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1.
Nat Rev Mol Cell Biol ; 24(1): 1-2, 2023 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-36319695
2.
PLoS Biol ; 22(8): e3002737, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-39159271

RESUMEN

Lipid transfer proteins (LTPs) are key players in cellular homeostasis and regulation, as they coordinate the exchange of lipids between different cellular organelles. Despite their importance, our mechanistic understanding of how LTPs function at the molecular level is still in its infancy, mostly due to the large number of existing LTPs and to the low degree of conservation at the sequence and structural level. In this work, we use molecular simulations to characterize a representative dataset of lipid transport domains (LTDs) of 12 LTPs that belong to 8 distinct families. We find that despite no sequence homology nor structural conservation, the conformational landscape of LTDs displays common features, characterized by the presence of at least 2 main conformations whose populations are modulated by the presence of the bound lipid. These conformational properties correlate with their mechanistic mode of action, allowing for the interpretation and design of experimental strategies to further dissect their mechanism. Our findings indicate the existence of a conserved, fold-independent mechanism of lipid transfer across LTPs of various families and offer a general framework for understanding their functional mechanism.


Asunto(s)
Proteínas Portadoras , Conformación Proteica , Proteínas Portadoras/metabolismo , Proteínas Portadoras/química , Simulación de Dinámica Molecular , Humanos , Metabolismo de los Lípidos , Dominios Proteicos , Transporte Biológico
3.
EMBO J ; 40(20): e107766, 2021 10 18.
Artículo en Inglés | MEDLINE | ID: mdl-34516001

RESUMEN

The Golgi apparatus, the main glycosylation station of the cell, consists of a stack of discontinuous cisternae. Glycosylation enzymes are usually concentrated in one or two specific cisternae along the cis-trans axis of the organelle. How such compartmentalized localization of enzymes is achieved and how it contributes to glycosylation are not clear. Here, we show that the Golgi matrix protein GRASP55 directs the compartmentalized localization of key enzymes involved in glycosphingolipid (GSL) biosynthesis. GRASP55 binds to these enzymes and prevents their entry into COPI-based retrograde transport vesicles, thus concentrating them in the trans-Golgi. In genome-edited cells lacking GRASP55, or in cells expressing mutant enzymes without GRASP55 binding sites, these enzymes relocate to the cis-Golgi, which affects glycosphingolipid biosynthesis by changing flux across metabolic branch points. These findings reveal a mechanism by which a matrix protein regulates polarized localization of glycosylation enzymes in the Golgi and controls competition in glycan biosynthesis.


Asunto(s)
Glicoesfingolípidos/metabolismo , Aparato de Golgi/metabolismo , Proteínas de la Matriz de Golgi/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Autoantígenos/genética , Autoantígenos/metabolismo , Brefeldino A/farmacología , Ceramidas/metabolismo , Toxina del Cólera/farmacología , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Expresión Génica , Glicosilación/efectos de los fármacos , Aparato de Golgi/efectos de los fármacos , Aparato de Golgi/genética , Proteínas de la Matriz de Golgi/genética , Células HeLa , Humanos , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Toxina Shiga/farmacología
4.
EMBO J ; 40(8): e107238, 2021 04 15.
Artículo en Inglés | MEDLINE | ID: mdl-33749896

RESUMEN

Glycosphingolipids are important components of the plasma membrane where they modulate the activities of membrane proteins including signalling receptors. Glycosphingolipid synthesis relies on competing reactions catalysed by Golgi-resident enzymes during the passage of substrates through the Golgi cisternae. The glycosphingolipid metabolic output is determined by the position and levels of the enzymes within the Golgi stack, but the mechanisms that coordinate the intra-Golgi localisation of the enzymes are poorly understood. Here, we show that a group of sequentially-acting enzymes operating at the branchpoint among glycosphingolipid synthetic pathways binds the Golgi-localised oncoprotein GOLPH3. GOLPH3 sorts these enzymes into vesicles for intra-Golgi retro-transport, acting as a component of the cisternal maturation mechanism. Through these effects, GOLPH3 controls the sub-Golgi localisation and the lysosomal degradation rate of specific enzymes. Increased GOLPH3 levels, as those observed in tumours, alter glycosphingolipid synthesis and plasma membrane composition thereby promoting mitogenic signalling and cell proliferation. These data have medical implications as they outline a novel oncogenic mechanism of action for GOLPH3 based on glycosphingolipid metabolism.


Asunto(s)
Proliferación Celular , Glicoesfingolípidos/biosíntesis , Aparato de Golgi/metabolismo , Proteínas de la Membrana/metabolismo , Células Cultivadas , Células HeLa , Humanos , Lisosomas/metabolismo , Proteínas de la Membrana/genética , Proteínas Oncogénicas/genética , Proteínas Oncogénicas/metabolismo , Transducción de Señal
5.
EMBO J ; 37(7)2018 04 03.
Artículo en Inglés | MEDLINE | ID: mdl-29282205

RESUMEN

Neural development is accomplished by differentiation events leading to metabolic reprogramming. Glycosphingolipid metabolism is reprogrammed during neural development with a switch from globo- to ganglio-series glycosphingolipid production. Failure to execute this glycosphingolipid switch leads to neurodevelopmental disorders in humans, indicating that glycosphingolipids are key players in this process. Nevertheless, both the molecular mechanisms that control the glycosphingolipid switch and its function in neurodevelopment are poorly understood. Here, we describe a self-contained circuit that controls glycosphingolipid reprogramming and neural differentiation. We find that globo-series glycosphingolipids repress the epigenetic regulator of neuronal gene expression AUTS2. AUTS2 in turn binds and activates the promoter of the first and rate-limiting ganglioside-producing enzyme GM3 synthase, thus fostering the synthesis of gangliosides. By this mechanism, the globo-AUTS2 axis controls glycosphingolipid reprogramming and neural gene expression during neural differentiation, which involves this circuit in neurodevelopment and its defects in neuropathology.


Asunto(s)
Diferenciación Celular/fisiología , Reprogramación Celular/fisiología , Glicoesfingolípidos/metabolismo , Neurogénesis/fisiología , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Reprogramación Celular/efectos de los fármacos , Proteínas del Citoesqueleto , Epigenómica , Gangliósidos/metabolismo , Expresión Génica , Silenciador del Gen , Glicoesfingolípidos/farmacología , Células HeLa , Histonas/metabolismo , Humanos , Trastornos del Neurodesarrollo , Neurogénesis/efectos de los fármacos , Neurogénesis/genética , Neuronas/metabolismo , Regiones Promotoras Genéticas/efectos de los fármacos , Proteínas/genética , Proteínas/metabolismo , Sialiltransferasas/genética , Sialiltransferasas/metabolismo , Factores de Transcripción
6.
Medicina (Kaunas) ; 58(9)2022 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-36143962

RESUMEN

During an acute SARS-CoV-2 infection, a diagnosis of Aplastic Anaemia associated with Paroxysmal Nocturnal Haemoglobinuria (AA/PNH) was made in a 78-year-old woman who had presented to the emergency department with severe pancytopenia. It is possible that she had subclinical AA/PNH that was unmasked during the acute COVID-19 infection, but we can also suspect a direct role of the virus in the pathogenesis of the disease, or we can hypothesize that COVID-19 infection changed the phosphatidylinositol glycan class A (PIGA) gene pathway.


Asunto(s)
Anemia Aplásica , COVID-19 , Hemoglobinuria Paroxística , Pancitopenia , Anciano , Anemia Aplásica/complicaciones , Anemia Aplásica/diagnóstico , Anemia Aplásica/genética , COVID-19/complicaciones , Femenino , Glicosilfosfatidilinositoles , Hemoglobinuria Paroxística/complicaciones , Hemoglobinuria Paroxística/diagnóstico , Humanos , Pancitopenia/complicaciones , SARS-CoV-2
7.
EMBO J ; 36(12): 1736-1754, 2017 06 14.
Artículo en Inglés | MEDLINE | ID: mdl-28495678

RESUMEN

Sphingolipids are membrane lipids globally required for eukaryotic life. The sphingolipid content varies among endomembranes with pre- and post-Golgi compartments being poor and rich in sphingolipids, respectively. Due to this different sphingolipid content, pre- and post-Golgi membranes serve different cellular functions. The basis for maintaining distinct subcellular sphingolipid levels in the presence of membrane trafficking and metabolic fluxes is only partially understood. Here, we describe a homeostatic regulatory circuit that controls sphingolipid levels at the trans-Golgi network (TGN). Specifically, we show that sphingomyelin production at the TGN triggers a signalling pathway leading to PtdIns(4)P dephosphorylation. Since PtdIns(4)P is required for cholesterol and sphingolipid transport to the trans-Golgi network, PtdIns(4)P consumption interrupts this transport in response to excessive sphingomyelin production. Based on this evidence, we envisage a model where this homeostatic circuit maintains a constant lipid composition in the trans-Golgi network and post-Golgi compartments, thus counteracting fluctuations in the sphingolipid biosynthetic flow.


Asunto(s)
Fosfatidilinositoles/metabolismo , Esfingolípidos/metabolismo , Red trans-Golgi/metabolismo , Células HeLa , Homeostasis , Humanos , Modelos Biológicos
8.
J Cell Sci ; 132(15)2019 07 31.
Artículo en Inglés | MEDLINE | ID: mdl-31371572

RESUMEN

Sphingolipids are a fundamental class of molecules that are involved in structural, organizational and signaling properties of eukaryotic membranes. Defects in their production or disposal lead to acquired and inherited human diseases. A growing community of scientists has embraced the challenge to dissect different aspects of sphingolipid biology using a variety of approaches, and a substantial part of this community met last May in the beautiful town of Cascais in Portugal. Over 200 scientists from 26 countries animated the conference, held in a 15th century citadel, sharing their data and opinions on the current understanding and future challenges in sphingolipid research. Here, we report some of their contributions to provide the readers with a bird's-eye view of the themes discussed at the meeting.


Asunto(s)
Membrana Celular/metabolismo , Transducción de Señal , Esfingolípidos/metabolismo , Animales , Congresos como Asunto , Humanos , Portugal
9.
Curr Heart Fail Rep ; 18(4): 191-199, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34181210

RESUMEN

PURPOSE OF REVIEW: Oncological treatments are known to induce cardiac toxicity, but the impact of new-onset cancer in patients with pre-existing HF remains unknown. This review focuses on the epidemiology, pathophysiological mechanisms, and clinical implications of HF patients who develop malignancies. RECENT FINDINGS: Novel findings suggest that HF and cancer, beside common risk factors, are deeply linked by shared pathophysiological mechanisms. In particular, HF itself may enhance carcinogenesis by producing pro-inflammatory cytokines, and it has been suggested that neurohormonal activation, commonly associated with the failing heart, might play a pivotal role in promoting neoplastic transformation. The risk of malignancies seems to be higher in HF patients compared to the general population, probably due to shared risk factors and common pathophysiological pathways. Additionally, management of these patients represents a challenge for clinicians, considering that the co-existence of these diseases significantly worsens patients' prognosis and negatively affects therapeutic options for both diseases.


Asunto(s)
Insuficiencia Cardíaca , Neoplasias , Cardiotoxicidad , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/terapia , Humanos , Neoplasias/epidemiología , Neoplasias/terapia , Pronóstico , Factores de Riesgo
10.
J Cell Sci ; 131(24)2018 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-30559216

RESUMEN

Glycosphingolipids (GSLs) are ubiquitous components of eukaryotic plasma membranes that consist of a ceramide backbone linked to a glycan moiety. Both the ceramide and the glycan parts of GSLs display structural variations that result in a remarkable repertoire of diverse compounds. This diversity of GSLs is exploited during embryogenesis, when different GSLs are produced at specific developmental stages and along several differentiation trajectories. Importantly, plasma membrane receptors interact with GSLs to modify their activities. Consequently, two otherwise identical cells can respond differently to the same stimulus owing to their different GSL composition. The metabolic reprograming of GSLs is in fact a necessary part of developmental programs, as its impairment results in developmental failure or tissue-specific defects. Moreover, single-cell variability is emerging as a fundamental player in development: GSL composition displays cell-to-cell variability in syngeneic cell populations owing to the regulatory gene expression circuits involved in microenvironment adaptation and in differentiation. Here, we discuss how GSLs are synthesized and classified and review the role of GSLs in the establishment and maintenance of cell identity. We further highlight the existence of the regulatory circuits that modify GSL pathways and speculate how GSL heterogeneity might contribute to developmental patterning.


Asunto(s)
Diferenciación Celular/fisiología , Membrana Celular/metabolismo , Glicoesfingolípidos/metabolismo , Receptores de Superficie Celular/metabolismo , Animales , Ceramidas/química , Desarrollo Embrionario/fisiología , Humanos
11.
Nature ; 501(7465): 116-20, 2013 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-23913272

RESUMEN

Newly synthesized proteins and lipids are transported across the Golgi complex via different mechanisms whose respective roles are not completely clear. We previously identified a non-vesicular intra-Golgi transport pathway for glucosylceramide (GlcCer)--the common precursor of the different series of glycosphingolipids-that is operated by the cytosolic GlcCer-transfer protein FAPP2 (also known as PLEKHA8) (ref. 1). However, the molecular determinants of the FAPP2-mediated transfer of GlcCer from the cis-Golgi to the trans-Golgi network, as well as the physiological relevance of maintaining two parallel transport pathways of GlcCer--vesicular and non-vesicular--through the Golgi, remain poorly defined. Here, using mouse and cell models, we clarify the molecular mechanisms underlying the intra-Golgi vectorial transfer of GlcCer by FAPP2 and show that GlcCer is channelled by vesicular and non-vesicular transport to two topologically distinct glycosylation tracks in the Golgi cisternae and the trans-Golgi network, respectively. Our results indicate that the transport modality across the Golgi complex is a key determinant for the glycosylation pattern of a cargo and establish a new paradigm for the branching of the glycosphingolipid synthetic pathway.


Asunto(s)
Glucosilceramidas/metabolismo , Glicosilación , Aparato de Golgi/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Transporte Biológico , Línea Celular , Globósidos/biosíntesis , Globósidos/química , Globósidos/metabolismo , Glucosilceramidas/química , Glicoesfingolípidos/biosíntesis , Glicoesfingolípidos/química , Glicoesfingolípidos/metabolismo , Humanos , Ratones , Ratones Endogámicos C57BL , Fosfatos de Fosfatidilinositol/metabolismo , Red trans-Golgi/metabolismo
12.
Blood ; 125(1): 140-3, 2015 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-25331116

RESUMEN

The genetic and transcriptional signature of EVI1 (ecotropic viral integration site 1)-rearranged (EVI1-r) acute myeloid leukemias (AMLs) remains poorly defined. We performed RNA sequencing of 12 EVI1-r AMLs and compared the results with those of other AML subtypes (n = 139) and normal CD34(+) cells (n = 17). Results confirm high frequencies of RAS and other activated signaling mutations (10/12 AMLs) and identify new recurrent mutations in splicing factors (5/12 AMLs in SF3B1 and 2/12 AMLs in U2AF1), IKZF1 (3/12 AMLs), and TP53 (3/12 AMLs). Mutations in IKZF1, a gene located on chromosome 7, and monosomy 7 are mutually exclusive in this disease. Moreover IKZF1 expression is halved in monosomy 7 leukemias. EVI-r AMLs are also characterized by a unique transcriptional signature with high expression levels of MECOM, PREX2, VIP, MYCT1, and PAWR. Our results suggest that EVI1-r AMLs could be molecularly defined by specific transcriptomic anomalies and a hitherto unseen mutational pattern. Larger patient cohorts will better determine the frequency of these events.


Asunto(s)
Proteínas de Unión al ADN/genética , Regulación Leucémica de la Expresión Génica , Leucemia Mieloide Aguda/genética , Mutación , Proto-Oncogenes/genética , Factores de Transcripción/genética , Proteínas Reguladoras de la Apoptosis/genética , Cromosomas Humanos Par 7/genética , Perfilación de la Expresión Génica , Factores de Intercambio de Guanina Nucleótido/genética , Humanos , Factor de Transcripción Ikaros/genética , Proteína del Locus del Complejo MDS1 y EV11 , Proteínas Nucleares/genética , Transducción de Señal , Transcriptoma , Proteína p53 Supresora de Tumor/genética , Péptido Intestinal Vasoactivo/genética
13.
Int J Mol Sci ; 17(10)2016 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-27754465

RESUMEN

Glycosphingolipids (GSLs) are a class of ceramide-based glycolipids essential for embryo development in mammals. The synthesis of specific GSLs depends on the expression of distinctive sets of GSL synthesizing enzymes that is tightly regulated during development. Several reports have described how cell surface receptors can be kept in a resting state or activate alternative signalling events as a consequence of their interaction with GSLs. Specific GSLs, indeed, interface with specific protein domains that are found in signalling molecules and which act as GSL sensors to modify signalling responses. The regulation exerted by GSLs on signal transduction is orthogonal to the ligand-receptor axis, as it usually does not directly interfere with the ligand binding to receptors. Due to their properties of adjustable production and orthogonal action on receptors, GSLs add a new dimension to the control of the signalling in development. GSLs can, indeed, dynamically influence progenitor cell response to morphogenetic stimuli, resulting in alternative differentiation fates. Here, we review the available literature on GSL-protein interactions and their effects on cell signalling and development.


Asunto(s)
Glicoesfingolípidos/metabolismo , Receptores de Superficie Celular/metabolismo , Transducción de Señal/fisiología , Animales , Diferenciación Celular/fisiología , Gangliósidos/metabolismo , Mamíferos/embriología , Mamíferos/metabolismo , Unión Proteica
14.
Genome Res ; 22(6): 1163-72, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22345618

RESUMEN

MicroRNAs (miRNAs) and transcription factors control eukaryotic cell proliferation, differentiation, and metabolism through their specific gene regulatory networks. However, differently from transcription factors, our understanding of the processes regulated by miRNAs is currently limited. Here, we introduce gene network analysis as a new means for gaining insight into miRNA biology. A systematic analysis of all human miRNAs based on Co-expression Meta-analysis of miRNA Targets (CoMeTa) assigns high-resolution biological functions to miRNAs and provides a comprehensive, genome-scale analysis of human miRNA regulatory networks. Moreover, gene cotargeting analyses show that miRNAs synergistically regulate cohorts of genes that participate in similar processes. We experimentally validate the CoMeTa procedure through focusing on three poorly characterized miRNAs, miR-519d/190/340, which CoMeTa predicts to be associated with the TGFß pathway. Using lung adenocarcinoma A549 cells as a model system, we show that miR-519d and miR-190 inhibit, while miR-340 enhances TGFß signaling and its effects on cell proliferation, morphology, and scattering. Based on these findings, we formalize and propose co-expression analysis as a general paradigm for second-generation procedures to recognize bona fide targets and infer biological roles and network communities of miRNAs.


Asunto(s)
Redes Reguladoras de Genes , Genómica/métodos , MicroARNs/genética , Genoma Humano , Humanos , Transducción de Señal/genética , Factor de Crecimiento Transformador beta/metabolismo
15.
Curr Opin Cell Biol ; 20(4): 360-70, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18490149

RESUMEN

Compartmentalization is a defining feature of eukaryotic cells that allows the spatial segregation of different functions, such as protein and lipid synthesis, and ensures their fidelity and efficiency. This imposes the need for an intense flux of metabolic intermediates between segregated enzymatic activities, as seen for the sequential transport of neosynthesized proteins through the segments of the secretory pathway during their post-translational modification. For lipid synthesis, the identification of proteins that transfer lipids between membranes has revealed an additional mechanism for this intercompartment exchange. The intense interest elicited by the lipid-transfer proteins over the last few years has led to the definition of their central role in key processes, such as lipid metabolism, membrane trafficking, and signaling.


Asunto(s)
Vías Biosintéticas , Proteínas Portadoras/fisiología , Membranas Intracelulares/metabolismo , Metabolismo de los Lípidos , Animales , Transporte Biológico , Humanos , Transducción de Señal
16.
Bioessays ; 35(7): 612-22, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23712958

RESUMEN

Initially identified as a key phosphoinositide that controls membrane trafficking at the Golgi complex, phosphatidylinositol-4-phosphate (PI4P) has emerged as a key molecule in the regulation of a diverse array of cellular functions. In this review we will discuss selected examples of the findings that in the last few years have significantly increased our awareness of the regulation and roles of PI4P in the Golgi complex and beyond. We will also highlight the role of PI4P in infection and cancer. We believe that, with the increasing number of regulators and effectors of PI4P identified, the time is ripe for a more integrated approach of study. A first step in this direction is the delineation of PI4P-centered molecular networks that we provide using data from low and high throughput studies in yeast and mammals.


Asunto(s)
Aparato de Golgi/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Animales , Línea Celular Tumoral , Humanos , Mamíferos/genética , Mamíferos/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Transducción de Señal
17.
J Med Chem ; 67(8): 6052-6063, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38592948

RESUMEN

Akt kinase is vital in cell growth, survival, metabolism, and migration. Dysregulation of Akt signaling is implicated in cancer and metabolic disorders. In the context of cancer, overactive Akt promotes cell survival and proliferation. This has spurred extensive research into developing Akt inhibitors as potential therapeutic agents to disrupt aberrant Akt signaling. Akt inhibitors are classified into three main types: ATP-competitive, allosteric, and covalent-allosteric inhibitors (CAAIs). ATP-competitive inhibitors compete with ATP for binding to Akt, allosteric inhibitors interact with the Pleckstrin homology (PH) domain, and covalent-allosteric inhibitors form covalent bonds, making them more potent and selective. Notably, capivasertib (AZD5363), a potent ATP-competitive Akt inhibitor, received FDA approval in November 2023 for use in combination with the estrogen receptor degrader fulvestrant to treat breast cancer. Challenges remain, including improving selectivity, identifying biomarkers to tailor treatments, and enhancing therapeutic efficacy while minimizing adverse effects. Particularly covalent-allosteric inhibitors hold promise for future more effective and personalized treatments.


Asunto(s)
Inhibidores de Proteínas Quinasas , Proteínas Proto-Oncogénicas c-akt , Pirimidinas , Humanos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Pirimidinas/uso terapéutico , Regulación Alostérica/efectos de los fármacos , Aprobación de Drogas , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Pirroles/química , Pirroles/farmacología , Pirroles/síntesis química , Animales
18.
iScience ; 27(9): 110820, 2024 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-39297163

RESUMEN

Besides its beneficial effect on weight loss, gastric bypass surgery (GBS) may impact the circulating levels of phospho- and sphingolipids. However, long-term effects have not been explored. To investigate alterations in lipidomic signatures associated with massive weight loss following GBS, we conducted direct infusion tandem mass spectrometry on serum and subcutaneous adipose tissue (SAT) samples collected in a longitudinal cohort of morbid obese patients prior to GBS and 1 year following the surgery. A tissue-specific rearrangement of 13% among over 400 phospholipid and sphingolipid species quantified in serum and SAT was observed 1 year following GBS, with a substantial reduction of ceramide levels and increased amount of hexosylceramides detected in both tissues. The comparison of these new lipidomic profiles with the serum and SAT lipidomes established from an independent cohort of lean and morbid obese subjects revealed that GBS partly restored the lipid alterations associated with morbid obesity.

19.
Biochim Biophys Acta ; 1821(8): 1089-95, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22266015

RESUMEN

Next to the protein-based machineries composed of small G-proteins, coat complexes, SNAREs and tethering factors, the lipid-based machineries are emerging as important players in membrane trafficking. As a component of these machineries, lipid transfer proteins have recently attracted the attention of cell biologists for their involvement in trafficking along different segments of the secretory pathway. Among these, the four-phosphate adaptor protein 2 (FAPP2) was discovered as a protein that localizes dynamically with the trans-Golgi network and regulates the transport of proteins from the Golgi complex to the cell surface. Later studies have highlighted a role for FAPP2 as lipid transfer protein involved in glycosphingolipid metabolism at the Golgi complex. Here we discuss the available evidence on the function of FAPP2 in both membrane trafficking and lipid metabolism and propose a mechanism of action of FAPP2 that integrates its activities in membrane trafficking and in lipid transfer. This article is part of a Special Issue entitled Lipids and Vesicular Transport.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Glicoesfingolípidos/metabolismo , Lípidos/biosíntesis , Vesículas Transportadoras/metabolismo , Red trans-Golgi/metabolismo , Proteínas Adaptadoras Transductoras de Señales/química , Proteínas Adaptadoras Transductoras de Señales/genética , Secuencia de Aminoácidos , Animales , Transporte Biológico , Membrana Celular/metabolismo , Expresión Génica , Humanos , Metabolismo de los Lípidos , Datos de Secuencia Molecular , Estructura Terciaria de Proteína , Alineación de Secuencia
20.
Nature ; 449(7158): 62-7, 2007 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-17687330

RESUMEN

The molecular machinery responsible for the generation of transport carriers moving from the Golgi complex to the plasma membrane relies on a tight interplay between proteins and lipids. Among the lipid-binding proteins of this machinery, we previously identified the four-phosphate adaptor protein FAPP2, the pleckstrin homology domain of which binds phosphatidylinositol 4-phosphate and the small GTPase ARF1. FAPP2 also possesses a glycolipid-transfer-protein homology domain. Here we show that human FAPP2 is a glucosylceramide-transfer protein that has a pivotal role in the synthesis of complex glycosphingolipids, key structural and signalling components of the plasma membrane. The requirement for FAPP2 makes the whole glycosphingolipid synthetic pathway sensitive to regulation by phosphatidylinositol 4-phosphate and ARF1. Thus, by coupling the synthesis of glycosphingolipids with their export to the cell surface, FAPP2 emerges as crucial in determining the lipid identity and composition of the plasma membrane.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Glucosilceramidas/metabolismo , Glicoesfingolípidos/biosíntesis , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Transporte Biológico , Línea Celular , Membrana Celular/química , Membrana Celular/metabolismo , Ceramidas/metabolismo , Humanos , Modelos Biológicos , Fosfatos de Fosfatidilinositol/metabolismo , Esfingosina/metabolismo , Red trans-Golgi/metabolismo
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