the importance of glutamine metabolism and providing support for GMPS as a therapeutic target in prostate cancer. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Asunto(s)
Ligasas de Carbono-Nitrógeno/antagonistas & inhibidores , Glutamina/metabolismo , Neoplasias de la Próstata/enzimología , Animales , Ligasas de Carbono-Nitrógeno/genética , Ligasas de Carbono-Nitrógeno/metabolismo , Línea Celular Tumoral , Proliferación Celular , Estudios de Cohortes , Biología Computacional , Modelos Animales de Enfermedad , Técnicas de Silenciamiento del Gen , Humanos , Masculino , Redes y Vías Metabólicas , Metabolómica , Ratones , Prostatectomía , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía , Purinas/metabolismo , Análisis de Matrices Tisulares , Regulación hacia Arriba , Ensayos Antitumor por Modelo de Xenoinjerto
12.
Paediatr Anaesth ; 32(4): 504-508, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35108423

RESUMEN

In this educational article, we summarize the changes in the new European Resuscitation Council guidelines on Newborn Resuscitation and Support of the Transition of Infants at Birth, emphasizing important aspects for the pediatric anesthesiologist including umbilical cord management, airway management, inflation pressure, and oxygen in relation with gestational age and situation. Using a fictitious case to illustrate the main points, we give a summary of the changes and the evidence behind them.


Asunto(s)
Insuflación , Resucitación , Niño , Femenino , Edad Gestacional , Humanos , Lactante , Recién Nacido , Oxígeno , Parto , Embarazo
13.
Paediatr Anaesth ; 32(4): 497-503, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-34964208

RESUMEN

In this educational article, we summarize the changes in the new European Resuscitation Council guidelines for Pediatric Life Support, emphasizing the most important aspects for the anesthesiologist. Among these are: the use of two-thumb-encircling technique for thorax compressions in infants, 10 ml/kg as the standard volume fluid bolus and ventilation after intubation at an age-dependent rate. Using a fictitious case, we present a point-by-point summary of the changes and briefly mention some of the evidence behind them, referring the reader to the full guidelines for further evidence. We also give a summary of the incidence, causes, challenges, treatment, and prognosis of pediatric cardiac arrest in the operating room.


Asunto(s)
Anestesia , Reanimación Cardiopulmonar , Paro Cardíaco , Anestesia/efectos adversos , Reanimación Cardiopulmonar/métodos , Niño , Paro Cardíaco/etiología , Paro Cardíaco/terapia , Humanos , Lactante , Resucitación/métodos
14.
BMC Emerg Med ; 22(1): 202, 2022 12 12.
Artículo en Inglés | MEDLINE | ID: mdl-36510149

RESUMEN

BACKGROUND: The Airway, Breathing, Circulation, Disability and Exposure (ABCDE) approach is a universal, priority-based approach for the assessment and treatment of critically ill patients. Although the ABCDE approach is widely recommended, adherence in practice appears to be suboptimal. The cause of this non-compliance is unknown. As knowledge is a prerequisite for adherence, the aim of this study was to assess healthcare professionals' knowledge of the ABCDE approach. METHODS: A cross-sectional study was conducted at the Radboud University Medical Center, the Netherlands. A digital multiple-choice assessment tool of the ABCDE approach was developed by an expert panel through a mini-Delphi method and validated by performing test item statistics and an expert-novice comparison. The validated test was sent to healthcare professionals (nurses, residents and medical specialists) of the participating departments: Anaesthesiology, Paediatrics, Emergency Department and the Neonatal, Paediatric and Adult Intensive Care Units. Primary outcome was the test score, reflecting individual level of knowledge. Descriptive statistics, regression analysis and ANOVA were used. RESULTS: Test validation showed a Cronbach's alpha of 0.71 and an expert-novice comparison of 91.9% (standard deviation (SD) 9.1) and 72.4% (15.2) respectively (p < 0.001). Of 954 eligible participants, 240 filled out the questionnaire. The mean (SD) test score (% of correct answers) was 80.1% (12.2). Nurses had significantly lower scores (74.9% (10.9)) than residents (92.3% (7.5)) and medical specialists (88.0% (8.6)) (p < 0.001). The Neonatal Intensive Care Unit (75.9% (12.6)) and Adult Intensive Care Unit (77.4% (11.2)) had significantly lower scores than Paediatric Intensive Care Unit (85.6% (10.6)), Emergency Department (85.5% (10.4)) and Anaesthesiology (85.3% (10.6)) (p < 0.05). Younger participants scored higher than older participants (-0.30% (-0.46;-0.15) in test score/year increase in age). CONCLUSION: Scores of a validated knowledge test regarding the ABCDE approach vary among healthcare professionals caring for critically ill patients. Type of department, profession category and age had a significant influence on the test score. Further research should relate theoretical knowledge level to clinical practice. Tailored interventions to increase ABCDE-related knowledge are recommended.


Asunto(s)
Personal de Salud , Unidades de Cuidados Intensivos , Adulto , Recién Nacido , Humanos , Niño , Estudios Transversales , Enfermedad Crítica , Atención a la Salud
15.
Can J Psychiatry ; 66(8): 747-756, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33504212

RESUMEN

OBJECTIVE: The objective of the current research was to examine the association between time spent on social media and serious psychological distress between 2013 and 2017, a period when the rates of both were trending upward. METHODS: The current study analyzed population-based data from 3 waves of the Ontario Student Drug Use and Health Survey (N = 15,398). Multivariate logistic regression models were used to examine the association between time spent on social media and serious psychological distress controlling for theoretically relevant covariates. Interactions were tested to assess whether the association changed over time. RESULTS: The prevalence of serious psychological distress increased from 10.9% in 2013 to 16.8% in 2017 concomitantly with substantial increases in social media usage, especially at the highest levels. In the multivariate context, we found a significant interaction between social media use and the survey year which indicates that the association between time spent on social media and psychological distress has decreased from 2013 to 2017. CONCLUSION: Although both social media use and psychological distress increased between 2013 and 2017, the interaction between these variables indicates that the strength of this association has decreased over time. This finding suggests that the higher rate of heavy social media use in 2017 compared to 2013 is not actually associated with the higher rate of serious psychological distress during the same time period. From a diffusion of innovation perspective, it is possible that more recent adopters of social media may be less prone to psychological distress. More research is needed to understand the complex and evolving association between social media use and psychological distress. Researchers attempting to isolate the factors associated with the recent increases in psychological distress could benefit from broadening their investigation to factors beyond time spent on social media.


Asunto(s)
Distrés Psicológico , Medios de Comunicación Sociales , Estudios Transversales , Humanos , Ontario/epidemiología , Estrés Psicológico/epidemiología , Estudiantes
16.
J Gambl Stud ; 37(4): 1245-1262, 2021 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-33486640

RESUMEN

Voluntary self-exclusion programs allow gamblers to voluntarily be denied access to gambling venues for an agreed upon period. Many people who self-exclude decide to return to gambling venues after the exclusion period has ended, however people who reinstate may be at risk for the recurrence of gambling problems. This study was designed to determine the efficacy of a tutorial created with the intent of reducing the risk of harm to those who reinstate. People who wished to be reinstated were asked to complete a survey on gambling related issues and then watch the tutorial video. An online video-based tutorial designed to reduce gambling related harm and to provide information about treatment services was developed. The control group (N = 131) consisted of people who reinstated in the year prior to the implementation of the online tutorial. The experimental intervention group (N = 104) were those who reinstated after the implementation of the online tutorial. There was a significant decrease in gambling and problem gambling comparing pre-exclusion to during exclusion in both the experimental and control group. Furthermore, this drop in gambling problem was sustained for 6-months and 12-months after reinstatement. However, no main effect or interaction was found that supported the efficacy of the tutorial. Self-exclusion by itself was associated with a sustained reduction in problem gambling. There was no significant evidence that the educational tutorial had any additional impact on the reinstatement process.


Asunto(s)
Juego de Azar , Juego de Azar/psicología , Humanos , Programas Voluntarios
17.
Notf Rett Med ; 24(4): 750-772, 2021.
Artículo en Alemán | MEDLINE | ID: mdl-34093075

RESUMEN

These European Resuscitation Council education guidelines are based on the 2020 International Consensus on Cardiopulmonary Resuscitation Science with Treatment Recommendations. This section provides guidance to citizens and healthcare professionals with regard to teaching and learning the knowledge, skills and attitudes of resuscitation with the ultimate aim of improving patient survival after cardiac arrest.

18.
Notf Rett Med ; 24(4): 650-719, 2021.
Artículo en Alemán | MEDLINE | ID: mdl-34093080

RESUMEN

The European Resuscitation Council (ERC) Paediatric Life Support (PLS) guidelines are based on the 2020 International Consensus on Cardiopulmonary Resuscitation Science with Treatment Recommendations of the International Liaison Committee on Resuscitation (ILCOR). This section provides guidelines on the management of critically ill or injured infants, children and adolescents before, during and after respiratory/cardiac arrest.

19.
Semin Cell Dev Biol ; 81: 149-153, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-28733164

RESUMEN

Oxysterol-binding protein (OSBP) and its related proteins (ORPs) constitute a large, evolutionarily conserved family of lipid-binding proteins that are associated with a wide range of cellular activities. The core function of OSBP/ORPs appears to be moving lipids between cellular membranes in a non-vesicular manner. Recent studies have unveiled a novel, counter-transport mechanism of cellular lipid transfer mediated by OSBP/ORPs at the membrane contact sites that involves phosphatidylinositol 4-phosphate. Importantly, the OSBP/ORPs family has also been implicated in cell signalling pathways and cancer development. Here, we summarize recent progress in understanding the role of OSBP/ORPs in cancer development, and discuss how the lipid transfer function of OSBP/ORPs may underpin their role in tumorigenesis.


Asunto(s)
Metabolismo de los Lípidos/fisiología , Neoplasias/metabolismo , Receptores de Esteroides/fisiología , Transducción de Señal/fisiología , Animales , Transporte Biológico , Membrana Celular/metabolismo , Oxiesteroles/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo
20.
J Biol Chem ; 294(50): 19306-19321, 2019 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-31727739

RESUMEN

Cholesterol plays essential structural and signaling roles in mammalian cells, but too much cholesterol can cause cytotoxicity. Acyl-CoA:cholesterol acyltransferases 1 and 2 (ACAT1/2) convert cholesterol into its storage form, cholesteryl esters, regulating a key step in cellular cholesterol homeostasis. Adipose tissue can store >50% of whole-body cholesterol. Interestingly, however, almost no ACAT activity is present in adipose tissue, and most adipose cholesterol is stored in its free form. We therefore hypothesized that increased cholesterol esterification may have detrimental effects on adipose tissue function. Here, using several approaches, including protein overexpression, quantitative RT-PCR, immunofluorescence, and various biochemical assays, we found that ACAT1 expression is significantly increased in the adipose tissue of the ob/ob mice. We further demonstrated that ACAT1/2 overexpression partially inhibited the differentiation of 3T3-L1 preadipocytes. In mature adipocytes, increased ACAT activity reduced the size of lipid droplets (LDs) and inhibited lipolysis and insulin signaling. Paradoxically, the amount of free cholesterol increased on the surface of LDs in ACAT1/2-overexpressing adipocytes, accompanied by increased LD localization of caveolin-1. Moreover, cholesterol depletion in adipocytes by treating the cells with cholesterol-deficient media or ß-cyclodextrins induced changes in cholesterol distribution that were similar to those caused by ACAT1/2 overexpression. Our results suggest that ACAT1/2 overexpression increases the level of free cholesterol on the LD surface, thereby impeding adipocyte function. These findings provide detailed insights into the role of free cholesterol in LD and adipocyte function and suggest that ACAT inhibitors have potential utility for managing disorders associated with extreme obesity.


Asunto(s)
Acetil-CoA C-Acetiltransferasa/metabolismo , Adipocitos/metabolismo , Colesterol/metabolismo , Gotas Lipídicas/metabolismo , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Tamaño de la Partícula , Propiedades de Superficie
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA