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1
Hilgemann, Donald W., Gucan Dai, Anthony Collins, Vincenzo Larricia, Simona Magi, Christine Deisl e Michael Fine. "Lipid signaling to membrane proteins: From second messengers to membrane domains and adapter-free endocytosis". Journal of General Physiology 150, n. 2 (11 gennaio 2018): 211–24. http://dx.doi.org/10.1085/jgp.201711875.
Abstract (sommario):
Lipids influence powerfully the function of ion channels and transporters in two well-documented ways. A few lipids act as bona fide second messengers by binding to specific sites that control channel and transporter gating. Other lipids act nonspecifically by modifying the physical environment of channels and transporters, in particular the protein–membrane interface. In this short review, we first consider lipid signaling from this traditional viewpoint, highlighting innumerable Journal of General Physiology publications that have contributed to our present understanding. We then switch to our own emerging view that much important lipid signaling occurs via the formation of membrane domains that influence the function of channels and transporters within them, promote selected protein–protein interactions, and control the turnover of surface membrane.
2
Dionysopoulou, Mariangela, e George Diallinas. "Impact of Membrane Lipids on UapA and AzgA Transporter Subcellular Localization and Activity in Aspergillus nidulans". Journal of Fungi 7, n. 7 (28 giugno 2021): 514. http://dx.doi.org/10.3390/jof7070514.
Abstract (sommario):
Recent biochemical and biophysical evidence have established that membrane lipids, namely phospholipids, sphingolipids and sterols, are critical for the function of eukaryotic plasma membrane transporters. Here, we study the effect of selected membrane lipid biosynthesis mutations and of the ergosterol-related antifungal itraconazole on the subcellular localization, stability and transport kinetics of two well-studied purine transporters, UapA and AzgA, in Aspergillus nidulans. We show that genetic reduction in biosynthesis of ergosterol, sphingolipids or phosphoinositides arrest A. nidulans growth after germling formation, but solely blocks in early steps of ergosterol (Erg11) or sphingolipid (BasA) synthesis have a negative effect on plasma membrane (PM) localization and stability of transporters before growth arrest. Surprisingly, the fraction of UapA or AzgA that reaches the PM in lipid biosynthesis mutants is shown to conserve normal apparent transport kinetics. We further show that turnover of UapA, which is the transporter mostly sensitive to membrane lipid content modification, occurs during its trafficking and by enhanced endocytosis, and is partly dependent on autophagy and Hect-type HulARsp5 ubiquitination. Our results point out that the role of specific membrane lipids on transporter biogenesis and function in vivo is complex, combinatorial and transporter-dependent.
3
Chen, Ru, Yasuyo Yamaoka, Yanbin Feng, Zhanyou Chi, Song Xue e Fantao Kong. "Co-Expression of Lipid Transporters Simultaneously Enhances Oil and Starch Accumulation in the Green Microalga Chlamydomonas reinhardtii under Nitrogen Starvation". Metabolites 13, n. 1 (10 gennaio 2023): 115. http://dx.doi.org/10.3390/metabo13010115.
Abstract (sommario):
Lipid transporters synergistically contribute to oil accumulation under normal conditions in microalgae; however, their effects on lipid metabolism under stress conditions are unknown. Here, we examined the effect of the co-expression of lipid transporters, fatty acid transporters, (FAX1 and FAX2) and ABC transporter (ABCA2) on lipid metabolism and physiological changes in the green microalga Chlamydomonas under nitrogen (N) starvation. The results showed that the TAG content in FAX1-FAX2-ABCA2 over-expressor (OE) was 2.4-fold greater than in the parental line. Notably, in FAX1-FAX2-ABCA2-OE, the major membrane lipids and the starch and cellular biomass content also significantly increased compared with the control lines. Moreover, the expression levels of genes directly involved in TAG, fatty acid, and starch biosynthesis were upregulated. FAX1-FAX2-ABCA2-OE showed altered photosynthesis activity and increased ROS levels during nitrogen (N) deprivation. Our results indicated that FAX1-FAX2-ABCA2 overexpression not only enhanced cellular lipids but also improved starch and biomass contents under N starvation through modulation of lipid and starch metabolism and changes in photosynthesis activity. The strategy developed here could also be applied to other microalgae to produce FA-derived energy-rich and value-added compounds.
4
Langmann, Thomas, Richard Mauerer e Gerd Schmitz. "Human ATP-Binding Cassette Transporter TaqMan Low-Density Array: Analysis of Macrophage Differentiation and Foam Cell Formation". Clinical Chemistry 52, n. 2 (1 febbraio 2006): 310–13. http://dx.doi.org/10.1373/clinchem.2005.059774.
Abstract (sommario):
Abstract Background: ATP-binding cassette (ABC) transporters cause various diseases and regulate many physiologic processes, such as lipid homeostasis, iron transport, and immune mechanisms. Several ABC transporters are involved in bile acid, phospholipid, and sterol transport, and their expression is itself controlled by lipids. In addition, ABC proteins mediate drug export in tumor cells and promote the development of multidrug resistance. Methods: We created an ABC Transporter TaqMan Low-Density Array based on an Applied Biosystems 7900HT Micro Fluidic Card. We used a 2-μL reaction well with 2 ng of sample. To evaluate this method for lipidomic research and to characterize expression patterns of ABC transporters in cells relevant for atherosclerosis research, we monitored mRNA expression in human primary monocytes, in vitro–differentiated macrophages, and cells stimulated with the liver-X-receptor and retinoid-X-receptor agonists T0901317 and 9-cis retinoic acid, mimicking sterol loading. Results: The method enabled simultaneous analysis of 47 human ABC transporters and the reference gene 18S rRNA in 2 replicates of 4 samples per run. Conclusions: The new system uses only 2 ng of sample and small volumes of reagent, and the precaptured primers and probes avoided labor-intensive pipetting steps. The ABC Transporter TaqMan Low-Density Array may be a useful tool to monitor dysregulated ABC transporter mRNA profiles in human lipid disorders and cancer-related multidrug resistance and to analyze the pharmacologic and metabolic regulation of ABC transporter expression important for drug development in large-scale screening approaches.
5
Nagahashi, Masayuki, Kazuaki Takabe, Krista P. Terracina, Daiki Soma, Yuki Hirose, Takashi Kobayashi, Yasunobu Matsuda e Toshifumi Wakai. "Sphingosine-1-Phosphate Transporters as Targets for Cancer Therapy". BioMed Research International 2014 (2014): 1–7. http://dx.doi.org/10.1155/2014/651727.
Abstract (sommario):
Sphingosine-1-phosphate (S1P) is a pleiotropic lipid mediator that regulates cell survival, migration, the recruitment of immune cells, angiogenesis, and lymphangiogenesis, all of which are involved in cancer progression. S1P is generated inside cancer cells by sphingosine kinases then exported outside of the cell into the tumor microenvironment where it binds to any of five G protein coupled receptors and proceeds to regulate a variety of functions. We have recently reported on the mechanisms underlying the “inside-out” signaling of S1P, its export through the plasma membrane, and its interaction with cell surface receptors. Membrane lipids, including S1P, do not spontaneously exchange through lipid bilayers since the polar head groups do not readily go through the hydrophobic interior of the plasma membrane. Instead, specific transporter proteins exist on the membrane to exchange these lipids. This review summarizes what is known regarding S1P transport through the cell membrane via ATP-binding cassette transporters and the spinster 2 transporter and discusses the roles for these transporters in cancer and in the tumor microenvironment. Based on our research and the emerging understanding of the role of S1P signaling in cancer and in the tumor microenvironment, S1P transporters and S1P signaling hold promise as new therapeutic targets for cancer drug development.
6
McKinlay, Colin J., Nancy L. Benner, Ole A. Haabeth, Robert M. Waymouth e Paul A. Wender. "Enhanced mRNA delivery into lymphocytes enabled by lipid-varied libraries of charge-altering releasable transporters". Proceedings of the National Academy of Sciences 115, n. 26 (11 giugno 2018): E5859—E5866. http://dx.doi.org/10.1073/pnas.1805358115.
Abstract (sommario):
We report a strategy for generating a combinatorial library of oligonucleotide transporters with varied lipid domains and their use in the efficient transfection of lymphocytes with mRNA in vitro and in vivo. This library is based on amphiphilic charge-altering releasable transporters (CARTs) that contain a lipophilic block functionalized with various side-chain lipids and a polycationic α-amino ester mRNA-binding block that undergoes rearrangement to neutral small molecules, resulting in mRNA release. We show that certain binary mixtures of these lipid-varied CARTs provide up to a ninefold enhancement in mRNA translation in lymphocytes in vitro relative to either a single-lipid CART component alone or the commercial reagent Lipofectamine 2000, corresponding to a striking increase in percent transfection from 9–12% to 80%. Informed by the results with binary mixtures, we further show that CARTs consisting of optimized ratios of the two lead lipids incorporated into a single hybrid-lipid transporter molecule maintain the same delivery efficacy as the noncovalent mixture of two CARTs. The lead lipid CART mixtures and hybrid-lipid CARTs show enhanced lymphocyte transfection in primary T cells and in vivo in mice. This combinatorial approach for rapidly screening mRNA delivery vectors has provided lipid-varied CART mixtures and hybrid-lipid CARTs that exhibit significant improvement in mRNA delivery to lymphocytes, a finding of potentially broad value in research and clinical applications.
7
Kotlyarov, Stanislav, e Anna Kotlyarova. "The Role of ABC Transporters in Lipid Metabolism and the Comorbid Course of Chronic Obstructive Pulmonary Disease and Atherosclerosis". International Journal of Molecular Sciences 22, n. 13 (23 giugno 2021): 6711. http://dx.doi.org/10.3390/ijms22136711.
Abstract (sommario):
Chronic obstructive pulmonary disease (COPD) ranks among the leading causes of morbidity and mortality worldwide. COPD rarely occurs in isolation and is often combined with various diseases. It is considered that systemic inflammation underlies the comorbid course of COPD. The data obtained in recent years have shown the importance of violations of the cross-links of lipid metabolism and the immune response, which are links in the pathogenesis of both COPD and atherosclerosis. The role of lipid metabolism disorders in the pathogenesis of the comorbid course of COPD and atherosclerosis and the participation of ATP-binding cassette (ABC) transporters in these processes is discussed in this article. It is known that about 20 representatives of a large family of ABC transporters provide lipid homeostasis of cells by moving lipids inside the cell and in its plasma membrane, as well as removing lipids from the cell. It was shown that some representatives of the ABC-transporter family are involved in various links of the pathogenesis of COPD and atherosclerosis, which can determine their comorbid course.
8
Kok, Jan Willem, Karin Klappe e Ina Hummel. "The Role of the Actin Cytoskeleton and Lipid Rafts in the Localization and Function of the ABCC1 Transporter". Advances in Biology 2014 (5 maggio 2014): 1–11. http://dx.doi.org/10.1155/2014/105898.
Abstract (sommario):
ATP-binding cassette (ABC) transporters are known to be important factors in multidrug resistance of tumor cells. Lipid rafts have been implicated in their localization in the plasma membrane, where they function as drug efflux pumps. This specific localization in rafts may support the activity of ABC/Abc transporters. This raises questions regarding the nature and composition of the lipid rafts that harbor ABC/Abc transporters and the dependence of ABC/Abc transporters—concerning their localization and activity—on lipid raft constituents. Here we review our work of the past 10 years aimed at evaluating whether ABC/Abc transporters are dependent on a particular membrane environment for their function. What is the nature of this membrane environment and which of the lipid raft constituents are important for this dependency? It turns out that cortical actin is of major importance for stabilizing the localization and function of the ABC/Abc transporter, provided it is localized in an actin-dependent subtype of lipid rafts, as is the case for human ABCC1/multidrug resistance-related protein 1 (MRP1) and rodent Abcc1/Mrp1 but not human ABCB1/P-glycoprotein (PGP). On the other hand, sphingolipids do not appear to be modulators of ABCC1/MRP1 (or Abcc1/Mrp1), even though they are coregulated during drug resistance development.
9
Kotlyarov, S. N., e A. A. Kotlyarova. "Participation of ABC-transporters in lipid metabolism and pathogenesis of atherosclerosis". Genes & Cells 15, n. 3 (15 settembre 2020): 22–28. http://dx.doi.org/10.23868/202011003.
Abstract (sommario):
Atherosclerosis is one of the key causes of morbidity and mortality worldwide. It is known that a leading role in the development and progression of atherosclerosis is played by a violation of lipid metabolism. ABC transporters provide lipid cell homeostasis, performing a number of transport functions - moving lipids inside the cell, in the plasma membrane, and also removing lipids from the cell. In a large group of ABC transporters, about 20 take part in lipid homeostasis, playing, among other things, an important role in the pathogenesis of atherosclerosis. It was shown that cholesterol is not only a substrate for a number of ABC transporters, but also able to modulate their activity. Regulation of activity is carried out due to specific lipid-protein interactions.
10
Jedlitschky, Gabriele, Andreas Greinacher e Heyo K. Kroemer. "Transporters in human platelets: physiologic function and impact for pharmacotherapy". Blood 119, n. 15 (12 aprile 2012): 3394–402. http://dx.doi.org/10.1182/blood-2011-09-336933.
Abstract (sommario):
Platelets store signaling molecules (eg, serotonin and ADP) within their granules. Transporters mediate accumulation of these molecules in platelet granules and, on platelet activation, their translocation across the plasma membrane. The balance between transporter-mediated uptake and elimination of signaling molecules and drugs in platelets determines their intracellular concentrations and effects. Several members of the 2 major transporter families, ATP-binding cassette (ABC) transporters and solute carriers (SLCs), have been identified in platelets. An example of an ABC transporter is MRP4 (ABCC4), which facilitates ADP accumulation in dense granules. MRP4 is a versatile transporter, and various additional functions have been proposed, notably lipid mediator release and a role in aspirin resistance. Several other ABC proteins have been detected in platelets with functions in glutathione and lipid homeostasis. The serotonin transporter (SERT, SLC6A4) in the platelet plasma membrane represents a well-characterized example of the SLC family. Moreover, recent experiments indicate expression of OATP2B1 (SLCO2B1), a high affinity transporter for certain statins, in platelets. Changes in transporter localization and expression can affect platelet function and drug sensitivity. This review summarizes available data on the physiologic and pharmacologic role of transporters in platelets.
11
Kraya, Adam A., Run Jin, Chao Zhao, Ariana Familiar, Philip B. Storm, Kathryn Wellen, Adam C. Resnick e Ali Nabavizadeh. "TMET-29. THE GLUTAMINE TRANSPORTER SLC1A5 IS ASSOCIATED WITH REWIRING OF AMINO ACID, LIPID, AND IMMUNE PATHWAYS AND TUMOR PROGNOSIS IN PEDIATRIC BRAIN CANCERS". Neuro-Oncology 24, Supplement_7 (1 novembre 2022): vii268. http://dx.doi.org/10.1093/neuonc/noac209.1034.
Abstract (sommario):
Abstract Glutamine transporters play an important role in supporting increased tumor nutritional demands, often through overexpression of the solute carrier (SLC) family of membrane transporters. We aimed to understand the relationship of SLC transporter expression with pediatric brain tumor subtypes, lipid metabolism and their potential prognostic significance using data from the Pediatric Brain Tumor Atlas (PBTA). Using the expression of amino acid transporter genes, we found that elevated expression of glutamine transporters (SLC1A5, SLC7A5, SLC7A11, SLC38A5, SLC38A3) predicted shorter progression-free survival (PFS) in low-grade gliomas (LGGs) and poorer overall survival in pediatric ependymomas, high-grade gliomas (HGGs), and medulloblastomas. We focused specifically on SLC1A5 given the availability of imaging probes (18 F-Fluoroglutamine and 18F-Fluciclovine) for the corresponding amino acid transporter (ASCT2). Kaplan-Meier analysis found that higher expression of SLC1A5 was associated with shorter OS in ependymoma and medulloblastoma (p = 0.032 and p = 9.8e-4) and shorter PFS in LGG (p = 0.022). We found a universally higher expression of ATP citrate lyase (ACLY) and Acetyl-CoA carboxylase 1 (ACC) relative to normal brain tissue across all histologies. BRAF driven low grade gliomas and SHH-driven medulloblastomas showed differential expression of ACLY compared to other histologies. In addition, Acyl-CoA synthetase short chain family member 1 and 2 (ACSS1 and 2) were universally downregulated in pediatric gliomas, indicating that pediatric CNS tumors seem to rely on ACLY over ACSS for lipid synthesis. Gene set analysis showed higher expression and network rewiring of amino acid, lipid, and immune pathways in SLC1A5-high expressing clusters. SLC1A5 correlated negatively with pathways associated with lipid metabolic breakdown/degradation and correlated positively with pathways associated with lipid biosynthesis. In conclusion, our work demonstrates that glutamine transporters, particularly SLC1A5, represent compelling targets in pediatric brain tumors and can be exploited with theranostic approaches and amino-acid PET imaging.
12
Kotlyarov, Stanislav, e Anna Kotlyarova. "Clinical Significance of Lipid Transport Function of ABC Transporters in the Innate Immune System". Membranes 12, n. 11 (31 ottobre 2022): 1083. http://dx.doi.org/10.3390/membranes12111083.
Abstract (sommario):
ABC transporters are a large family of proteins that transport a variety of substrates across cell plasma membranes. Because of this, they are involved in many physiological processes. It is of interest to note that many ABC transporters are involved in the transport of various lipids. In addition, this function may be related to the innate immune system. The evidence that ABC transporters are involved in the regulation of the innate immune system through the transport of various substances greatly enhances the understanding of their clinical significance. ABC transporters are involved in the cellular homeostasis of cholesterol as well as in the regulation of its content in lipid rafts. Through these mechanisms, they can regulate the function of membrane proteins, including receptors of the innate immune system. By regulating lipid transport, some members of ABC transporters are involved in phagocytosis. In addition, ABC transporters are involved in the transport of lipopolysaccharide, lipid mediators of inflammation, and perform other functions in the innate immune system.
13
Vecera, R., A. Zacharova, J. Orolin, N. Skottova e P. Anzenbacher. " The effect of silymarin on expression of selected ABC transporters in the rat". Veterinární Medicína 56, No. 2 (4 marzo 2011): 59–62. http://dx.doi.org/10.17221/1579-vetmed.
Abstract (sommario):
Silymarin (standardized extract from the seeds of the Silybum marianum) has been used in the supportive therapy of liver diseases and its cytoprotective activity is believed to be based on antioxidant properties. Our previous works showed hypolipidemic effects of silymarin. The ATP-binding cassette (ABC) transporters G5 and G8 play a major role in biliary cholesterol secretion. The ABCA1 transporter plays a significant role in movement of cellular cholesterol to high density lipoproteins. We investigated the possibility that silymarin affects the regulation of lipid metabolism via selected ABC transporters using rats fed a high-cholesterol diet with silymarin. The major finding in this study is that silymarin up-regulated mRNA of ABC transporters (G5, G8 and A1). This result suggests that silymarin positively affects the plasma lipoprotein profile via up-regulation of ABC transporters involved in lipid metabolism. Furthermore, this study shows for the first time that silymarin up-regulates the expression of these ABC transporters at the mRNA level.
14
Barreto-Ojeda, Estefania, Valentina Corradi, Ruo-Xu Gu e D. Peter Tieleman. "Coarse-grained molecular dynamics simulations reveal lipid access pathways in P-glycoprotein". Journal of General Physiology 150, n. 3 (6 febbraio 2018): 417–29. http://dx.doi.org/10.1085/jgp.201711907.
Abstract (sommario):
P-glycoprotein (P-gp) exports a broad range of dissimilar compounds, including drugs, lipids, and lipid-like molecules. Because of its substrate promiscuity, P-gp is a key player in the development of cancer multidrug resistance. Although P-gp is one of the most studied ABC transporters, the mechanism by which its substrates access the cavity remains unclear. In this study, we perform coarse-grained molecular dynamics simulations to explore possible lipid access pathways in the inward-facing conformation of P-gp embedded in bilayers of different lipid compositions. In the inward-facing orientation, only lipids from the lower leaflet access the cavity of the transporter. We identify positively charged residues at the portals of P-gp that favor lipid entrance to the cavity, as well as lipid-binding sites at the portals and within the cavity, which is in good agreement with previous experimental studies. This work includes several examples of lipid pathways for phosphatidylcholine and phosphatidylethanolamine lipids that help elucidate the molecular mechanism of lipid binding in P-gp.
15
Hresko, Richard C., Thomas E. Kraft, Andrew Quigley, Elisabeth P. Carpenter e Paul W. Hruz. "Mammalian Glucose Transporter Activity Is Dependent upon Anionic and Conical Phospholipids". Journal of Biological Chemistry 291, n. 33 (14 giugno 2016): 17271–82. http://dx.doi.org/10.1074/jbc.m116.730168.
Abstract (sommario):
The regulated movement of glucose across mammalian cell membranes is mediated by facilitative glucose transporters (GLUTs) embedded in lipid bilayers. Despite the known importance of phospholipids in regulating protein structure and activity, the lipid-induced effects on the GLUTs remain poorly understood. We systematically examined the effects of physiologically relevant phospholipids on glucose transport in liposomes containing purified GLUT4 and GLUT3. The anionic phospholipids, phosphatidic acid, phosphatidylserine, phosphatidylglycerol, and phosphatidylinositol, were found to be essential for transporter function by activating it and stabilizing its structure. Conical lipids, phosphatidylethanolamine and diacylglycerol, enhanced transporter activity up to 3-fold in the presence of anionic phospholipids but did not stabilize protein structure. Kinetic analyses revealed that both lipids increase the kcat of transport without changing the Km values. These results allowed us to elucidate the activation of GLUT by plasma membrane phospholipids and to extend the field of membrane protein-lipid interactions to the family of structurally and functionally related human solute carriers.
16
Castro-Torres, Ibrahim Guillermo, Minarda De la O-Arciniega, Elia Brosla Naranjo-Rodríguez, Víctor Alberto Castro-Torres, Miguel Ángel Domínguez-Ortíz e Mariano Martínez-Vázquez. "The Hypocholesterolemic Effects of Eryngium carlinae F. Delaroche Are Mediated by the Involvement of the Intestinal Transporters ABCG5 and ABCG8". Evidence-Based Complementary and Alternative Medicine 2017 (2017): 1–7. http://dx.doi.org/10.1155/2017/3176232.
Abstract (sommario):
Hypercholesterolemia is a metabolic disorder characterized by a high concentration of cholesterol in the blood. Eryngium carlinae is a medicinal plant used to treat lipid diseases. The goal of this work was to evaluate, in a model of hypercholesterolemia in mice, the hypocholesterolemic effect of a hydroalcoholic extract of E. carlinae and its main metabolite, D-mannitol. Biochemical analyses of serum lipids and hepatic enzymes were performed by photocolorimetry. We performed histopathological studies of the liver and the expression of the intestinal cholesterol transporters Abcg5 and Abcg8 was determined by standard western blot method. Our results showed that hydroalcoholic extract at doses of 100 mg/kg and D-mannitol at doses of 10 mg/kg reduced the concentration of both total cholesterol and non-HDL cholesterol, without altering the concentration of HDL cholesterol and without damage to hepatocytes. Treatment with the extract increased Abcg8 intestinal transporter expression, while D-mannitol decreased the expression of the two Abcg5/Abcg8 transporters, compared with the hypercholesterolemic group. Considering that Abcg5/Abcg8 transporters perform cholesterol efflux, our results demonstrate that the lipid-lowering effect of the hydroalcoholic extract may be associated with the increase of Abcg8 expression, but the hypocholesterolemic effect of D-mannitol is independent of overexpression of these intestinal transporters and probably they have another mechanism of action.
17
Garaeva, Alisa A., e Dirk J. Slotboom. "Elevator-type mechanisms of membrane transport". Biochemical Society Transactions 48, n. 3 (5 maggio 2020): 1227–41. http://dx.doi.org/10.1042/bst20200290.
Abstract (sommario):
Membrane transporters are integral membrane proteins that mediate the passage of solutes across lipid bilayers. These proteins undergo conformational transitions between outward- and inward-facing states, which lead to alternating access of the substrate-binding site to the aqueous environment on either side of the membrane. Dozens of different transporter families have evolved, providing a wide variety of structural solutions to achieve alternating access. A sub-set of structurally diverse transporters operate by mechanisms that are collectively named ‘elevator-type’. These transporters have one common characteristic: they contain a distinct protein domain that slides across the membrane as a rigid body, and in doing so it ‘drags” the transported substrate along. Analysis of the global conformational changes that take place in membrane transporters using elevator-type mechanisms reveals that elevator-type movements can be achieved in more than one way. Molecular dynamics simulations and experimental data help to understand how lipid bilayer properties may affect elevator movements and vice versa.
18
YASUMIBA, Shigeyuki, Susumu TAZUMA, Hidenori OCHI, Kazuaki CHAYAMA e Goro KAJIYAMA. "Cyclosporin A reduces canalicular membrane fluidity and regulates transporter function in rats". Biochemical Journal 354, n. 3 (8 marzo 2001): 591–96. http://dx.doi.org/10.1042/bj3540591.
Abstract (sommario):
Changes of the biliary canalicular membrane lipid content can affect membrane fluidity and biliary lipid secretion in rats. The immunosuppressant cyclosporin A is known to cause intrahepatic cholestasis. This study investigated whether cyclosporin A influenced canalicular membrane fluidity by altering membrane phospholipids or transporter expression. In male Sprague–Dawley rats, a bile-duct cannula was inserted to collect bile, and sodium taurocholate was infused (100nmol/min per 100g) for 60min. During steady-state taurocholate infusion, cyclosporin A (20mg/kg) or vehicle was injected intravenously and then bile was collected for 80min. After killing the rats, canalicular membrane vesicles were prepared. Expression of canalicular membrane transporters was assessed by Western blotting and canalicular membrane vesicle fluidity was estimated by fluorescence polarization. Cyclosporin A reduced biliary lipid secretion along with a disproportionate reduction of lipids relative to bile acids. Cyclosporin A significantly decreased canalicular membrane fluidity along with an increase of the cholesterol/phospholipid molar ratio. Only expression of the transporter P-glycoprotein was increased by cyclosporin A. Because canalicular membrane transporter expression was largely unchanged by cyclosporin A despite a marked decrease of biliary lipid secretion, transporter activity may partly depend upon canalicular membrane fluidity.
19
Alketbi, Latifa, Abeer Al-Ali, Iman M. Talaat, Qutayba Hamid e Khuloud Bajbouj. "The Role of ATP-Binding Cassette Subfamily A in Colorectal Cancer Progression and Resistance". International Journal of Molecular Sciences 24, n. 2 (10 gennaio 2023): 1344. http://dx.doi.org/10.3390/ijms24021344.
Abstract (sommario):
Colorectal cancer (CRC) is one of the most common malignancies worldwide; it is the fourth leading cause of cancer-related deaths. CRC arises due to mutations that can affect oncogenes, tumour suppressor genes and DNA repair genes. The lack of novel diagnostic and therapeutic targets and the development of chemoresistance are some of the major issues when dealing with CRC. The overexpression of ATP-binding cassette (ABC) transporters is considered one facilitating mechanism for chemoresistance. Furthermore, ABC transporters have additional roles in cancer development beyond multidrug resistance. In CRC, lipid dysregulation has a key role in tumour development and progression, as cancer cells rely on lipids for energy and rapid cell proliferation. ABC subfamily A (ABCA) contains the largest members of ABC proteins, mainly known for their role in lipid transport, mostly membrane lipids such as cholesterol and phospholipids. Although the exact mechanism of action of these members is not confirmed, their expression is usually correlated with tumour progression and therapy resistance, probably due to their role in lipid homeostasis. CRC shows alteration in the expression of ABCA transporters, which is usually linked to poor prognosis and overall survival. Therefore, as lipid transporters, their role in CRC is investigated, and their diagnostic and prognostic potential is evaluated. This minireview presents evidence from various studies suggesting that ABCA transporters might have an active role in CRC and can be utilized as potential diagnostic and therapeutic targets.
20
Zhao, Yan, Deren Hou, Xialu Feng, Fangbo Lin e Jing Luo. "Role of ABC transporters in the pathology of Alzheimer’s disease". Reviews in the Neurosciences 28, n. 2 (1 febbraio 2017): 155–59. http://dx.doi.org/10.1515/revneuro-2016-0060.
Abstract (sommario):
AbstractThe ATP-binding cassette (ABC) transporter superfamily is a large family of proteins that transport specific molecules across membranes. These proteins are associated with both cholesterol metabolism and Alzheimer’s disease (AD). Cholesterol homeostasis has a key role in AD, and ABC transporters are important mediators of lipid transportation. Emerging evidence suggests that decreased expression and hypofunction of ABC transporters are crucial to the occurrence and development of AD. In the present article, we review the current knowledge regarding ABC transporters and speculate on their role in the pathogenesis of AD.
21
Beltran, Jean L., Lila G. McGrath, Sophia Caruso, Richara K. Bain, Claire E. Hendrix, Hana Kamran, Hartlee G. Johnston et al. "Borate Transporters and SLC4 Bicarbonate Transporters Share Key Functional Properties". Membranes 13, n. 2 (15 febbraio 2023): 235. http://dx.doi.org/10.3390/membranes13020235.
Abstract (sommario):
Borate transporters are membrane transport proteins that regulate intracellular borate levels. In plants, borate is a micronutrient essential for growth but is toxic in excess, while in yeast, borate is unnecessary for growth and borate export confers tolerance. Borate transporters share structural homology with human bicarbonate transporters in the SLC4 family despite low sequence identity and differences in transported solutes. Here, we characterize the S. cerevisiae borate transporter Bor1p and examine whether key biochemical features of SLC4 transporters extend to borate transporters. We show that borate transporters and SLC4 transporters share multiple properties, including lipid-promoted dimerization, sensitivity to stilbene disulfonate-derived inhibitors, and a requirement for an acidic residue at the solute binding site. We also identify several amino acids critical for Bor1p function and show that disease-causing mutations in human SLC4A1 will eliminate in vivo function when their homologous mutations are introduced in Bor1p. Our data help elucidate mechanistic features of Bor1p and reveal significant functional properties shared between borate transporters and SLC4 transporters.
22
Mani, Orlando, Meike Körner, Martin T. Sorensen, Kristen Sejrsen, Carlos Wotzkow, Corneille E. Ontsouka, Robert R. Friis, Rupert M. Bruckmaier e Christiane Albrecht. "Expression, localization, and functional model of cholesterol transporters in lactating and nonlactating mammary tissues of murine, bovine, and human origin". American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 299, n. 2 (agosto 2010): R642—R654. http://dx.doi.org/10.1152/ajpregu.00723.2009.
Abstract (sommario):
Members of the ATP-binding cassette (ABC) transporters play a pivotal role in cellular lipid efflux. To identify candidate cholesterol transporters implicated in lipid homeostasis and mammary gland (MG) physiology, we compared expression and localization of ABCA1, ABCG1, and ABCA7 and their regulatory genes in mammary tissues of different species during the pregnancy-lactation cycle. Murine and bovine mammary glands (MGs) were investigated during different functional stages. The abundance of mRNAs was determined by quantitative RT-PCR. Furthermore, transporter proteins were localized in murine, bovine, and human MGs by immunohistochemistry. In the murine MG, ABCA1 mRNA abundance was elevated during nonlactating compared with lactating stages, whereas ABCA7 and ABCA1 mRNA profiles were not altered. In the bovine MG, ABCA1, ABCG1, and ABCA7 mRNAs abundances were increased during nonlactating stages compared with lactation. Furthermore, associations between mRNA levels of transporters and their regulatory genes LXRα, PPARγ, and SREBPs were found. ABCA1, ABCG1, and ABCA7 proteins were localized in glandular MG epithelial cells (MEC) during lactation, whereas during nonlactating stages, depending on species, the proteins showed distinct localization patterns in MEC and adipocytes. Our results demonstrate that ABCA1, ABCG1, and ABCA7 are differentially expressed between lactation and nonlactating stages and in association with regulatory genes. Combined expression and localization data suggest that the selected cholesterol transporters are universal MG transporters involved in transport and storage of cholesterol and in lipid homeostasis of MEC. Because of the species-specific expression patterns of transporters in mammary tissue, mechanisms of cholesterol homeostasis seem to be differentially regulated between species.
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Sampson, Connor D. D., Cristina Fàbregas Bellavista, Matthew J. Stewart e Christopher Mulligan. "Thermostability-based binding assays reveal complex interplay of cation, substrate and lipid binding in the bacterial DASS transporter, VcINDY". Biochemical Journal 478, n. 21 (9 novembre 2021): 3847–67. http://dx.doi.org/10.1042/bcj20210061.
Abstract (sommario):
The divalent anion sodium symporter (DASS) family of transporters (SLC13 family in humans) are key regulators of metabolic homeostasis, disruption of which results in protection from diabetes and obesity, and inhibition of liver cancer cell proliferation. Thus, DASS transporter inhibitors are attractive targets in the treatment of chronic, age-related metabolic diseases. The characterisation of several DASS transporters has revealed variation in the substrate selectivity and flexibility in the coupling ion used to power transport. Here, using the model DASS co-transporter, VcINDY from Vibrio cholerae, we have examined the interplay of the three major interactions that occur during transport: the coupling ion, the substrate, and the lipid environment. Using a series of high-throughput thermostability-based interaction assays, we have shown that substrate binding is Na+-dependent; a requirement that is orchestrated through a combination of electrostatic attraction and Na+-induced priming of the binding site architecture. We have identified novel DASS ligands and revealed that ligand binding is dominated by the requirement of two carboxylate groups in the ligand that are precisely distanced to satisfy carboxylate interaction regions of the substrate-binding site. We have also identified a complex relationship between substrate and lipid interactions, which suggests a dynamic, regulatory role for lipids in VcINDY's transport cycle.
24
Quazi, Faraz, e Robert S. Molday. "Lipid transport by mammalian ABC proteins". Essays in Biochemistry 50 (7 settembre 2011): 265–90. http://dx.doi.org/10.1042/bse0500265.
Abstract (sommario):
ABC (ATP-binding cassette) proteins actively transport a wide variety of substrates, including peptides, amino acids, sugars, metals, drugs, vitamins and lipids, across extracellular and intracellular membranes. Of the 49 hum an ABC proteins, a significant number are known to mediate the extrusion of lipids from membranes or the flipping of membrane lipids across the bilayer to generate and maintain membrane lipid asymmetry. Typical lipid substrates include phospholipids, sterols, sphingolipids, bile acids and related lipid conjugates. Members of the ABCA subfamily of ABC transporters and other ABC proteins such as ABCB4, ABCG1 and ABCG5/8 implicated in lipid transport play important roles in diverse biological processes such as cell signalling, membrane lipid asymmetry, removal of potentially toxic compounds and metabolites, and apoptosis. The importance of these ABC lipid transporters in cell physiology is evident from the finding that mutations in the genes encoding many of these proteins are responsible for severe inherited diseases. For example, mutations in ABCA1 cause Tangier disease associated with defective efflux of cholesterol and phosphatidylcholine from the plasma membrane to the lipid acceptor protein apoA1 (apolipoprotein AI), mutations in ABCA3 cause neonatal surfactant deficiency associated with a loss in secretion of the lipid pulmonary surfactants from lungs of newborns, mutations in ABCA4 cause Stargardt macular degeneration, a retinal degenerative disease linked to the reduced clearance of retinoid compounds from photoreceptor cells, mutations in ABCA12 cause harlequin and lamellar ichthyosis, skin diseases associated with defective lipid trafficking in keratinocytes, and mutations in ABCB4 and ABCG5/ABCG8 are responsible for progressive intrafamilial hepatic disease and sitosterolaemia associated with defective phospholipid and sterol transport respectively. This chapter highlights the involvement of various mammalian ABC transporters in lipid transport in the context of their role in cell signalling, cellular homoeostasis, apoptosis and inherited disorders.
25
Borst, P., N. Zelcer e A. van Helvoort. "ABC transporters in lipid transport". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1486, n. 1 (giugno 2000): 128–44. http://dx.doi.org/10.1016/s1388-1981(00)00053-6.
26
Theodoulou, Frederica L., David J. Carrier, Theresia A. Schaedler, Stephen A. Baldwin e Alison Baker. "How to move an amphipathic molecule across a lipid bilayer: different mechanisms for different ABC transporters?" Biochemical Society Transactions 44, n. 3 (9 giugno 2016): 774–82. http://dx.doi.org/10.1042/bst20160040.
Abstract (sommario):
Import of β-oxidation substrates into peroxisomes is mediated by ATP binding cassette (ABC) transporters belonging to subfamily D. In order to enter the β-oxidation pathway, fatty acids are activated by conversion to fatty acyl-CoA esters, a reaction which is catalysed by acyl-CoA synthetases (ACSs). Here, we present evidence for an unusual transport mechanism, in which fatty acyl-CoA substrates are accepted by ABC subclass D protein (ABCD) transporters, cleaved by the transporters during transit across the lipid bilayer to release CoA, and ultimately re-esterified in the peroxisome lumen by ACSs which interact with the transporter. We propose that this solves the biophysical problem of moving an amphipathic molecule across the peroxisomal membrane, since the intrinsic thioesterase activity of the transporter permits separate membrane translocation pathways for the hydrophobic fatty acid moiety and the polar CoA moiety. The cleavage/re-esterification mechanism also has the potential to control entry of disparate substrates into the β-oxidation pathway when coupled with distinct peroxisomal ACSs. A different solution to the movement of amphipathic molecules across a lipid bilayer is deployed by the bacterial lipid-linked oligosaccharide (LLO) flippase, PglK, in which the hydrophilic head group and the hydrophobic polyprenyl tail of the substrate are proposed to have distinct translocation pathways but are not chemically separated during transport. We discuss a speculative alternating access model for ABCD proteins based on the mammalian ABC transporter associated with antigen processing (TAP) and compare it to the novel mechanism suggested by the recent PglK crystal structures and biochemical data.
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Langmann, Thomas, Richard Mauerer, Alexandra Zahn, Christoph Moehle, Mario Probst, Wolfgang Stremmel e Gerd Schmitz. "Real-Time Reverse Transcription-PCR Expression Profiling of the Complete Human ATP-Binding Cassette Transporter Superfamily in Various Tissues". Clinical Chemistry 49, n. 2 (1 febbraio 2003): 230–38. http://dx.doi.org/10.1373/49.2.230.
Abstract (sommario):
Abstract Background: ATP-binding cassette (ABC) transporters are involved in many physiologic processes, such as lipid transport, sterol homeostasis, immune mechanisms, and drug transport, and cause various human inherited diseases. Thus, the analysis of ABC transporter mRNA expression profiles for basic research, especially in the field of lipid metabolism, for clinical diagnosis, and for monitoring of drug effects is of great interest. Methods: We have developed a rapid, accurate, and highly sensitive real-time reverse transcription-PCR (RT-PCR) method for detection and quantification of all 47 currently known members of the ABC transporter superfamily. Our expression analysis is based on relative quantification using a calibration curve method. With our assay, expression monitoring of a large number of RNA samples in a 384-well format with only 50 ng of total RNA is possible. Results: In contrast to previous expression analyses of single ABC genes, our method allows the rapid and complete analysis of all ABC transporters in given RNA samples. We used our newly established expression panel to study the gene expression of all human ABC transporters in 20 different human tissues. As a result, we identified tissues with high transcriptional activity for ABC transporters. These organs are mainly involved in secretory function (adrenal gland), metabolic function (liver), barrier function (lung, trachea, small intestine), and tropic function (placenta, uterus). Conclusions: Our RT-PCR assay allows rapid, high-throughput transcriptional profiling of the complete ABC transporter superfamily and thus provides a new enabling tool for research, clinical diagnosis of disease, and drug testing and development.
28
Kotlyarov, Stanislav, e Anna Kotlyarova. "Analysis of ABC Transporter Gene Expression in Atherosclerosis". Cardiogenetics 11, n. 4 (4 novembre 2021): 204–20. http://dx.doi.org/10.3390/cardiogenetics11040021.
Abstract (sommario):
ABC transporters are a large family of membrane proteins that transport chemically diverse substrates across the cell membrane. Disruption of transport mechanisms mediated by ABC transporters causes the development of various diseases, including atherosclerosis. Methods: A bioinformatic analysis of a dataset from Gene Expression Omnibus (GEO) was performed. A GEO dataset containing data on gene expression levels in samples of atherosclerotic lesions and control arteries without atherosclerotic lesions from carotid, femoral, and infrapopliteal arteries was used for analysis. To evaluate differentially expressed genes, a bioinformatic analysis was performed in comparison groups using the limma package in R (v. 4.0.2) and the GEO2R and Phantasus tools (v. 1.11.0). Results: The obtained data indicate the differential expression of many ABC transporters belonging to different subfamilies. The differential expressions of ABC transporter genes involved in lipid transport, mechanisms of multidrug resistance, and mechanisms of ion exchange are shown. Differences in the expression of transporters in tissue samples from different arteries are established. Conclusions: The expression of ABC transporter genes demonstrates differences in atherosclerotic samples and normal arteries, which may indicate the involvement of transporters in the pathogenesis of atherosclerosis.
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Jonker, Patrick, e Alexander Muir. "Abstract 6167: Pancreatic tumor environmental nutrients alter SREBP-mediated lipid homeostasis and drive reliance on extracellular lipids for growth". Cancer Research 82, n. 12_Supplement (15 giugno 2022): 6167. http://dx.doi.org/10.1158/1538-7445.am2022-6167.
Abstract (sommario):
Abstract Both the cell-intrinsic metabolic network and the uniquely altered cell-extrinsic tumor microenvironment dictate tumor metabolism. However, while much is known about how cell-intrinsic factors regulate tumor metabolism, the effects of cell-extrinsic factors remain poorly understood. In particular, despite evidence that tumor nutrient availability extrinsically regulates tumor metabolism, further investigation has been hindered by the lack of models to study physiological nutrient availability in vitro.To accurately model the tumor nutrient microenvironment, our group quantified nutrient availability in pancreatic ductal adenocarcinoma (PDAC) tumor perfusate and created a medium to mimic this in vitro, called tumor interstitial fluid medium (TIFM). We compare the effects of TIFM-culture to maintenance in conventional culture medium (RPMI-1640) as a control for standard laboratory conditions. Using this model, I found that TIFM-cultured PDAC cells downregulate lipid synthesis, making TIFM-cultured cells uniquely reliant upon extracellular lipid uptake for growth. Analysis of murine PDAC tumors confirms downregulated lipogenesis in vivo, suggesting cell-extrinsic nutrients render lipogenesis dispensable—and lipid uptake necessary—for PDAC tumor growth. Notably, this contrasts studies in conventional culture media that claim lipogenesis is critical for PDAC growth.I am currently working to: (1) understand how the nutrient microenvironment alters lipid metabolism and (2) determine the extracellular lipids and transporters pancreatic cancer cells require for growth. Regarding the first question, transcriptomic analysis of TIFM-cultured cells revealed significant deactivation of SREBPs, master regulators of intracellular lipid and sterol synthesis, suggesting cell-extrinsic nutrient cues suppress lipogenesis by altering SREBP signaling. I am currently investigating which TIFM nutrients alter this signaling. I am also performing lipidomics analysis and lipid transporter knockdown experiments to identify lipids and transporters that TIFM-cultured cells require for growth. Collectively, these experiments will clarify the role extracellular nutrients play in driving changes to PDAC lipid metabolism and may suggest novel therapeutic treatment options for PDAC patients. Citation Format: Patrick Jonker, Alexander Muir. Pancreatic tumor environmental nutrients alter SREBP-mediated lipid homeostasis and drive reliance on extracellular lipids for growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6167.
30
Stockner, Thomas, Anna Mullen e Fraser MacMillan. "Investigating the dynamic nature of the ABC transporters: ABCB1 and MsbA as examples for the potential synergies of MD theory and EPR applications". Biochemical Society Transactions 43, n. 5 (1 ottobre 2015): 1023–32. http://dx.doi.org/10.1042/bst20150138.
Abstract (sommario):
ABC transporters are primary active transporters found in all kingdoms of life. Human multidrug resistance transporter ABCB1, or P-glycoprotein, has an extremely broad substrate spectrum and confers resistance against chemotherapy drug treatment in cancer cells. The bacterial ABC transporter MsbA is a lipid A flippase and a homolog to the human ABCB1 transporter, with which it partially shares its substrate spectrum. Crystal structures of MsbA and ABCB1 have been solved in multiple conformations, providing a glimpse into the possible conformational changes the transporter could be going through during the transport cycle. Crystal structures are inherently static, while a dynamic picture of the transporter in motion is needed for a complete understanding of transporter function. Molecular dynamics (MD) simulations and electron paramagnetic resonance (EPR) spectroscopy can provide structural information on ABC transporters, but the strength of these two methods lies in the potential to characterise the dynamic regime of these transporters. Information from the two methods is quite complementary. MD simulations provide an all atom dynamic picture of the time evolution of the molecular system, though with a narrow time window. EPR spectroscopy can probe structural, environmental and dynamic properties of the transporter in several time regimes, but only through the attachment sites of an exogenous spin label. In this review the synergistic effects that can be achieved by combining the two methods are highlighted, and a brief methodological background is also presented.
31
Farke, Carolin, Heinrich H. D. Meyer, Rupert M. Bruckmaier e Christiane Albrecht. "Differential expression of ABC transporters and their regulatory genes during lactation and dry period in bovine mammary tissue". Journal of Dairy Research 75, n. 4 (14 agosto 2008): 406–14. http://dx.doi.org/10.1017/s002202990800335x.
Abstract (sommario):
ATP-binding cassette (ABC) transporters play a pivotal role in human physiology, and mutations in these genes often result in severe hereditary diseases. ABC transporters are expressed in the bovine mammary gland but their physiological role in this organ remains elusive. Based on findings in the context of human disorders we speculated that candidate ABC transporters are implicated in lipid and cholesterol transport in the mammary gland. Therefore we investigated the expression pattern of selected genes that are associated with sterol transport in lactating and nonlactating mammary glands of dairy cows. mRNA levels from mammary gland biopsies taken during lactation and in the first and second week of the dry period were analysed using quantitative PCR. Five ABC transporter genes, namely ABCA1, ABCA7, ABCG1, ABCG2 and ABCG5, their regulating genes LXRα, PPARγ, SREBP1 and the milk proteins lactoferrin and α-lactalbumin were assessed. A significantly enhanced expression in the dry period was observed for ABCA1 while a significant decrease of expression in this period was detected for ABCA7, ABCG2, SREBP1 and α-lactalbumin. ABCG1, ABCG5, LXRα, PPARγ and lactoferrin expression was not altered between lactation and dry period. These results indicate that candidate ABC transporters involved in lipid and cholesterol transport show differential mRNA expression between lactation and the dry period. This may be due to physiological changes in the mammary gland such as immigration of macrophages or the accumulation of fat due to the loss of liquid in the involuting mammary gland. The current mRNA expression analysis of transporters in the mammary gland is the prerequisite for elucidating novel molecular mechanisms underlying cholesterol and lipid transfer into milk.
32
López-Marqués, Rosa L., Pontus Gourdon, Thomas Günther Pomorski e Michael Palmgren. "The transport mechanism of P4 ATPase lipid flippases". Biochemical Journal 477, n. 19 (12 ottobre 2020): 3769–90. http://dx.doi.org/10.1042/bcj20200249.
Abstract (sommario):
P4 ATPase lipid flippases are ATP-driven transporters that translocate specific lipids from the exoplasmic to the cytosolic leaflet of biological membranes, thus establishing a lipid gradient between the two leaflets that is essential for many cellular processes. While substrate specificity, subcellular and tissue-specific expression, and physiological functions have been assigned to a number of these transporters in several organisms, the mechanism of lipid transport has been a topic of intense debate in the field. The recent publication of a series of structural models based on X-ray crystallography and cryo-EM studies has provided the first glimpse into how P4 ATPases have adapted the transport mechanism used by the cation-pumping family members to accommodate a substrate that is at least an order of magnitude larger than cations.
33
Stanchev, Lyubomir Dimitrov, Juliana Rizzo, Rebecca Peschel, Lilli A. Pazurek, Lasse Bredegaard, Sarina Veit, Sabine Laerbusch, Marcio L. Rodrigues, Rosa L. López-Marqués e Thomas Günther Pomorski. "P-Type ATPase Apt1 of the Fungal Pathogen Cryptococcus neoformans Is a Lipid Flippase of Broad Substrate Specificity". Journal of Fungi 7, n. 10 (8 ottobre 2021): 843. http://dx.doi.org/10.3390/jof7100843.
Abstract (sommario):
Lipid flippases of the P4-ATPase family are ATP-driven transporters that translocate lipids from the exoplasmic to the cytosolic leaflet of biological membranes. In the encapsulated fungal pathogen Cryptococcus neoformans, the P4-ATPase Apt1p is an important regulator of polysaccharide secretion and pathogenesis, but its biochemical characterization is lacking. Phylogenetic analysis revealed that Apt1p belongs to the subclade of P4A-ATPases characterized by the common requirement for a β-subunit. Using heterologous expression in S. cerevisiae, we demonstrate that Apt1p forms a heterodimeric complex with the C. neoformans Cdc50 protein. This association is required for both localization and activity of the transporter complex. Lipid flippase activity of the heterodimeric complex was assessed by complementation tests and uptake assays employing fluorescent lipids and revealed a broad substrate specificity, including several phospholipids, the alkylphospholipid miltefosine, and the glycolipids glucosyl- and galactosylceramide. Our results suggest that transbilayer lipid transport in C. neoformans is finely regulated to promote fungal virulence, which reinforces the potential of Apt1p as a target for antifungal drug development.
34
Markovich, Daniel. "Physiological Roles and Regulation of Mammalian Sulfate Transporters". Physiological Reviews 81, n. 4 (10 gennaio 2001): 1499–533. http://dx.doi.org/10.1152/physrev.2001.81.4.1499.
Abstract (sommario):
All cells require inorganic sulfate for normal function. Sulfate is among the most important macronutrients in cells and is the fourth most abundant anion in human plasma (300 μM). Sulfate is the major sulfur source in many organisms, and because it is a hydrophilic anion that cannot passively cross the lipid bilayer of cell membranes, all cells require a mechanism for sulfate influx and efflux to ensure an optimal supply of sulfate in the body. The class of proteins involved in moving sulfate into or out of cells is called sulfate transporters. To date, numerous sulfate transporters have been identified in tissues and cells from many origins. These include the renal sulfate transporters NaSi-1 and sat-1, the ubiquitously expressed diastrophic dysplasia sulfate transporter DTDST, the intestinal sulfate transporter DRA that is linked to congenital chloride diarrhea, and the erythrocyte anion exchanger AE1. These transporters have only been isolated in the last 10–15 years, and their physiological roles and contributions to body sulfate homeostasis are just now beginning to be determined. This review focuses on the structural and functional properties of mammalian sulfate transporters and highlights some of regulatory mechanisms that control their expression in vivo, under normal physiological and pathophysiological states.
35
Stryapunina, Iryna, Maurice A. Itoe, Queenie Trinh, Charles Vidoudez, Esrah Du, Lydia Mendoza, Oleksandr Hulai et al. "Precise coordination between nutrient transporters ensures fertility in the malaria mosquito Anopheles gambiae". PLOS Genetics 20, n. 1 (29 gennaio 2024): e1011145. http://dx.doi.org/10.1371/journal.pgen.1011145.
Abstract (sommario):
Females from many mosquito species feed on blood to acquire nutrients for egg development. The oogenetic cycle has been characterized in the arboviral vector Aedes aegypti, where after a bloodmeal, the lipid transporter lipophorin (Lp) shuttles lipids from the midgut and fat body to the ovaries, and a yolk precursor protein, vitellogenin (Vg), is deposited into the oocyte by receptor-mediated endocytosis. Our understanding of how the roles of these two nutrient transporters are mutually coordinated is however limited in this and other mosquito species. Here, we demonstrate that in the malaria mosquito Anopheles gambiae, Lp and Vg are reciprocally regulated in a timely manner to optimize egg development and ensure fertility. Defective lipid transport via Lp knockdown triggers abortive ovarian follicle development, leading to misregulation of Vg and aberrant yolk granules. Conversely, depletion of Vg causes an upregulation of Lp in the fat body in a manner that appears to be at least partially dependent on target of rapamycin (TOR) signaling, resulting in excess lipid accumulation in the developing follicles. Embryos deposited by Vg-depleted mothers are completely inviable, and are arrested early during development, likely due to severely reduced amino acid levels and protein synthesis. Our findings demonstrate that the mutual regulation of these two nutrient transporters is essential to safeguard fertility by ensuring correct nutrient balance in the developing oocyte, and validate Vg and Lp as two potential candidates for mosquito control.
36
Sontag, Timothy J., Catherine A. Reardon e Godfrey S. Getz. "ABC transporters: lipid transport and inflammation". Current Opinion in Lipidology 21, n. 2 (aprile 2010): 159–60. http://dx.doi.org/10.1097/mol.0b013e3283376910.
37
Schmitz, Gerd, Wolfgang E. Kaminski e Evelyn Orsó. "ABC transporters in cellular lipid trafficking". Current Opinion in Lipidology 11, n. 5 (ottobre 2000): 493–501. http://dx.doi.org/10.1097/00041433-200010000-00007.
38
Prasad, Rajendra, Nitesh Kumar Khandelwal e Atanu Banerjee. "Yeast ABC transporters in lipid trafficking". Fungal Genetics and Biology 93 (agosto 2016): 25–34. http://dx.doi.org/10.1016/j.fgb.2016.05.008.
39
Alrosan, Amjad, Shereen M. Aleidi, Alryel Yang, Andrew J. Brown e Ingrid C. Gelissen. "The Adaptor Protein Alix is Involved in the Interaction Between the Ubiquitin Ligase NEDD4-1 and its Targets, ABCG1 and ABCG4". International Journal of Molecular Sciences 20, n. 11 (2 giugno 2019): 2714. http://dx.doi.org/10.3390/ijms20112714.
Abstract (sommario):
Several ATP-Binding Cassette (ABC) transporters, including ABCG1 and the related ABCG4, are essential regulators of cellular lipid homeostasis. ABCG1 is expressed ubiquitously and is functional in the context of atherosclerosis. However, ABCG4 is expressed almost exclusively in brain and has been linked to Alzheimer’s disease (AD). These transporters are highly regulated post-translationally by E3 ubiquitin ligases, with the ligase NEDD4-1 (Neural precursor cell-expressed developmentally downregulated gene 4) implicated in their protein stability. In this study, we investigated interacting partners of ABCG1 using peptide-mass spectrometry and identified the potential adaptor protein, Alix (apoptosis-linked gene 2-interacting protein X). In this paper, we hypothesized and investigated whether Alix could facilitate the interaction between NEDD4-1 and the ABC transporters. We showed that Alix and NEDD4-1 proteins were co-expressed in several commonly used cell lines. Knockdown of Alix in cells overexpressing ABCG1 or ABCG4 increased transporter protein expression while co-immunoprecipitation experiments showed interaction between NEDD4-1, Alix, and ABC transporters. In summary, we provide evidence that Alix serves as a co-factor for the interaction between the E3-ubiquitin ligase NEDD4-1 and the ABC transporter targets, ABCG1 and ABCG4.
40
More, Vijay R., Christopher R. Campos, Rebecca A. Evans, Keith D. Oliver, Gary NY Chan, David S. Miller e Ronald E. Cannon. "PPAR-α, a lipid-sensing transcription factor, regulates blood–brain barrier efflux transporter expression". Journal of Cerebral Blood Flow & Metabolism 37, n. 4 (21 luglio 2016): 1199–212. http://dx.doi.org/10.1177/0271678x16650216.
Abstract (sommario):
Lipid sensor peroxisome proliferator-activated receptor alpha (PPAR- α) is the master regulator of lipid metabolism. Dietary release of endogenous free fatty acids, fibrates, and certain persistent environmental pollutants, e.g. perfluoroalkyl fire-fighting foam components, are peroxisome proliferator-activated receptor alpha ligands. Here, we define a role for peroxisome proliferator-activated receptor alpha in regulating the expression of three ATP-driven drug efflux transporters at the rat and mouse blood–brain barriers: P-glycoprotein (Abcb1), breast cancer resistance protein (Bcrp/Abcg2), and multidrug resistance-associated protein 2 (Mrp2/Abcc2). Exposing isolated rat brain capillaries to linoleic acid, clofibrate, or PKAs increased the transport activity and protein expression of the three ABC transporters. These effects were blocked by the PPAR- α antagonist, GW6471. Dosing rats with 20 mg/kg or 200 mg/kg of clofibrate decreased the brain accumulation of the P-glycoprotein substrate, verapamil, by 50% (in situ brain perfusion; effects blocked by GW6471) and increased P-glycoprotein expression and activity in capillaries ex vivo. Fasting C57Bl/6 wild-type mice for 24 h increased both serum lipids and brain capillary P-glycoprotein transport activity. Fasting did not alter P-glycoprotein activity in PPAR- α knockout mice. These results indicate that hyperlipidemia, lipid-lowering fibrates and exposure to certain fire-fighting foam components activate blood–brain barrier peroxisome proliferator-activated receptor alpha, increase drug efflux transporter expression and reduce drug delivery to the brain.
41
Ristovski, Miliça, Danny Farhat, Shelly Ellaine M. Bancud e Jyh-Yeuan Lee. "Lipid Transporters Beam Signals from Cell Membranes". Membranes 11, n. 8 (26 luglio 2021): 562. http://dx.doi.org/10.3390/membranes11080562.
Abstract (sommario):
Lipid composition in cellular membranes plays an important role in maintaining the structural integrity of cells and in regulating cellular signaling that controls functions of both membrane-anchored and cytoplasmic proteins. ATP-dependent ABC and P4-ATPase lipid transporters, two integral membrane proteins, are known to contribute to lipid translocation across the lipid bilayers on the cellular membranes. In this review, we will highlight current knowledge about the role of cholesterol and phospholipids of cellular membranes in regulating cell signaling and how lipid transporters participate this process.
42
Mikros, Emmanuel, e George Diallinas. "Tales of tails in transporters". Open Biology 9, n. 6 (giugno 2019): 190083. http://dx.doi.org/10.1098/rsob.190083.
Abstract (sommario):
Cell nutrition, detoxification, signalling, homeostasis and response to drugs, processes related to cell growth, differentiation and survival are all mediated by plasma membrane (PM) proteins called transporters. Despite their distinct fine structures, mechanism of function, energetic requirements, kinetics and substrate specificities, all transporters are characterized by a main hydrophobic body embedded in the PM as a series of tightly packed, often intertwined, α-helices that traverse the lipid bilayer in a zigzag mode, connected with intracellular or extracellular loops and hydrophilic N- and C-termini. Whereas longstanding genetic, biochemical and biophysical evidence suggests that specific transmembrane segments, and also their connecting loops, are responsible for substrate recognition and transport dynamics, emerging evidence also reveals the functional importance of transporter N- and C-termini, in respect to transport catalysis, substrate specificity, subcellular expression, stability and signalling. This review highlights selected prototypic examples of transporters in which their termini play important roles in their functioning.
43
ZORZANO, Antonio, César FANDOS e Manuel PALACÍN. "Role of plasma membrane transporters in muscle metabolism". Biochemical Journal 349, n. 3 (25 luglio 2000): 667–88. http://dx.doi.org/10.1042/bj3490667.
Abstract (sommario):
Muscle plays a major role in metabolism. Thus it is a major glucose-utilizing tissue in the absorptive state, and changes in muscle insulin-stimulated glucose uptake alter whole-body glucose disposal. In some conditions, muscle preferentially uses lipid substrates, such as fatty acids or ketone bodies. Furthermore, muscle is the main reservoir of amino acids and protein. The activity of many different plasma membrane transporters, such as glucose carriers and transporters of carnitine, creatine and amino acids, play a crucial role in muscle metabolism by catalysing the influx or the efflux of substrates across the cell surface. In some cases, the membrane transport process is subjected to intense regulatory control and may become a potential pharmacological target, as is the case with the glucose transporter GLUT4. The goal of this review is the molecular characterization of muscle membrane transporter proteins, as well as the analysis of their possible regulatory role.
44
Baczewska, Marta, Klaudia Bojczuk, Adrian Kołakowski, Jakub Dobroch, Paweł Guzik e Paweł Knapp. "Obesity and Energy Substrate Transporters in Ovarian Cancer—Review". Molecules 26, n. 6 (16 marzo 2021): 1659. http://dx.doi.org/10.3390/molecules26061659.
Abstract (sommario):
Ovarian cancer is the seventh most common cancer in women. It is characterized by a high mortality rate because of its aggressiveness and advanced stage at the time of diagnosis. It is a nonhomogenous group of neoplasms and, of which the molecular basics are still being investigated. Nowadays, the golden standard in the treatment is debulking cytoreductive surgery combined with platinum-based chemotherapy. We have presented the interactions and the resulting perspectives between fatty acid transporters, glucose transporters and ovarian cancer cells. Studies have shown the association between a lipid-rich environment and cancer progression, which suggests the use of correspondent transporter inhibitors as promising chemotherapeutic agents. This review summarizes preclinical and clinical studies highlighting the role of fatty acid transport proteins and glucose transporters in development, growth, metastasizing and its potential use in targeted therapies of ovarian cancer.
45
Nakamura, Nicole K., Darcy S. Tokunaga, Herena Y. Ha e Noemi Polgar. "The Exocyst Is Required for CD36 Fatty Acid Translocase Trafficking and Free Fatty Acid Uptake in Skeletal Muscle Cells". Cells 11, n. 15 (6 agosto 2022): 2440. http://dx.doi.org/10.3390/cells11152440.
Abstract (sommario):
In obesity, chronic membrane-localization of CD36 free fatty acid (FFA) translocase, but not other FFA transporters, enhances FFA uptake and intracellular lipid accumulation. This ectopic lipid accumulation promotes insulin resistance by inhibiting insulin-induced GLUT4 glucose transporter trafficking and glucose uptake. GLUT4 and CD36 cell surface delivery is triggered by insulin- and contraction-induced signaling, which share conserved downstream effectors. While we have gathered detailed knowledge on GLUT4 trafficking, the mechanisms regulating CD36 membrane delivery and subsequent FFA uptake in skeletal muscle are not fully understood. The exocyst trafficking complex facilitates the docking of membrane-bound vesicles, a process underlying the controlled surface delivery of fuel transporters. The exocyst regulates insulin-induced glucose uptake via GLUT4 membrane trafficking in adipocytes and skeletal muscle cells and plays a role in lipid uptake in adipocytes. Based on the high degree of conservation of the GLUT4 and CD36 trafficking mechanisms in adipose and skeletal muscle tissue, we hypothesized that the exocyst also contributes to lipid uptake in skeletal muscle and acts through the targeted plasma membrane delivery of CD36 in response to insulin and contraction. Here, we show that the exocyst complex is necessary for insulin- and contraction-induced CD36 membrane trafficking and FFA uptake in muscle cells.
46
Hui, David Y., Eric D. Labonté e Philip N. Howles. "Development and Physiological Regulation of Intestinal Lipid Absorption. III. Intestinal transporters and cholesterol absorption". American Journal of Physiology-Gastrointestinal and Liver Physiology 294, n. 4 (aprile 2008): G839—G843. http://dx.doi.org/10.1152/ajpgi.00061.2008.
Abstract (sommario):
Intestinal cholesterol absorption is modulated by transport proteins in enterocytes. Cholesterol uptake from intestinal lumen requires several proteins on apical brush-border membranes, including Niemann-Pick C1-like 1 (NPC1L1), scavenger receptor B-I, and CD36, whereas two ATP-binding cassette half transporters, ABCG5 and ABCG8, on apical membranes work together for cholesterol efflux back to the intestinal lumen to limit cholesterol absorption. NPC1L1 is essential for cholesterol absorption, but its function as a cell surface transporter or an intracellular cholesterol transport protein needs clarification. Another ATP transporter, ABCA1, is present in the basolateral membrane to mediate HDL secretion from enterocytes.
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Linton, Kenneth J. "Lipid flopping in the liver". Biochemical Society Transactions 43, n. 5 (1 ottobre 2015): 1003–10. http://dx.doi.org/10.1042/bst20150132.
Abstract (sommario):
Bile is synthesized in the liver and is essential for the emulsification of dietary lipids and lipid-soluble vitamins. It is a complex mixture of amphiphilic bile acids (BAs; which act as detergent molecules), the membrane phospholipid phosphatidylcholine (PC), cholesterol and a variety of endogenous metabolites and waste products. Over the last 20 years, the combined effort of clinicians, geneticists, physiologists and biochemists has shown that each of these bile components is transported across the canalicular membrane of the hepatocyte by its own specific ATP-binding cassette (ABC) transporter. The bile salt export pump (BSEP) ABCB11 transports the BAs and drives bile flow from the liver, but it is now clear that two lipid transporters, ABCB4 (which flops PC into the bile) and the P-type ATPase ATP8B1/CDC50 (which flips a different phospholipid in the opposite direction) play equally critical roles that protect the biliary tree from the detergent activity of the bile acids. Understanding the interdependency of these lipid floppases and flippases has allowed the development of an assay to measure ABCB4 function. ABCB4 harbours numerous mis-sense mutations which probably reflects the spectrum of liver disease rooted in ABCB4 aetiology. Characterization of the effect of these mutations at the protein level opens the possibility for the development of personalized prognosis and treatment.
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Busschaert, Nathalie, Robert B. P. Elmes, Dawid D. Czech, Xin Wu, Isabelle L. Kirby, Evan M. Peck, Kevin D. Hendzel et al. "Thiosquaramides: pH switchable anion transporters". Chem. Sci. 5, n. 9 (2014): 3617–26. http://dx.doi.org/10.1039/c4sc01629g.
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Samodelov, Sophia L., Gerd A. Kullak-Ublick, Zhibo Gai e Michele Visentin. "Organic Cation Transporters in Human Physiology, Pharmacology, and Toxicology". International Journal of Molecular Sciences 21, n. 21 (24 ottobre 2020): 7890. http://dx.doi.org/10.3390/ijms21217890.
Abstract (sommario):
Individual cells and epithelia control the chemical exchange with the surrounding environment by the fine-tuned expression, localization, and function of an array of transmembrane proteins that dictate the selective permeability of the lipid bilayer to small molecules, as actual gatekeepers to the interface with the extracellular space. Among the variety of channels, transporters, and pumps that localize to cell membrane, organic cation transporters (OCTs) are considered to be extremely relevant in the transport across the plasma membrane of the majority of the endogenous substances and drugs that are positively charged near or at physiological pH. In humans, the following six organic cation transporters have been characterized in regards to their respective substrates, all belonging to the solute carrier 22 (SLC22) family: the organic cation transporters 1, 2, and 3 (OCT1–3); the organic cation/carnitine transporter novel 1 and 2 (OCTN1 and N2); and the organic cation transporter 6 (OCT6). OCTs are highly expressed on the plasma membrane of polarized epithelia, thus, playing a key role in intestinal absorption and renal reabsorption of nutrients (e.g., choline and carnitine), in the elimination of waste products (e.g., trimethylamine and trimethylamine N-oxide), and in the kinetic profile and therapeutic index of several drugs (e.g., metformin and platinum derivatives). As part of the Special Issue Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations, this article critically presents the physio-pathological, pharmacological, and toxicological roles of OCTs in the tissues in which they are primarily expressed.
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Hossain, Md Aktar. "Mechanism of ABCA12 gene Mutation & its severity with improved management & Treatment". International Journal of Scientific & Engineering Research 14, n. 1 (25 gennaio 2023): 360–78. http://dx.doi.org/10.14299/ijser.2023.01.02.
Abstract (sommario):
Harlequin ichthyosis (HI) is a devastating skin disorder with an unknown underlying cause. Abnormal keratinocyte lamellar granules (LGs) are a hallmark of HI skin. ABCA12 is a member of the ATP-binding cassette transporter family, and members of the ABCA subfamily are known to have closely related functions as lipid transporters. ABCA3 is involved in lipid secretion via LGs from alveolar type II cells, and missense mutations in ABCA12 have been reported to cause lamellar ichthyosis type 2, a milder form of ichthyosis. Therefore, we hypothesized that HI might be caused by mutations that lead to serious ABCA12 defects.