RESUMEN
This study used a marsupial Monodelphis domestica, which is born very immature and most of its development is postnatal without placental protection. RNA-sequencing (RNA-Seq) was used to identify the expression of influx and efflux transporters (ATP-binding cassettes [ABCs] and solute carriers [SLCs]) and metabolizing enzymes in brains of newborn to juvenile Monodelphis. Results were compared to published data in the developing eutherian rat. To test the functionality of these transporters at similar ages, the entry of paracetamol (acetaminophen) into the brain and cerebrospinal fluid (CSF) was measured using liquid scintillation counting following a single administration of the drug along with its radiolabelled tracer [3H]. Drug permeability studies found that in Monodelphis, brain entry of paracetamol was already restricted at P5; it decreased further in the first week of life and then remained stable until the oldest age group tested (P110). Transcriptomic analysis of Monodelphis brain showed that expression of transporters and their metabolizing enzymes in early postnatal (P) pups (P0, P5, and P8) was relatively similar, but by P109, many more transcripts were identified. When transcriptomes of newborn Monodelphis brain and E19 rat brain and placenta were compared, several transporters present in the rat placenta were also found in the newborn Monodelphis brain. These were absent from E19 rat brain but were present in the adult rat brain. These data indicate that despite its extreme immaturity, the newborn Monodelphis brain may compensate for the lack of placental protection during early brain development by upregulating protective mechanisms, which in eutherian animals are instead present in the placenta.
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Transportadoras de Casetes de Unión a ATP , Encéfalo , Monodelphis , Animales , Encéfalo/metabolismo , Encéfalo/crecimiento & desarrollo , Monodelphis/crecimiento & desarrollo , Transportadoras de Casetes de Unión a ATP/metabolismo , Transportadoras de Casetes de Unión a ATP/genética , Animales Recién Nacidos , Acetaminofén , Proteínas Transportadoras de Solutos/metabolismo , Femenino , RatasRESUMEN
Rheumatoid arthritis (RA) is a complex autoimmune disease that leads to joint destruction. A number of immune cells that affect joint tissues are involved in the pathogenesis of this disease. This leads to the synthesis of many pro-inflammatory mediators. The transport of drugs, as well as many cytokines involved in the development of inflammation in RA patients, is mediated by membrane transporters. Membrane transporters are proteins that mediate the transfer of substrates across biological membranes. But to date there are no studies examining the expression of solute carrier (SLC) transporters in joint tissues. The aim of the study was to evaluate the expression of individual SLC family transporters in the synovial membranes (SMs) and infrapatellar fat pad (Hoffa's pad) of RA patients. The study included 20 patients with rheumatoid arthritis and 20 with osteoarthritis as the control group who were undergoing joint replacement surgery as a normal part of clinical care. In the SM and Hoffa's pad of RA patients the following 17 membrane transporters were defined at relevant expression levels for SLC transporter superfamily: SLC15A2, SLC16A3, SLC19A1, SLC2A9, SLC22A1, SLC22A3, SLC22A4, SLC22A5, SLC22A18, SLC33A1, SLC47A1, SLC51A, SLC7A5, SLC7A6, SLC01C1, SLC02B1, SLC04A1. The confirmed expression of these transporters in the SMs as well as Hoffa's pad of patients with RA and OA, and the differences in their expression between these groups, suggests the involvement of SLC transporters in both the maintenance of homeostasis under physiological conditions in the tissues of the joints, as well as in the inflammatory process in RA.
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Artritis Reumatoide , Proteínas Transportadoras de Solutos , Membrana Sinovial , Humanos , Artritis Reumatoide/metabolismo , Artritis Reumatoide/inmunología , Femenino , Membrana Sinovial/metabolismo , Membrana Sinovial/inmunología , Persona de Mediana Edad , Proteínas Transportadoras de Solutos/metabolismo , Masculino , Anciano , Tejido Adiposo/metabolismo , Adulto , Proteínas de Transporte de Membrana/metabolismo , Transporte Biológico , Osteoartritis/metabolismoRESUMEN
Transporters of the solute carrier superfamily (SLCs) are responsible for the transmembrane traffic of the majority of chemical substances in cells and tissues and are therefore of fundamental biological importance. As is often the case with membrane proteins that can be heavily glycosylated, a lack of reliable high-affinity binders hinders their functional analysis. Purifying and reconstituting transmembrane proteins in their lipidic environments remains challenging and standard approaches to generate binders for multi-transmembrane proteins, such as SLCs, channels or G protein-coupled receptors (GPCRs) are lacking. While generating protein binders to 27 SLCs, we produced full length protein or cell lines as input material for binder generation by selected binder generation platforms. As a result, we obtained 525 binders for 22 SLCs. We validated the binders with a cell-based validation workflow using immunofluorescent and immunoprecipitation methods to process all obtained binders. Finally, we demonstrated the potential applications of the binders that passed our validation pipeline in structural, biochemical, and biological applications using the exemplary protein SLC12A6, an ion transporter relevant in human disease. With this work, we were able to generate easily renewable and highly specific binders against SLCs, which will greatly facilitate the study of this neglected protein family. We hope that the process will serve as blueprint for the generation of binders against the entire superfamily of SLC transporters.
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Unión Proteica , Proteínas Transportadoras de Solutos , Humanos , Proteínas Transportadoras de Solutos/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/química , Células HEK293RESUMEN
BACKGROUND: Solute carrier (SLC) transporters, a diverse family of membrane proteins, are instrumental in orchestrating the intake and efflux of nutrients including amino acids, vitamins, ions, nutrients, etc, across cell membranes. This dynamic process is critical for sustaining the metabolic demands of cancer cells, promoting their survival, proliferation, and adaptation to the tumor microenvironment (TME). Amino acids are fundamental building blocks of cells and play essential roles in protein synthesis, nutrient sensing, and oncogenic signaling pathways. As key transporters of amino acids, SLCs have emerged as crucial players in maintaining cellular amino acid homeostasis, and their dysregulation is implicated in various cancer types. Thus, understanding the intricate connections between amino acids, SLCs, and cancer is pivotal for unraveling novel therapeutic targets and strategies. SCOPE OF REVIEW: In this review, we delve into the significant impact of amino acid carriers of the SLCs family on the growth and progression of cancer and explore the current state of knowledge in this field, shedding light on the molecular mechanisms that underlie these relationships and highlighting potential avenues for future research and clinical interventions. MAJOR CONCLUSIONS: Amino acids transportation by SLCs plays a critical role in tumor progression. However, some studies revealed the tumor suppressor function of SLCs. Although several studies evaluated the function of SLC7A11 and SLC1A5, the role of some SLC proteins in cancer is not studied well. To exert their functions, SLCs mediate metabolic rewiring, regulate the maintenance of redox balance, affect main oncogenic pathways, regulate amino acids bioavailability within the TME, and alter the sensitivity of cancer cells to therapeutics. However, different therapeutic methods that prevent the function of SLCs were able to inhibit tumor progression. This comprehensive review provides insights into a rapidly evolving area of cancer biology by focusing on amino acids and their transporters within the SLC superfamily.
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Sistemas de Transporte de Aminoácidos , Aminoácidos , Neoplasias , Humanos , Neoplasias/metabolismo , Sistemas de Transporte de Aminoácidos/metabolismo , Sistemas de Transporte de Aminoácidos/genética , Aminoácidos/metabolismo , Animales , Microambiente Tumoral , Proteínas Transportadoras de Solutos/metabolismo , Proteínas Transportadoras de Solutos/genéticaRESUMEN
Glioma is the most prevalent malignant brain tumour. Currently, reshaping its tumour microenvironment has emerged as an appealing strategy to enhance therapeutic efficacy. As the largest group of transmembrane transport proteins, solute carrier proteins (SLCs) are responsible for the transmembrane transport of various metabolites and ions. They play a crucial role in regulating the metabolism and functions of malignant cells and immune cells within the tumour microenvironment, making them a promising target in cancer therapy. Through multidimensional data analysis and experimental validation, we investigated the genetic landscape of SLCs in glioma. We established a classification system comprising 7-SLCs to predict the prognosis of glioma patients and their potential responses to immunotherapy and chemotherapy. Our findings unveiled specific SLC expression patterns and their correlation with the immune-suppressive microenvironment and metabolic status. The 7-SLC classification system was validated in distinguishing subgroups within the microenvironment, specifically identifying subsets involving malignant cells and tumour-associated macrophages. Furthermore, the orphan protein SLC43A3, a core member of the 7-SLC classification system, was identified as a key facilitator of tumour cell proliferation and migration, suggesting its potential as a novel target for cancer therapy.
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Neoplasias Encefálicas , Regulación Neoplásica de la Expresión Génica , Glioma , Proteínas Transportadoras de Solutos , Microambiente Tumoral , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Humanos , Glioma/genética , Glioma/inmunología , Glioma/patología , Glioma/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/inmunología , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/metabolismo , Proteínas Transportadoras de Solutos/genética , Proteínas Transportadoras de Solutos/metabolismo , Pronóstico , Proliferación Celular/genética , Perfilación de la Expresión Génica , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , MultiómicaRESUMEN
Transporting small molecules across cell membranes is an essential process in cell physiology. Many structurally diverse, secondary active transporters harness transmembrane electrochemical gradients of ions to power the uptake or efflux of nutrients, signalling molecules, drugs and other ions across cell membranes. Transporters reside in lipid bilayers on the interface between two aqueous compartments, where they are energized and regulated by symported, antiported and allosteric ions on both sides of the membrane and the membrane bilayer itself. Here we outline the mechanisms by which transporters couple ion and solute fluxes and discuss how structural and mechanistic variations enable them to meet specific physiological needs and adapt to environmental conditions. We then consider how general bilayer properties and specific lipid binding modulate transporter activity. Together, ion gradients and lipid properties ensure the effective transport, regulation and distribution of small molecules across cell membranes.
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Transporte Biológico Activo , Iones , Membrana Dobles de Lípidos , Lípidos , Proteínas de Transporte de Membrana , Transporte Iónico , Iones/metabolismo , Membrana Dobles de Lípidos/química , Membrana Dobles de Lípidos/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Proteínas Transportadoras de Solutos/metabolismoRESUMEN
Dendritic cells (DCs) are specialized antigen-presenting cells that initiate and regulate innate and adaptive immune responses. Solute carrier (SLC) transporters mediate diverse physiological functions and maintain cellular metabolite homeostasis. Recent studies have highlighted the significance of SLCs in immune processes. Notably, upon activation, immune cells undergo rapid and robust metabolic reprogramming, largely dependent on SLCs to modulate diverse immunological responses. In this review, we explore the central roles of SLC proteins and their transported substrates in shaping DC functions. We provide a comprehensive overview of recent studies on amino acid transporters, metal ion transporters, and glucose transporters, emphasizing their essential contributions to DC homeostasis under varying pathological conditions. Finally, we propose potential strategies for targeting SLCs in DCs to bolster immunotherapy for a spectrum of human diseases.
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Proteínas de Transporte de Membrana , Proteínas Transportadoras de Solutos , Humanos , Proteínas de Transporte de Membrana/metabolismo , Proteínas Transportadoras de Solutos/química , Proteínas Transportadoras de Solutos/metabolismo , Diferenciación Celular , Células DendríticasRESUMEN
By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only the uptake and efflux of nutrients, but also the metabolic state of the cell. With more than 450 members, the Solute Carriers (SLCs) are the largest transporter super-family, clustering into families with different substrate specificities and regulatory properties. Cells of different types are, therefore, able to tailor their transporter expression signatures depending on their metabolic requirements, and the physiological importance of these proteins is illustrated by their mis-regulation in a number of disease states. In cancer, transporter expression is heterogeneous, and the SLC family has been shown to facilitate the accumulation of biomass, influence redox homeostasis, and also mediate metabolic crosstalk with other cell types within the tumour microenvironment. This Review explores the roles of membrane transporters in physiological and malignant settings, and how these roles can affect drug response, through either indirect modulation of sensitivity or the direct transport of small-molecule therapeutic compounds into cells.
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Proteínas de Transporte de Membrana , Neoplasias , Humanos , Proteínas de Transporte de Membrana/metabolismo , Proteínas Transportadoras de Solutos/química , Proteínas Transportadoras de Solutos/metabolismo , Transporte Biológico/fisiología , Neoplasias/tratamiento farmacológico , Fenómenos Fisiológicos Celulares , Microambiente TumoralRESUMEN
Solute carriers (SLCs) are membrane transporters that import and export a range of endogenous and exogenous substrates, including ions, nutrients, metabolites, neurotransmitters, and pharmaceuticals. Despite having emerged as attractive therapeutic targets and markers of disease, this group of proteins is still relatively underdrugged by current pharmaceuticals. Drug discovery projects for these transporters are impeded by limited structural, functional, and physiological knowledge, ultimately due to the difficulties in the expression and purification of this class of membrane-embedded proteins. Here, we demonstrate methods to obtain high-purity, milligram quantities of human SLC transporter proteins using codon-optimized gene sequences. In conjunction with a systematic exploration of construct design and high-throughput expression, these protocols ensure the preservation of the structural integrity and biochemical activity of the target proteins. We also highlight critical steps in the eukaryotic cell expression, affinity purification, and size-exclusion chromatography of these proteins. Ultimately, this workflow yields pure, functionally active, and stable protein preparations suitable for high-resolution structure determination, transport studies, small-molecule engagement assays, and high-throughput in vitro screening.
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Proteínas de Transporte de Membrana , Proteínas Transportadoras de Solutos , Humanos , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Proteínas Transportadoras de Solutos/química , Proteínas Transportadoras de Solutos/metabolismo , Descubrimiento de Drogas/métodos , Ensayos Analíticos de Alto Rendimiento , Proteínas de la Membrana/metabolismo , Preparaciones FarmacéuticasRESUMEN
Environmental health science seeks to predict how environmental toxins, chemical toxicants, and prescription drugs accumulate and interact within the body. Xenobiotic transporters of the ATP-binding cassette (ABC) and solute carrier (SLC) superfamilies are major determinants of the uptake and disposition of xenobiotics across the kingdoms of life. The goal of this study was to integrate drug and environmental chemical interactions of mammalian ABC and SLC proteins in a centralized, integrative database. We built upon an existing publicly accessible platform-the "TransPortal"-which was updated with novel data and searchable features on transporter-interfering chemicals from manually curated literature data. The integrated resource TransPortal-TICBase (https://transportal.compbio.ucsf.edu) now contains information on 46 different mammalian xenobiotic transporters of the ABC- and SLC-type superfamilies, including 13 newly added rodent and 2 additional human drug transporters, 126 clinical drug-drug interactions, and a more than quadrupled expansion of the initial in vitro chemical interaction data from 1,402 to 6,296 total interactions. Based on our updated database, environmental interference with major human and rodent drug transporters occurs across the ABC- and SLC-type superfamilies, with kinetics indicating that some chemicals, such as the ionic liquid 1-hexylpyridinium chloride and the antiseptic chlorhexidine, can act as strong inhibitors with potencies similar or even higher than pharmacological model inhibitors. The new integrated web portal serves as a central repository of current and emerging data for interactions of prescription drugs and environmental chemicals with human drug transporters. This archive has important implications for predicting adverse drug-drug and drug-environmental chemical interactions and can serve as a reference website for the broader scientific community of clinicians and researchers.
Asunto(s)
Proteínas de Transporte de Membrana , Xenobióticos , Animales , Humanos , Proteínas de Transporte de Membrana/metabolismo , Transporte Biológico , Interacciones Farmacológicas , Proteínas Transportadoras de Solutos/metabolismo , Mamíferos/metabolismoRESUMEN
Solute carrier (SLCs) transporters mediate the transport of a broad range of solutes across biological membranes. Dysregulation of SLCs has been associated with various pathologies, including metabolic and neurological disorders, as well as cancer and rare diseases. SLCs are therefore emerging as key targets for therapeutic intervention with several recently approved drugs targeting these proteins. Unlocking this large and complex group of proteins is essential to identifying unknown SLC targets and developing next-generation SLC therapeutics. Recent progress in experimental and computational techniques has significantly advanced SLC research, including drug discovery. Here, we review emerging topics in therapeutic discovery of SLCs, focusing on state-of-the-art approaches in structural, chemical, and computational biology, and discuss current challenges in transporter drug discovery.
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Neoplasias , Proteínas Transportadoras de Solutos , Humanos , Proteínas Transportadoras de Solutos/química , Proteínas Transportadoras de Solutos/metabolismo , Proteínas de Transporte de Membrana/química , Transporte Biológico/fisiología , Descubrimiento de Drogas/métodos , Neoplasias/metabolismoRESUMEN
Solute carriers (SLCs) are essential for brain physiology and homeostasis due to their role in transporting necessary substances across cell membranes. There is an increasing need to further unravel their pathophysiological implications since they have been proposed to play a pivotal role in brain tumor development, progression, and the formation of the tumor microenvironment (TME) through the upregulation and downregulation of various amino acid transporters. Due to their implication in malignancy and tumor progression, SLCs are currently positioned at the center of novel pharmacological targeting strategies and drug development. In this review, we discuss the key structural and functional characteristics of the main SLC family members involved in glioma pathogenesis, along with their potential targeting options to provide new opportunities for CNS drug design and more effective glioma management.
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Glioma , Proteínas Transportadoras de Solutos , Humanos , Proteínas Transportadoras de Solutos/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Transporte Biológico , Diseño de Fármacos , Microambiente TumoralRESUMEN
Transmembrane transport of small organic and inorganic molecules is one of the cornerstones of cellular metabolism. Among transmembrane transporters, solute carrier (SLC) proteins form the largest, albeit very diverse, superfamily with over 400 members. It was recognized early on that xenobiotics can directly interact with SLCs and that this interaction can fundamentally determine their efficacy, including bioavailability and intertissue distribution. Apart from the well-established prodrug strategy, the chemical ligation of transporter substrates to nanoparticles of various chemical compositions has recently been used as a means to enhance their targeting and absorption. In this review, we summarize efforts in drug design exploiting interactions with specific SLC transporters to optimize their therapeutic effects. Furthermore, we describe current and future challenges as well as new directions for the advanced development of therapeutics that target SLC transporters.
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Proteínas de Transporte de Membrana , Profármacos , Proteínas de Transporte de Membrana/metabolismo , Transporte Biológico , Proteínas Transportadoras de Solutos/metabolismo , Sistemas de Liberación de MedicamentosRESUMEN
Cell death, survival, or growth decisions in T-cell subsets depend on interplay between cytokine-dependent and metabolic processes. The metabolic requirements of T-regulatory cells (Tregs) for their survival and how these are satisfied remain unclear. Herein, we identified a necessary requirement of methionine uptake and usage for Tregs survival upon IL-2 deprivation. Activated Tregs have high methionine uptake and usage to S-adenosyl methionine, and this uptake is essential for Tregs survival in conditions of IL-2 deprivation. We identify a solute carrier protein SLC43A2 transporter, regulated in a Notch1-dependent manner that is necessary for this methionine uptake and Tregs viability. Collectively, we uncover a specifically regulated mechanism of methionine import in Tregs that is required for cells to adapt to cytokine withdrawal. We highlight the need for methionine availability and metabolism in contextually regulating cell death in this immunosuppressive population of T cells.
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Metionina , Linfocitos T Reguladores , Linfocitos T Reguladores/metabolismo , Metionina/metabolismo , Interleucina-2/metabolismo , Racemetionina/metabolismo , Proteínas Transportadoras de Solutos/metabolismoRESUMEN
The solute carrier (SLC) superfamily is the largest group of proteins responsible for the transmembrane transport of substances in human cells. It includes more than 400 members that are organized into 65 families according to their physiological function and sequence similarity. Different families of SLCs can adopt the same or different folds that determine the mechanism and reflect the evolutionary relationship between SLC members. Analysis of structural data in the literature before this work showed 13 different folds in the SLC superfamily covering 40 families and 343 members. To further study their mechanism, we systematically explored the SLC superfamily to look for more folds. Based on our results, at least three new folds are found for the SLC superfamily, one of which is in the choline-like transporter family (SLC44) and has been experimentally verified. Our work has laid a foundation and provided important insights for the systematic and comprehensive study of the structure and function of SLC.
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Proteínas de Transporte de Membrana , Proteínas Transportadoras de Solutos , Transporte Biológico , Humanos , Proteínas de Transporte de Membrana/metabolismo , Proteínas Transportadoras de Solutos/metabolismoRESUMEN
Solute carrier transporters (SLCs) limit receptor activation via uptake of extracellular ligands. Novel concepts are emerging that describe the modulation of intracellular and plasma membrane receptors by ligand influx and efflux via SLCs, respectively. Here, we evaluate recent insights and provide an outlook for developing potential therapeutic strategies.
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Proteínas de Transporte de Membrana , Proteínas Transportadoras de Solutos , Transporte Biológico , Membrana Celular/metabolismo , Humanos , Ligandos , Proteínas de Transporte de Membrana/metabolismo , Proteínas Transportadoras de Solutos/metabolismoRESUMEN
Background: The most commonly preferred chemotherapeutic agents to treat cancers are small-molecule drugs. However, the differential sensitivity of various cancer cells to small molecules and untargeted delivery narrow the range of potential therapeutic applications. The mechanisms responsible for drug resistance in a variety of cancer cells are also largely unknown. Several deubiquitinating enzymes (DUBs) are the main determinants of drug resistance in cancer cells. Methods: We used CRISPR-Cas9 to perform genome-scale knockout of the entire set of genes encoding ubiquitin-specific proteases (USPs) and systematically screened for DUBs resistant to the clinically evaluated anticancer compound YM155. A series of in vitro and in vivo experiments were conducted to reveal the relationship between USP32 and SLC35F2 on YM155-mediated DNA damage in cancer cells. Results: CRISPR-based dual-screening method identified USP32 as a novel DUB that governs resistance for uptake of YM155 by destabilizing protein levels of SLC35F2, a solute-carrier protein essential for the uptake of YM155. The expression of USP32 and SLC35F2 was negatively correlated across a panel of tested cancer cell lines. YM155-resistant cancer cells in particular exhibited elevated expression of USP32 and low expression of SLC35F2. Conclusion: Collectively, our DUB-screening strategy revealed a resistance mechanism governed by USP32 associated with YM155 resistance in breast cancers, one that presents an attractive molecular target for anti-cancer therapies. Targeted genome knockout verified that USP32 is the main determinant of SLC35F2 protein stability in vitro and in vivo, suggesting a novel way to treat tumors resistant to small-molecule drugs.
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Imidazoles/farmacología , Proteínas de Transporte de Membrana/metabolismo , Naftoquinonas/farmacología , Ubiquitina Tiolesterasa/metabolismo , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Daño del ADN , Enzimas Desubicuitinizantes/genética , Enzimas Desubicuitinizantes/metabolismo , Enzimas Desubicuitinizantes/farmacología , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/fisiología , Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Imidazoles/metabolismo , Proteínas Inhibidoras de la Apoptosis/metabolismo , Proteínas de Transporte de Membrana/genética , Naftoquinonas/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Proteínas Transportadoras de Solutos/metabolismo , Ubiquitina Tiolesterasa/genética , Proteasas Ubiquitina-Específicas/genética , Proteasas Ubiquitina-Específicas/metabolismoRESUMEN
Metformin (MET), the most common medicine for type 2 diabetes (T2DM), improves insulin sensitivity by targeting the liver, intestine and other organs. Its impact on expression of the solute carrier (Slc) transporter genes have not been reported in the mechanism of insulin sensitization. In this study, we examined Slc gene expression in the liver and colon of diet-induced obese (DIO) mice treated with MET by transcriptomic analysis. There were 939 differentially expressed genes (DEGs) in the liver of DIO mice vs lean mice, which included 34 Slc genes. MET altered 489 DEGs in the liver of DIO mice, in which 23 were Slc genes. Expression of 20 MET-responsive Slc DEGs was confirmed by qRT-PCR, in which 15 Slc genes were altered in DIO mice and their expressions were restored by MET, including Slc2a10, Slc2a13, Slc5a9, Slc6a14, Slc7a9, Slc9a2, Slc9a3, Slc13a2, Slc15a2, Slc26a3, Slc34a2, Slc37a1, Slc44a4, Slc51b and Slc52a3. While, there were only 97 DEGs in the colon of DIO mice with 5 Slc genes, whose expression was not restored by MET. The data suggest that more genes were altered in the liver over the colon by the high fat diet (HFD). There were 20 Slc genes with alteration confirmed in the liver of DIO mice and 15 of them were restored by MET, which was associated with improvement of insulin sensitivity and obesity. The restoration may improve the uptake of glucose, amino acids, mannose, fructose, 1,5-anhydro-D-glucitol and bumetanide in hepatocytes of the liver of DIO mice. The study provides new insight into the mechanism of metformin action in insulin sensitization and obesity.
Asunto(s)
Hígado/efectos de los fármacos , Metformina/farmacología , Obesidad , Proteínas Transportadoras de Solutos/genética , Animales , Dieta Alta en Grasa , Regulación de la Expresión Génica/efectos de los fármacos , Glucosa/metabolismo , Prueba de Tolerancia a la Glucosa , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Hepatocitos/patología , Resistencia a la Insulina/genética , Hígado/metabolismo , Hígado/patología , Masculino , Metformina/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/tratamiento farmacológico , Obesidad/genética , Obesidad/metabolismo , Obesidad/patología , ARN Mensajero/metabolismo , Proteínas Transportadoras de Solutos/efectos de los fármacos , Proteínas Transportadoras de Solutos/metabolismoRESUMEN
Nutrient supply and demand delineate cell behavior in health and disease. Mammalian cells have developed multiple strategies to secure the necessary nutrients that fuel their metabolic needs. This is more evident upon disruption of homeostasis in conditions such as cancer, when cells display high proliferation rates in energetically challenging conditions where nutritional sources may be scarce. Here, we summarize the main routes of nutrient acquisition that fuel mammalian cells and their implications in tumorigenesis. We argue that the molecular mechanisms of nutrient acquisition not only tip the balance between nutrient supply and demand but also determine cell behavior upon nutrient limitation and energetic stress and contribute to nutrient partitioning and metabolic coordination between different cell types in inflamed or tumorigenic environments.
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Proteínas de Transporte de Membrana/metabolismo , Neoplasias/metabolismo , Nutrientes/metabolismo , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Transporte Biológico/fisiología , Carcinogénesis/metabolismo , Membrana Celular/metabolismo , Homeostasis/fisiología , Humanos , Proteínas Transportadoras de Solutos/metabolismoRESUMEN
Mitochondrial, autophagic impairment, excitotoxicity, and also neuroinflammation are implicated in Alzheimer's disease (AD) pathophysiology. We postulated that inhibiting the mitochondrial pyruvate carrier-1 (MPC-1), which inhibits the activation of the mammalian target of rapamycin (mTOR), may ameliorate the neurodegeneration of hippocampal neurons in the rat AD model. To assess this, we used lapatinib ditosylate (LAP), an anti-cancer drug that inhibits MPC-1 through suppression of estrogen-related receptor-alpha (ERR-α), in D-galactose/ovariectomized rats. AD characteristics were developed in ovariectomized (OVX) rats following an 8-week injection of D-galactose (D-gal) (150 mg/kg, i.p.). The human epidermal growth factor receptor-2 (HER-2) inhibitor, LAP (100 mg/kg, p.o.) was daily administered for 3 weeks. LAP protected against D-gal/OVX-induced changes in cortical and hippocampal neurons along with improvement in learning and memory, as affirmed using Morris water maze (MWM) and novel object recognition (NOR) tests. Furthermore, LAP suppressed the hippocampal expression of Aß1-42, p-tau, HER-2, p-mTOR, GluR-II, TNF-α, P38-MAPK, NOX-1, ERR-α, and MPC-1. Also, LAP treatment leads to activation of the pro-survival PI3K/Akt pathway. As an epilogue, targeting MPC-1 in the D-gal-induced AD in OVX rats resulted in the enhancement of autophagy, and suppression of neuroinflammation and excitotoxicity. Our work proves that alterations in metabolic signaling as a result of inhibiting MPC-1 were anti-inflammatory and neuroprotective in the AD model, revealing that HER-2, MPC-1, and ERR-α may be promising therapeutic targets for AD.