Letteratura scientifica selezionata sul tema "Lipid transporters"
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Articoli di riviste sul tema "Lipid transporters":
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.
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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.
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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.
Tesi sul tema "Lipid transporters":
1
Raggers, René John. "Lipid translocation by multidrug transporters". [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2001. http://dare.uva.nl/document/60218.
2
Alrosan, Amjad. "Characterization of Interacting Partners of ABC Lipid Transporters". Thesis, University of Sydney, 2020. https://hdl.handle.net/2123/22999.
Abstract (sommario):
This thesis outlines a series of experimental approaches that aim to investigate the roles of the co-factor Alix (apoptosis-linked gene 2-interacting protein X), the deubiquitinase USP9X (Ubiquitin-specific protease 9, X-linked), and sterols, including cholesterol synthesis intermediates and oxysterols, in the post-translational regulation of ATP-binding cassette (ABC) lipid transporters, ABCG1 and ABCG4. Alix and USP9X were identified in our laboratory using peptide mass spectrometry analysis as binding partners of ABCG1. The experiments presented in the following chapters characterize the effects of Alix, USP9X as well as sterols on the ABC transporters’ protein expression. Chapter 1 provides a general introduction about atherosclerosis and the important roles of ABC lipid transporters, including ABCA1 and ABCG1, in mediating cellular cholesterol balance through the reverse cholesterol transport (RCT) pathway. It presents also a general overview of Alzheimer’s disease (AD), and the suggested roles of the ABCA1, ABCG1 and ABCG4 transporters on AD progression. In addition, it describes the transcriptional and post-translational regulatory pathways of ABCA1, ABCG1 and ABCG4. This Chapter also outlines the roles of oxidized metabolites of cholesterol, i.e.‘oxysterols’, in atherosclerosis and AD. As an additional topic, it describes the roles of E3-ubiquitin ligases as well as deubiquitinases on the stability of proteins, such as the ABC lipid transporters, through the ubiquitin proteasomal pathway (UPS). Finally, this Chapter highlights the potential for therapeutic targeting of the UPS, and describes the hypotheses and aims of this thesis. In Chapter 2, materials and methods that are common to all the data chapters as described, including cell culture, optimization of siRNA transfection, preparation of cell lysates, SDS-PAGE and Western blotting, immunoprecipitations and cholesterol efflux experiments. Chapter 3 describes experiments investigating the role of the adaptor protein, Alix, as a potential cofactor between the E3-ubiquitin ligase NEDD4-1 (Neural precursor cell-expressed developmentally down regulated gene 4) and its target, ABCG1. NEDD4-1 is a HECT-domain E3-ubiquitin ligase that was previously identified in our laboratory as a regulator of ABCG1/ABCG4 protein expression (Aleidi, Howe et al. 2015). The experiments presented in this Chapter demonstrate that Alix and NEDD4-1 are co-expressed in a number of brain cell lines including astrocytes and neurons where ABCG1 is expressed. ABCG1 protein levels were significantly increased after knockdown of Alix when ABCG1 overexpressing CHOK1 cells were incubated only with full serum media (i.e. high cholesterol content). Interaction of Alix, NEDD4-1 and ABCG1 was established using a co-immunoprecipitation (co-IP) approach. These observations confirm that Alix is a novel player in regulating ABCG1 expression and facilitates the interaction between NEDD4-1 with ABCG1. Chapter 4 describes experiments investigating the role of Alix in the NEDD4-1 mediated regulation of ABCG4 protein, a close relative of ABCG1. Unlike ABCG1 that was increased after Alix knockdown only when the cells were maintained in full serum media (Chapter 3), Alix knockdown resulted in an upregulation of ABCG4 expression when ABCG4 overexpressing CHOK1 cells were incubated with full as well as low serum media (i.e. high and low cholesterol content). Like ABCG1, Alix and NEDD4-1 were co-immunoprecipitated with ABCG4 using a co-IP approach. These observations confirm that Alix regulates ABCG4 expression by being a potential co-factor between NEDD4-1 and ABCG4. Chapter 5 demonstrates experiments examining the effect of deubiquitinases (DUBs) and specifically USP9X, on ABCG1 and ABCG4 protein levels. Firstly, experiments presented indicated that the use of the general DUB inhibitor PR-619 produced toxic side effects on our cell models. However, treatment of these cells with WP1130, which is a more selective inhibitor for specific DUBs, including USP9X, significantly reduced ABCG1 protein levels in ABCG1 overexpressing CHOK1 cells. Further experiments described the effect of USP9X knockdown on ABCG1 protein levels, however these experiments were complicated by the fact that inconsistent results were found between three independent USP9X siRNA primers, each being effective in reducing USP9X protein expression. Overall, these experiments indicated a role for deubiquitinases in the regulation of ABCG1 protein expression, but were not able to confirm that this was solely due to USP9X. Chapter 6 outlines experiments investigating the role of sterols, including cholesterol, oxysterols and cholesterol synthesis intermediates in the regulation of ABCG1 and ABCG4. Incubating ABCG1 overexpressing CHOK1 cells with cholesterol, oxysterols and cholesterol synthesis intermediates enhanced ABCG1 protein levels, with the highest increase after the addition of Liver X Receptor (LXR) ligands, specifically 24S-OH. However, ABCG4 stabilization was enhanced when ABCG4 overexpressing CHOK1 cells were incubated with cholesterol as well as cholesterol synthesis intermediates, including desmosterol, lathosterol and lanosterol. Consequently, ABCG1 and ABCG4 are regulated differently at the post-translational levels by oxysterols and cholesterol synthesis intermediates. The toxicity of sterols on cells, assessed using a variety of methods, made overall conclusions complicated and indicated that further experiments are warranted. In conclusion, the work presented in this thesis shows promising regulators of cholesterol homeostasis in cells. It describes newly discovered roles for the cofactor Alix, inhibition of deubiquitinases, and sterols in the regulation of ABCG1 and ABCG4 protein expression. Unravelling these pathways by which cells can fine-tune their lipid transporter expression and hence cellular lipid levels provides avenues in future to find novel therapeutic targets for treatments in the setting of atherosclerosis and AD.
3
Charalambous, Kalypso Nicola. "The effect of lipid bilayer composition on small multidrug resistance transporters". Thesis, University of Bristol, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.432740.
4
Wei, Liang Shen. "Drug and lipid interactions on the ABC transporters ABCG1 and MsbA". Thesis, University of Cambridge, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609340.
5
Frangos, Zachary Joseph. "Investigating the molecular mechanism of bioactive lipid inhibitors of GlyT2". Thesis, The University of Sydney, 2022. https://hdl.handle.net/2123/28029.
Abstract (sommario):
Lipid modulation of glycine transport has attracted significant attention as a potential analgesic pathway for neuropathic pain conditions. An array of bioactive lipids that potently inhibit GlyT2 have recently been developed with one compound, C18 ω9 D-lysine (IC50 = 48 nM), demonstrating metabolic stability and analgesic properties in a neuropathic pain model. Despite this, the clinical viability of these bioactive lipids is limited due to their significant lipophilicity preventing effective clearance from the CNS. The first aim of my study was to perform structure activity relationships on second-generation bioactive lipids to identify a potent structural framework from which to reduce the lipophilicity of these compounds. In addition, I also sought to deepen our understanding of the molecular mechanisms that underlie the inhibitory activity of these lipids. The reversibility of oleoyl-L-carnitine has been shown to be enhanced by co-application of the cholesterol sequestering agent methyl-β-cyclodextrin (MβCD), suggesting a modulatory role of cholesterol on the activity of these GlyT2 inhibitors. The second aim of my study was to examine the influence of membrane cholesterol on the activity of bioactive lipid inhibitors of GlyT2. To achieve my first two aims wild-type and mutant GlyT2 transporters were expressed in Xenopus laevis oocytes with glycine transport and bioactive lipid inhibition measured using two-electrode voltage clamp electrophysiology.
18 bioactive lipids were synthesised, and their inhibitory activity was examined at GlyT2 and the closely related GlyT1. The double bond of the acyl lipid tail was exchanged for a phenylene ring substituted in the ortho, meta or para position and conjugated to various amino acid headgroups and tail lengths. In terms of potency, I found a tail substitution preference of meta > ortho > para and a headgroup preference for positively charged amino acids. There was also an optimal tail length for conferring potency (C18 > C16 > C14 > C12) with the most potent compound identified in this series, 8-8 meta-phenylene L-lysine (IC50 = 32 nM), demonstrating similar potency to its acyl equivalent. Molecular modelling of these compounds predicts that potency is dependent on the ability of the tail group to insert deeply into its binding site, highlighting the importance of this region, and suggesting that further optimisation of the physicochemical properties should focus on the lipid headgroup.
Treatment with MβCD suggests membrane cholesterol plays an important role in modulating the activity of bioactive lipids as cholesterol depletion decreased the potency and enhanced the reversibility of inhibition. A combination of molecular dynamics and site-directed mutagenesis studies revealed that this interaction is mediated via association of cholesterol, following bioactive lipid binding, to a conserved cholesterol site on neurotransmitter transporters formed by TMs 1, 5 and 7. In this site, cholesterol adopts a unique, flipped orientation and closely associates with the terminal end of the lipid tail. I propose that this interaction produces a complementary mechanism of action that enhances potency and alters the dissociation pathway from the lipid binding site, increasing reversibility. Due to the conserved nature of this site, it is likely that this modulation could readily be applied to other family members.
Currently the library of bioactive lipid inhibitors of GlyT2 consists of approximately 80 compounds, with only one examined in vivo. As this library continues to expand, it becomes increasingly important to explore alternative in vivo models that can identify lead compounds to test in neuropathic pain models. The final aim of my study was to examine the viability of zebrafish larvae as an in vivo model to test the activity of these compounds. This was achieved by investigating the role of glycinergic neurotransmission in larval zebrafish escape responses. Knockdown of zGlyT2 induced an impaired escape response which could be rescued by expression of hGlyT2, indicating the importance of glycinergic signalling in this response. Application of the bioactive lipid C18 ω9 D-lysine was able to re-establish this phenotype in larvae ectopically expressing hGlyT2, suggesting that zebrafish larvae are a viable alternative to test the in vivo activity of bioactive lipid GlyT2 inhibitors and identify lead compounds for analgesia studies.
The structure activity relationships performed here, in combination with the molecular mechanisms uncovered, will help drive the rational design of subsequent GlyT2 inhibitors that can be readily assessed in vivo.
6
Aleidi, Shereen Mohammad Suleimann. "Characterization of the Post-Translational Regulation of the ABCA1 and ABCG1 Lipid Transporters by E3 Ligases". Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/15477.
Abstract (sommario):
This thesis present a series of experimental approaches that aim to characterize the roles of three E3 ubiquitin ligase enzymes in the post-translational regulation of two ABC lipid transporters; ABCA1 and ABCG1. These E3 ligases, namely HECTD1 ( Homologous to E6Ap C-terminus Domain 1), HUWE1 (HECT, UBA, and WWE domain containing 1), and NEDD4-1 (Neural precursor cell-expressed developmentally down regulated gene 4), were identified during a previous work in our laboratory using peptide mass spectrometry analysis as associate proteins with ABCG1. The experiments presented in the following chapters investigate the effect of these ligases on the ABC transporters' protein expression and cholesterol activity. In addition, the possible mechanism underlying the mode of interaction between these ligases and the ABC transporters is also investigated in attempt to provide a more specific approach to future targeting strategies. Chapter1 provides an overview of atherosclerosis and the essential roles of ABCA1 and ABCG1 lipid transporters in maintaining cellular lipid homeostasis and mediating the macrophage reverse cholesterol transport (RCT) pathway. This chapter also presents a general overview regarding the developed anti-atherogenic therapeutic strategies, including those that attempted to upregulate these ABC transporters, although they were precluded due to drawbacks, indicating the need for a novel specific therapeutic strategy. In addition, it discusses the different regulatory pathways of ABCA1 and ABCG1, in particular the ubiquitin proteasomal pathway, and the role of E3 ligases that determine the specificity of the overall pathway. Chapter 2 describes the main experimental procedures that have been used throughout this thesis, including optimization of siRNA silencing as well as transient overexpression of the ligases in cultured cells, measurement of the ABC transporters' protein expression, immunoprecipitation approaches that detect the interaction between each ligase and ABC transporter, and cholesterol efflux assays that measure the activity of the transporter in exporting cholesterol from cultured cells to extracellular acceptors. Chapter 3 presents experiments investigating the role of the first E3 ligase, HECTD1, in the regulation of ABCA1 and ABCG1. These experiments propose that this newly discovered E3 ligase specifically regulates ABCA1 expression and activity, in a manner that is independent of any change in ABCG1. Silencing of HECTD1 substantially increased ABCA1 expression and cholesterol efflux from THP-1 macrophages to apoA-I, without affecting the ABCG1-mediated cholesterol export to HDL from these cells. The role of the other E3 ligases, HUWE1 and NEDD4-1, are addressed via experiments presented in chapter 4. These two E3 ligases seemed to have an additive effect on ABCG1 protein expression and activity, but not ABCA1. Simultaneous silencing of both ligases significantly increased ABCG1 protein levels and substantially more than the individual silencing. These effects on ABCG1 protein levels were translated to upregulation of the transporter activity. Silencing of both ligases significantly increased the ABCG1- mediated cholesterol export to HDL from cells overexpressing the transporter as well as from THP-1 macrophages. Reciprocally, overexpression of both ligases resulted in a significant decrease in ABCG1 protein levels, confirming their roles in the regulation of the transporter degradation. Chapter 5 illustrates a research strategy used to understand how NEDD4-1 can interact with ABCG1 and also to identify potential candidate adaptor proteins that may perhaps mediate this interaction. This strategy involved looking for specific proline-rich consensus sequences, which are essential for NEDD4-1 interaction with its substrate, in the original mass spectrometry peptide hits. Out of twenty three potential candidates that were investigated, four candidates fulfilled the requirements to act as an adaptor proteins. These findings highlight the probability that one of the identified candidate proteins might recruitNEDD4-1 to ABCG1 and thus facilitate ABCG1 ubiquitination. In conclusion, the work presented in this thesis explores the roles of three E3 ubiquitin ligases in the post-translational regulation of ABC lipid transporters. Identifying these ligases as specific molecular determinates for ABCA1 and ABCG1 ubiquitination and subsequent degradation would provide a new insight into the post-translational regulation of these lipid transporters, as well as into the discovery of a selective therapeutic approach to promote their upregulation.
7
Chantemargue, Benjamin. "In silico investigation of xenobiotic interactions with lipid bilayers and ABC membrane transporters, the case of ABCC4/MRP4". Thesis, Limoges, 2018. http://www.theses.fr/2018LIMO0077/document.
Abstract (sommario):
L’appréhension des mécanismes d’action biologiques des protéines membranaires nécessite de comprendre les interactions des xénobiotiques avec ces protéines et avec les membranes lipidiques. Les méthodes expérimentales sont parfois coûteuses et ne permettent d’obtenir que des informations partielles sur les interactions xénobiotiques-membrane-protéine. La modélisation moléculaire est une sérieuse alternative. Les simulations de dynamique moléculaire et de dynamique biaisées ont ouvert de nombreuses perspectives en permettant de décrire ces interactions moléculaires à l’échelle atomique. Grâce à des simulations de dynamique moléculaire, nous avons été capables de construire un modèle de transporteur humain ABC : ABCC4/MRP4. Cette protéine a été choisie pour sa présence dans le rein, notamment, et son importance clinique. Nous avons évalué l’influence du cholestérol sur cette protéine. L’étude de domaines spécifiques et l’impact d’un polymorphisme a été reliée à l’activité de transport de cette protéine. Nous avons également étudié l’interaction de xénobiotiques avec ce transporteur humain. Le cycle de transport des transporteurs ABC a été examiné afin de comprendre leur fonctionnement. L’incorporation de cholestérol a montré un impact significatif sur la protéine humaine ABCC4/MRP4 et sur les xénobiotiques étudiés. L’importance de domaines constituant la protéine ABCC4/MRP4 ainsi que l’importance de résidus individuels a clairement été prouvée. Nous avons également pu observer des intermédiaires du cycle de transport d’un transporteur ABC conjointement avec des changements structurauxUnderstanding the biological mechanisms of action of membrane proteins requires the comprehension of the interactions of xenobiotics with these proteins and with lipid membranes. Experimental methods are often demanding and only partially respond to xenobiotic-membrane-protein interactions. In silico molecular modeling is a serious alternative to tackle these issues. Molecular dynamics (MD) and biased dynamics simulations have opened many perspectives by providing an atomistic description of these intermolecular interactions. Using MD simulations, we built a model of the human ABC ABCC4/MRP4 transporter. We explored the influence of cholesterol on this protein as well as the impact of a polymorphism known to shut down the transport activity of this protein. We also studied the interaction of xenobiotics with this human transporter. The transport cycle of the ABC transporters was investigated in an attempt to better understand how it works.Interactions between lipid membranes and xenobiotics were explored by examining their ability to incorporate lipid membranes. Lipid mixtures with cholesterol showed a significant impact on the human protein ABCC4/MRP4 and on the xenobiotics studied. The importance of regions, domains constituting the ABCC4/MRP4 protein as well as the importance of specific residues has been clearly demonstrated. We also observed intermediates in the transport cycle of an ABC transporter in conjunction with structural changes occurring during this cycle
8
Basante-Bedoya, Miguel Angel. "Transporteurs lipidiques dans la morphogenèse du champignon pathogène opportuniste de l’Homme Candida albicans". Electronic Thesis or Diss., Université Côte d'Azur, 2021. http://theses.univ-cotedazur.fr/2021COAZ6030.
Abstract (sommario):
Candida albicans est un champignon pathogène opportuniste de l'homme qui peut causer des infections superficielles ou systémiques; sa capacité à passer d'une forme ovoïde à une forme filamenteuse est associée à sa virulence. Pendant cette croissance filamenteuse hautement polarisée, une accumulation de vésicules (Spitzenkörper), caractéristique des champignons filamenteux, ainsi qu'une distribution enrichie de lipides, tels que l'ergostérol, les dérivés phosphorylés du phosphatidylinositol (PI(4)P, PI(4,5)P2) et la phosphatidylsérine (PS) est observée à l'apex des filaments. Cependant, l'importance de l'asymétrie de ces lipides dans la bicouche membranaire est méconnue. Les flippases (P4-ATPases) transportent les lipides à travers la bicouche membranaire pour générer et maintenir son asymétrie. C. albicans a 5 flippases, incluant Drs2 qui est critique pour la croissance filamenteuse et la distribution de phosphatidylsérine (PS). De plus, un mutant de délétion drs2 est hypersensible au fluconazole et au cuivre et nous montrons ici qu’un tel mutant est aussi critique à la virulence dans un modèle murin d'infection systémique. Pour préciser le rôle de Drs2 pendant la croissance filamenteuse de C. albicans, nous avons étudié la distribution de cette ATPase, ainsi que celle de lipides et régulateurs clés, pendant l'initiation et le maintien de ce processus de croissance. Nous avons également caractérisé des mutants ponctuels de Drs2, analogues à ceux altérés pour le transport de PS chez S. cerevisiae. De plus, nous avons examiné l’importance d'autres flippases, telles que Dnf1-3, dans la croissance filamenteuse invasive ainsi que le rôle de transporteurs de lipides appartenant à la famille des « oxysterol binding protein » (Osh). Nos résultats indiquent que Drs2 joue un rôle unique dans le maintien de la croissance filamenteuse de C. albicans, qui paraît particulièrement critique après la formation du premier septum, et indiquent qu’une interaction entre Drs2 et Osh4, via PI(4)P, joue un rôle essentiel pour la croissance filamenteuseCandida albicans is a human opportunistic fungal pathogen that can cause superficial or systemic infections; its ability to change from an ovoid to a filamentous form is associated with its virulence. During this highly polarized filamentous growth, an accumulation of vesicles (Spitzenkörper), characteristic of filamentous fungi, as well as a polarized distribution of lipids, such as ergosterol, phosphorylated derivatives of phosphatidylinositol (PI(4)P, PI(4,5)P2) and phosphatidylserine (PS) is observed at the apex of filaments. However, the importance of the asymmetry of these lipids in the membrane bilayer is not completely understood. Flippases (P4-ATPases) transport lipids across the membrane bilayer to generate and maintain its asymmetry. C. albicans has 5 flippases, including Drs2 which is critical for filamentous growth and phosphatidylserine (PS) distribution. Furthermore, a drs2 deletion mutant is hypersensitive to fluconazole and copper. We show here that such a mutant is also critical to virulence in a mouse model of systemic infection. To clarify the role of Drs2 during C. albicans filamentous growth, we studied the distribution of this ATPase, as well as that of key lipids and regulators, during the initiation and maintenance of this growth process. We also characterized point mutants of Drs2, analogous to those altered for PS transport in S. cerevisiae. In addition, we examined the importance of other flippases, such as Dnf1-3, in invasive growth and the role of lipid transporters belonging to the oxysterol binding protein (Osh) family. Our results indicate in particular that Drs2 plays a unique role in the maintenance of invasive filamentous growth of C. albicans, which appears to be more critical after the first septum formation, and that an interaction between Drs2 and Osh4, via PI(4)P, plays an essential role during invasive filamentous growth
9
Lacabanne, Denis. "Solid-state NMR studies of the ABC transporter BmrA in its lipid environment". Thesis, Lyon, 2017. http://www.theses.fr/2017LYSE1243/document.
Abstract (sommario):
Les transporteurs à ATP binding cassette (ABC) peuvent transporter une grande variété de substrats utilisant l'ATP-Mg2+ comme source d'énergie. Ces transporteurs sont présents dans toutes les formes de vie et sont impliqués dans la résistance aux médicaments, comprenant les anticancéreux et les antibiotiques. Mes travaux de thèse se concentrent sur le transporteur BmrA (130 kDa) de Bacillus subtilis utilisé en tant que système modèle et homologue de la P-glycoprotéine humaine impliquée dans la multirésistance aux anticancéreux. Dans ces travaux nous montrons que la reconstitution de cette protéine dans les lipides de Bacillus subtilis répond aux deux exigences centrales pour RMN: haut rapport signal sur bruit et la stabilité de l'échantillon sur une période de plusieurs années. Les spectres obtenus indiquent une protéine bien repliée et une préparation très homogène, comme en témoignent les lignes de résonance étroites et la dispersion du signal typique de la distribution de structure secondaire attendue de la protéine membranaire. Nous avons adapté la méthode GRecon utilisée dans les études de microscopie électronique pour la reconstitution des protéines membranaires pour la RMN à l'état solide. Nous avons suivi en détail la reconstitution du transporteur ABC BmrA par dialyse comme référence, et établi des conditions optimales de reconstitution en utilisant un gradient combiné de saccharose / cyclodextrine / lipide caractérisant GRecon. Les spectres RMN de l‘échantillon reconstitué par GRecon sont très similaire à ceux obtenus précédemment sur des échantillons reconstitués par dialyse. La préparation d'échantillons par GRecon présente un gain de temps de près d'un ordre de grandeur. Afin d'étudier les états ouvert vers l'intérieur (inward-facing IF) et ouvert vers l'extérieur (outward-facing OF) du transporteur, nous avons développé un protocole reproductible et quantitatif induisant l'état OF. Nous avons enregistré des spectres bidimensionnels RMN à l'état solide avec différents temps de mélange (20 et 200 ms) afin de suivre les changements des déplacements chimiques et d'identifier les résidus par des corrélations séquentielles. L'apparition très apparente de nouveaux signaux concomitants à la grande amplitude des perturbations de déplacement chimique (CSP) met en évidence l'importante flexibilité et les changements conformationnels de la protéine en présence d'ATP: Mg2+. Afin d'identifier les résidus apparaissant dans les spectres, nous avons utilisé le remplacement paramagnétique du co-facteur Mg2+ par du Mn2+. Cette méthode a révélé que les acides aminés apparaissant dans les spectres sont situés à proximité du site de liaison de l'ATP. En outre, les mesures EPR ont confirmé l'état fermé de la protéine en identifiant la distance correspondant à 1,8 nm entre deux atomes de Mn2+. Nous avons étudié les différences conformationnelles entre l'état IF et OF de BmrA. L'observation de nombreux CSP, ainsi que l'apparition de nouveaux signaux sont observés pour un mutant ne pouvant pas hydrolyser l'ATP, indiquant que l'hydrolyse n'est pas nécessaire pour la transition IF à OF dans BmrA. Nous avons également analysé le mécanisme lié au motif X-loop décrit comme étant impliqué dans la communication entre deux domaines de la protéine. Nous avons observé pour une protéine mutante dans laquelle le transport est aboli mais qui reste ATPase active, une transition incomplète puisque seul un sous-ensemble de CSPs est observé, ainsi qu'un manque de rigidification. Ces mesures suggèrent que la flexibilité semble être le point central dans la transmission des changements conformationnels nécessaires de la partie motrice à la partie d'exportation de molécules. Ces observations montrent que ce système serait semblable à un moteur tournant à plein régime qui ne serait pas connecté de manière rigide à un arbre de transmission le reliant au système de transportATP binding cassette (ABC) transporters can translocate a variety of molecules by coupling drug/lipid efflux with an ATP-Mg2+ fuelled engine. They are found in all forms of life and they are involved in a number of drug resistances including anti-cancer drugs and antibiotics. My studies focus on the drug exporter BmrA (130 kDa) from Bacillus subtilis as a model system and homologue of the human P-glycoprotein that is involved in multidrug resistance in cancer. We show that the reconstitution of this protein in lipids from Bacillus subtilis at a lipid-protein ratio of 0.5 m/m allows an optimal protein insertion into lipid bilayer as well as it complies with the two central NMR requirements: high signal-to-noise in the spectra and sample stability over a time period of years. The obtained spectra point to a well-folded protein and a highly homogenous preparation, as witnessed by the narrow resonance lines and the signal dispersion typical of the expected secondary structure distribution of the membrane protein. In the same time, we adapted the GRecon method used in electron microscopy studies for membrane protein reconstitution to the needs of solid-state NMR sample preparation. We followed in detail the reconstitution of the ABC transporter BmrA by dialysis as a reference, and established optimal reconstitution conditions using the combined sucrose/cyclodextrin/lipid gradient characterizing GRecon. NMR spectra recorded on a sample produced by GRecon showed a highly similar fingerprint as those recorded previously on samples reconstituted by dialysis. GRecon sample preparation presents a gain in time of nearly an order of magnitude for reconstitution. In order to study the inward-facing (IF) and the outward-facing (OF) state of the transporter, we developed a reproducible and quantitative protocol of ATP:Mg2+:VO43- addition inducing the OF state. We used selectively labelled samples obtained by the addition of natural abundance residues in the bacterial medium in order to reduce the number of signals in the spectra of this large protein. We recorded solid-state NMR two-dimensional spectra with different mixing times (20 and 200 ms) in order to follow chemical shift changes and identify residues by sequential correlations. The very noticeable apparition of new signals concomitant with the large amplitude of chemical shift perturbations (CSPs) highlight the important flexibility and conformational changes of the protein in presence of ATP:Mg2+:VO43- substrate. In order to identify the residues appearing in the spectra, we use paramagnetic replacement by Mn2+ of the Mg2+ acting as a co-factor in the active site. The paramagnetic relaxation enhancements caused the Mn2+ revealed that the amino acids appearing in the spectra are located in proximity to the ATP binding pocket. Besides, EPR measurements confirmed the closed state of the protein by identifying the corresponding 1.8 nm distances between two Mn2+. We investigate on the conformational differences identified between the IF and OF state in the ABC transporter BmrA reconstituted in its natural lipids. The observation of numerous CSPs, as well as the apparition new signals are observed for a hydrolysis-incompetent mutant on addition of ATP, indicating that hydrolysis is not required for the IF to OF transition in BmrA. We also analyze the mechanistic of the X-loop motif described to be involved in the communication between two domains of the protein. We observe for a mutant protein in which transport is abolished, but which remains ATPase active, an incomplete transition since only a subset of CSPs is observed, as well as lack of rigidification. This suggests that the change in dynamics might be central for transmitting the relevant conformational changes to the part of the protein driving transport, concomitant of an engine which is turning an input shaft, but which fails to connect in a rigid manner, trough adequate gears, with the output shaft driving the pump
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Mathey, Aline. "Nouvelles stratégies thérapeutiques et chimiorésistance : molécules bioactives et métabolisme lipidique". Electronic Thesis or Diss., Bourgogne Franche-Comté, 2023. http://www.theses.fr/2023UBFCI014.
Abstract (sommario):
De nombreux échecs thérapeutiques persistent à cause de mécanismes d’adaptation et de résistance tumorale, tels que l’insensibilité aux signaux de mort cellulaire, la surexpression de transporteurs d’efflux de drogues (i.e. les transporteurs ABC caractéristiques du phénotype de résistance multiple aux drogues ou MDR), des mutations dans les voies de détection et de réparation des dommages à l’ADN ou encore une reprogrammation du métabolisme énergétique. Plus particulièrement, de plus en plus d’études suggèrent que des dérégulations du métabolisme des lipides de la mitochondrie, les cardiolipines, jouent un rôle dans la progression et l’agressivité tumorale, représentant une cible thérapeutique attractive depuis ces dernières années. De ce fait, de nouveaux protocoles thérapeutiques innovants reposant sur l’utilisation de molécules bioactives de faible toxicité sont apparus afin de surmonter la chimiorésistance, réduire la toxicité, les effets secondaires et potentialiser l’efficacité de l’agent chimiothérapeutique afin de prolonger l’espérance de vie et améliorer la qualité de vie des patients. Concernant la première partie de ce projet, nous avons démontré pour la première fois la capacité du xanthohumol, un flavonoïde prénylé extrait du houblon, à restaurer l’induction de dommages à l’ADN dans des cellules de cancer colorectal et à sensibiliser ces dernières à un agent anticancéreux couramment utilisé en clinique, le SN38. Nous avons également montré la capacité de deux huiles essentielles extraites d’Apiacées de Tunisie, Pituranthos chloranthus et Teucrium ramosissimum, à restaurer la sensibilité de cellules de sarcome utérin présentant le phénotype MDR, notamment à la doxorubicine, médiée par l’induction de l’apoptose, la diminution de la surexpression et de l’activité du transporteur ABC P-gp. Les travaux issus de la seconde partie de ce projet ont permis d’apporter une meilleure compréhension des relations existantes entre le métabolisme des cardiolipines et la chimiorésistance grâce à l’identification d’altérations du contenu, de la composition en cardiolipines et de facteurs moléculaires clés qui représentent de nouvelles cibles thérapeutiques potentielles afin de restaurer la sensibilité des tumeurs aux chimiothérapiesMany therapeutic failures persist due to adaptation and tumor resistance mechanisms, such as insensitivity to cell death signals, the overexpression of drug efflux transporters (i.e. ABC transporters involved in the multidrug resistance phenotype or MDR), mutations in DNA damage detection and repair pathways or reprogramming of energy metabolism. More specifically, an increasing number of studies suggest that deregulations of mitochondrial lipid metabolism, cardiolipins, play a role in tumor progression and aggressiveness, thereby representing an attractive therapeutic target in recent years. As a result, new innovative therapeutic protocols based on the use of bioactive molecules of low toxicity have appeared in order to overcome chemoresistance, reduce toxicity, side effects and potentiate the effectiveness of the chemotherapeutic drug in order to extend the life expectancy and enhance the quality of life of patients. Concerning the first part of this project, we demonstrated for the first time the ability of xanthohumol, a prenylated flavonoid extracted from hops, to restore the induction of DNA damage in colorectal cancer cells and to sensitize the latter to a commonly used clinically anticancer agent, SN38. We have also shown the ability of two essential oils extracted from Apiaceae in Tunisia, Pituranthos chloranthus and Teucrium ramosissimum, to restore the sensitivity of uterine sarcoma cells presenting the MDR phenotype, in particular to doxorubicin, mediated by the induction of apoptosis, the decrease in the overexpression and activity of the ABC transporter P-gp. The work resulting from the second part of this project provided a deeper insight into the existing relationships between cardiolipin metabolism and chemoresistance thanks to the identification of alterations in content, composition of cardiolipins and key molecular factors which represent new potential therapeutic targets in order to restore the sensitivity of tumors to chemotherapies
Capitoli di libri sul tema "Lipid transporters":
1
Nagao, Kohjiro, Naoto Juni e Masato Umeda. "Membrane Lipid Transporters in Drosophila melanogaster". In Bioactive Lipid Mediators, 165–80. Tokyo: Springer Japan, 2015. http://dx.doi.org/10.1007/978-4-431-55669-5_12.
2
Apell, Hans-Jürgen, e Valerij S. Sokolov. "Study of Ion Pump Activity Using Black Lipid Membranes". In Pumps, Channels, and Transporters, 23–49. Hoboken, NJ: John Wiley & Sons, Inc, 2015. http://dx.doi.org/10.1002/9781119085126.ch2.
3
Hisano, Yu, Tsuyoshi Nishi e Atsuo Kawahara. "Sphingosine 1-Phosphate Signaling via Transporters in Zebrafish and Mice". In Bioactive Lipid Mediators, 207–20. Tokyo: Springer Japan, 2015. http://dx.doi.org/10.1007/978-4-431-55669-5_15.
4
Salajegheh, Ali. "Adenosine Triphosphate-Binding Cassette (ABC) Lipid Transporters". In Angiogenesis in Health, Disease and Malignancy, 11–15. Cham: Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-28140-7_2.
5
Marcel, Yves L., Mireille Ouimet e Ming-Dong Wang. "Cellular Lipid Traffic and Lipid Transporters: Regulation of Efflux and HDL Formation". In Cellular Lipid Metabolism, 73–106. Berlin, Heidelberg: Springer Berlin Heidelberg, 2009. http://dx.doi.org/10.1007/978-3-642-00300-4_3.
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Modi, Chetna, Kaushik Kanada, Bhupendra Prajapati, Sohansinh Vaghela e Hiteshi Chadhaa. "Transfersomes as Transporters via Lipid-Based Drug Delivery System". In Lipid-Based Drug Delivery Systems, 185–212. New York: Jenny Stanford Publishing, 2023. http://dx.doi.org/10.1201/9781003459811-7.
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Bonen, Arend, Joost J. F. R. Luiken e Jan F. C. Glatz. "Regulation of fatty acid transport and membrane transporters in health and disease". In Cellular Lipid Binding Proteins, 181–92. Boston, MA: Springer US, 2002. http://dx.doi.org/10.1007/978-1-4419-9270-3_23.
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Alpy, Fabien, e Catherine L. Tomasetto. "STARD3: A Lipid Transfer Protein in Breast Cancer and Cholesterol Trafficking". In Cholesterol Transporters of the START Domain Protein Family in Health and Disease, 119–38. New York, NY: Springer New York, 2014. http://dx.doi.org/10.1007/978-1-4939-1112-7_6.
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Iaea, David B., Shu Mao e Frederick R. Maxfield. "Steroidogenic Acute Regulatory Protein-related Lipid Transfer (START) Proteins in Non-vesicular Cholesterol Transport". In Cholesterol Transporters of the START Domain Protein Family in Health and Disease, 173–88. New York, NY: Springer New York, 2014. http://dx.doi.org/10.1007/978-1-4939-1112-7_8.
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Clark, Barbara J., e Douglas M. Stocco. "An Introduction to the Steroidogenic Acute Regulatory Protein (StAR)-Related Lipid Transfer Domain Protein Family". In Cholesterol Transporters of the START Domain Protein Family in Health and Disease, 1–14. New York, NY: Springer New York, 2014. http://dx.doi.org/10.1007/978-1-4939-1112-7_1.
Atti di convegni sul tema "Lipid transporters":
1
Sundaresan, Vishnu Baba, e Donald J. Leo. "Actuation Using Protein Transporters Driven by Proton Gradient". In ASME 2006 International Mechanical Engineering Congress and Exposition. ASMEDC, 2006. http://dx.doi.org/10.1115/imece2006-15523.
Abstract (sommario):
A new mechanical actuation concept is demonstrated based on the controlled transport of fluid across semipermeable membranes. This concept is based on the pressurization of cells similar to the process that plants use to maintain homeostasis and regulate cell function. In all plant systems, the transport of ions and fluid produce localized pressure changes (called turgor pressure) that perform many cell functions, such as maintaining cell integrity and controlling plant growth. In this paper we demonstrate that the concept of fluid transport caused by protein transporters can be used to control the actuation properties of a mesoscale device. The device considered in this work consists of two chambers separated by a semipermeable membrane substrate that contains protein transporters suspended in a lipid bilayer. The protein transporters convert biochemical energy in the form of ATP into a protein gradient across the semipermeable membrane. The proton gradient, in turn, induces a flow of fluid across the porous substrate and pressurizes a closed volume. The experimental demonstration uses a directly applied gradient The pressurization of the closed volume produces a deformation in the coverplate of the chamber, thus transforming the chemical energy of the ATP into a measurable motion in the actuator. Experiments on the device demonstrate that micron-scale displacements can be induced in a millimeter-scale actuator. The time constant of the response is on the order of tens of seconds, and results clearly demonstrate that the amount of ATP and ATPase control the actuation properties of the device. To our knowledge this is the first demonstration of using natural protein transporters as the active component of a mechanical actuator.
2
Makhoul-Mansour, Michelle M., e Eric C. Freeman. "Photo-Triggered Soft Materials With Differentiated Diffusive Pathways". In ASME 2019 Conference on Smart Materials, Adaptive Structures and Intelligent Systems. American Society of Mechanical Engineers, 2019. http://dx.doi.org/10.1115/smasis2019-5525.
Abstract (sommario):
Abstract Controlled diffusive transport between regions within a compartmentalized structure is an essential feature of cellular-inspired materials. Using the droplet interface bilayer (DIB) technique, biomolecular soft materials can be constructed in an oil medium by connecting multiple lipid-coated microdroplets together through interfacial bilayers. While traditionally achieved through the incorporation of pore forming toxins (PFTs), signal propagation within DIB assemblies can be remotely controlled through the integration of photopolymerizable phospholipids (23:2 DiynePC) into the aqueous phase. Since such strategy allows for the formation of UV-C triggered pathways only between droplets both containing DiynePC, polymerizable phospholipids have shown an advantage of reducing undesired diffusion and forming conductive pathways. The partial polymerization of lipid bilayers formed through the DIB platform is still to this date underexplored in the literature. In a previous work, we have shown that the incorporation of 23:2 DiynePC into lipid bilayers allows for the creation of patterned conductive pathways in a 2D DIB structure. The properties of photosensitive bilayers were also investigated but not their channel activity. The functionalization of bilayers-based photosensitive structures through transmembrane channels remains an under-investigated mean of achieving further differentiated conductive channels. This work explores the reconstitution of several transmembrane channels such as alpha-hemolysin (αHL) and alamethicin (ALM) into partially polymerized lipid bilayers. We believe that the ability to incorporate transmembrane channels into photosensitive DIB soft structures allows for further differentiation of signal propagation pathways by including both edge-defect induced pores as well as more traditional and bio-derived transporters.
3
Sundaresan, Vishnu Baba, e Donald J. Leo. "Experimental Investigation for Chemo-Mechanical Actuation Using Biological Transport Mechanisms". In ASME 2005 International Mechanical Engineering Congress and Exposition. ASMEDC, 2005. http://dx.doi.org/10.1115/imece2005-81366.
Abstract (sommario):
Plants have the ability to develop large mechanical force from chemical energy available with bio-fuels. The energy released by the cleavage of a terminal phosphate ion during the hydrolysis of bio-fuel assists the transport of ions and fluids in cellular homeostasis. Materials that develop pressure and hence strain similar to the response of plants to an external stimuli are classified as nastic materials. Calculations for controlled actuation of an active material inspired by biological transport mechanism demonstrated the feasibility of developing such a material with actuation energy densities on the order of 100kJ/m3 by Sundaresan et. al [2004]. The mathematical model for a simplified proof of concept actuator referred to as micro hydraulic actuator uses ion transporters extracted from plants reconstituted on a synthetic bilayer lipid membrane (BLM). Thermodynamic model of the concept actuator discussed in Sundaresan et. al [2005] predicted the ability to develop 5% normalized deformation in thickness of the micro-hydraulic actuator. Our experimental demonstration of controlled fluid transport through AtSUT4 reconstituted on a 1-Palmitoyl-2-Oleoyl-sn-Glycero-3-[Phospho-L-Serine] (Sodium Salt) (POPS), 1-Palmitoyl-2-Oleoyl-sn-Glycero-3-Phosphoethanolamine (POPE) BLM on lead silicate glass plate having an array of 50 μm holes driven by proton gradient is discussed here.
4
Malcata, F. Xavier. "Engineering of microalgae toward biodiesel: Facts and prospects". In 2022 AOCS Annual Meeting & Expo. American Oil Chemists' Society (AOCS), 2022. http://dx.doi.org/10.21748/jeul5047.
Abstract (sommario):
Excessive release to the atmosphere of greenhouse-effect gases—arising from combustion of fossil fuels, has urged a worldwide search for alternative sources of environment-friendly fuels; microalgae constitute an interesting possibility, owing to their widespread presence in most habitats and unique ability to synthesize oil. Microalgae require indeed only sunlight and water to grow—both freely available; together with CO2 as source of carbon—which concomitantly conveys a path for its direct sequestering from the atmosphere; and low-cost inorganic sources of phosphorus and nitrogen. However, the efficiency of the associated metabolic processes is still poor—and this has so far hampered economic feasibility of such microbial factories for eventual manufacture of biodiesel. Recent advances in genetic engineering tools, systems and synthetic biology, and bioinformatics and omics have widened the portfolio of possibilities for tailor-made genome engineering of microalgae. A holistic approach is needed to metabolic engineering, in which various aspects of cellular metabolism—including transcription factors, transporters, competing pathways, and balance between growth and proliferation are to be taken into account. In attempts to harness the potential of genetic engineering upon microalga-mediated oil production, a realistic assessment of risks and opportunities is a must. The current state-of-the-art of metabolic engineering approaches will accordingly be presented, aimed at enhancing lipid productivity by microalgal strains; technical issues will be critically discussed as well. An overview of the challenges and prospects for technical applicability of such techniques will be tackled, focused on oil for esterification downstream as biodiesel—along with ethical concerns associated to large-scale utilization of such tools.
5
Zibert, A., S. Guttmann e HH Schmidt. "New role of copper transporter ATP7B in lipid metabolism of enterocytes". In 36. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber. Georg Thieme Verlag KG, 2020. http://dx.doi.org/10.1055/s-0039-3402196.
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Sundaresan, Vishnu Baba, e Donald J. Leo. "Modeling and Characterization of a Chemomechanical Actuator Based on Protein Transporters". In ASME 2007 International Mechanical Engineering Congress and Exposition. ASMEDC, 2007. http://dx.doi.org/10.1115/imece2007-43712.
Abstract (sommario):
Plants and animal cells are naturally occurring actuators that exhibit force and motion driven by fluid transport through the cell membrane. The protein transporters embedded in the cell membrane serve as the selective gateway for ion and fluid transport. The actuator presented in this work generates force and deformation from mass transport through an artificial membrane with protein transporters extracted from plant cell membranes. The artificial membrane is formed from purified 1-Palmitoyl-2-Oleoyl-sn-Glycero-3-[Phospho-L-Serine] (Sodium Salt) (POPS), 1-Palmitoyl-2-Oleoyl-sn-Glycero-3-Phosphoethanolamine (POPE) lipids and supported on a porous substrate. The protein transporter used in the actuator membrane is a proton-sucrose cotransporter, SUT4, extracted from yeast cells that genetically modified to grow the cotransporter in their cell membranes. The SUT4 transporter conducts proton and sucrose from the side of the membrane with higher concentration and carries water molecules across the membrane. It is observed from transport characterization experiments that fluid flux through the membrane varies with the applied sucrose concentration and hence is chosen as the control stimulus in the actuator. A modified four-state facilitated diffusion model is applied to the transport characterization data to compute the two characteristic parameters for fluid transport, saturation concentration and translocation rate, through the membrane. The flux rate through the membrane is observed to increase with the concentration till a particular value and saturates at a higher concentration. The concentration at which the flux rate through the membrane saturates is referred to as the saturation concentration. The saturation concentration for the actuator is experimentally found to be 6±0.6mM sucrose on the side with lower pH. The corresponding maximum translocation rate is found to be 9.6±1.2 nl/μ.cm2.min. The maximum steady state deformation produced by the actuator is observed at 30 mM sucrose that corresponds to a force of 0.89 mN.
7
Chowdhury, Saiful M., Xuewei Zhu, Jason G. Williams, Kathleen M. Azzam, B. A. Merrick, Kenneth B. Tomer, John S. Parks e Michael B. Fessler. "ATP Binding Cassette Transporter A1 Regulates The Lipid Raft Proteome Of The Macrophage". In American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California. American Thoracic Society, 2012. http://dx.doi.org/10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a1970.
8
Dixon, J. Brandon. "Engineering Tools for Studying the Interplay Between Mechanics and Biology in Lymphatic Lipid Transport". In ASME 2010 Summer Bioengineering Conference. American Society of Mechanical Engineers, 2010. http://dx.doi.org/10.1115/sbc2010-19364.
Abstract (sommario):
The lymphatic vasculature extends through most tissues of the body and plays an essential role in maintaining fluid balance, immune cell trafficking, and lipid transport. Nearly all dietary lipid is transported from the intestine to the circulation via the lymphatic system in the form of triglyceride-rich lipoproteins called chylomicrons. This process can be described through two different mechanisms: 1) entry of the chylomicron into the initial lymphatic vessels of the small intestine, known as lacteals, and 2) the transport of these chylomicrons through the larger collecting lymphatics by a complex and coordinated system of individual contracting vessel units (lymphangions) and valve leaflets. We describe here a set of in vitro and in vivo tools we have developed to study the mechanisms that modulate lipid transport under these two different paradigms and show how these tools are uncovering important biological features involved in these mechanisms. Lymphatic pump function is known to be sensitive to the mechanical load on the vessel as the contractility of isolated vessels has been shown to be both shear and stretch sensitive [1], yet whether these mechanisms are important in regulating contractile function in vivo remains uncertain.
9
Nara, Matsunori. "Invention Using a Liposome of a Bio-Micromachine". In ASME 4th Integrated Nanosystems Conference. ASMEDC, 2005. http://dx.doi.org/10.1115/nano2005-87031.
Abstract (sommario):
It is thought that a minus hydrogen ion is useful to the apotosis of a mitochondria and prevention of a necrosis, or prevention of the illness resulting from the oxygen radical in a human body. So, in this research, examination about the possibility and its practical use method of production of the hydrogen ion by which it was minus electrified was performed. First, the lipid bilayer as a medicine transporter of DDS (Drug Delivery System) was produced using the supercritical fluid. Next, experimental examination was performed for the purpose of enclosing the substance for hydrogen ion generating, and the substance for electronic accumulation with the inside of a lipid bilayer. Furthermore, fundamental examination was performed in order to use the enclosed minus hydrogen ion. In order to check what the electron of oxygen ion was taken into the hydrogen ion, and the minus hydrogen ion generated, electrical conductivity measurement was performed. By mixing and heating, 12CaO · 7Al2O3 and metal calcium, the electron was accumulated in the inside of the reaction object of 12CaO7Al2O3. The check of accumulation of the electron (anion) inside a reaction object was judged by measurement of the electrical conductivity before and behind processing. That is, when the electron was accumulated, I thought that the electrical conductivity of a reaction object increased. Moreover, this reaction object was used as an electronic transporter. In the range of the temperature set up in the liposome production experiment, and pressure, it could not say that the influence temperature and pressure affect the determination of the particle diameter of a liposome was large, but average particle diameter was about 10 micrometers. The following conclusions were obtained as a result of conducting a fundamental experiment for the purpose of production of a medicine which made the minus hydrogen ion include inside a lipid bilayer (liposome), and a confirmation of the validity as DDS in the living body. (1) The liposome suitable for DDS was able to be obtained. (2) By using metal magnesium and metal calcium, the minus hydrogen ion was able to be accumulated in the reaction inside of the body of alumina cement.
10
Mulugeta, S., e M. Zhao. "Chronic Expression of an Aberrantly Trafficked Mutant ABCA3 Lipid Transporter Promotes Selective Upregulation of the Unfolded Protein Response and Increased Amphisome-Mediated Autophagy". In American Thoracic Society 2021 International Conference, May 14-19, 2021 - San Diego, CA. American Thoracic Society, 2021. http://dx.doi.org/10.1164/ajrccm-conference.2021.203.1_meetingabstracts.a4248.
Rapporti di organizzazioni sul tema "Lipid transporters":
1
Cai, TingYu, Li Zhang, Ting Yang e Yang Gao. Effects of different dosages of Sodium-Glucose Transporter 2 Inhibitors on lipid levels in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. INPLASY - International Platform of Registered Systematic Review Protocols, aprile 2020. http://dx.doi.org/10.37766/inplasy2020.4.0201.
2
Barg, Rivka, Kendal D. Hirschi, Avner Silber, Gozal Ben-Hayyim, Yechiam Salts e Marla Binzel. Combining Elevated Levels of Membrane Fatty Acid Desaturation and Vacuolar H+ -pyrophosphatase Activity for Improved Drought Tolerance. United States Department of Agriculture, dicembre 2012. http://dx.doi.org/10.32747/2012.7613877.bard.
Abstract (sommario):
Background to the topic: In previous works we have shown that Arabidopsis and tomato over-expressing H+-pyrophosphatase show increased tolerance to drought imposed by withholding irrigation of young plants in pots (Park et al. 2005). In addition, young tobacco plants over-expressing fatty acid desaturase 3 (OEX-FAD3) also showed increasing tolerance to drought stress (Zhang et al 2005), and similarly OEX-FAD3 young tomato plants (unpublished data from ARO), hence raising the possibility that pyramiding the two could further improve drought tolerance in tomato. Based on these findings the specific objects originally set were: 1. To analyze the impact of pyramiding transgenes for enhanced fatty acid desaturation and for elevated H+-PPase activity on tomato yielding under water deficit stress conditions. 2. To elucidate the biochemical relationship between elevated desaturation of the membrane lipids and the activities of selected vacuolar transporters in the context of drought responses. 3. To explore the S. pennellii introgression lines as alternative genetic sources for drought tolerance related to enhanced fatty acid desaturation and/or H+-PPase activity. 4. Since OEX-FAD3 increases the levels of linolenic acid which is the precursor of various oxylipins including the stress hormone Jasmonate. (JA), study of the effect of this transgene on tolerance to herbivore pests was added as additional goal. The Major conclusions, solutions, and achievements are: (1) The facts that ectopic over-expression of vacuolarH+-PPases (in line OEX-AVP1) does not change the fatty acid profile compared to the parental MoneyMaker (MM) line and that elevated level of FA desaturation (by OEX-FAD3) does not change the activity of either H+-PPase, H+-ATPaseor Ca2+ /H+ antiport, indicate that the observed increased drought tolerance reported before for increase FA desaturation in tobacco plants and increased H+PPase in tomato plants involves different mechanisms. (2) After generating hybrid lines bringing to a common genetic background (i.e. F1 hybrids between line MP-1 and MM) each of the two transgenes separately and the two transgenes together the effect of various drought stress regimes including recovery from a short and longer duration of complete water withhold as well as performance under chronic stresses imposed by reducing water supply to 75-25% of the control irrigation regime could be studied. Under all the tested conditions in Israel, for well established plants grown in 3L pots or larger, none of the transgenic lines exhibited a reproducible significantly better drought tolerance compare to the parental lines. Still, examining the performance of these hybrids under the growth practices followed in the USA is called for. (3) Young seedlings of none of the identified introgression lines including the S. pennellii homologs of two of the H+-PPase genes and one of the FAD7 genes performed better than line M82 upon irrigation withhold. However, differences in the general canopy structures between the IL lines and M82 might mask such differences if existing. (4). Over-expression of FAD3 in the background of line MP-1 was found to confer significant tolerance to three important pest insects in tomato: Bordered Straw (Heliothis peltigera), Egyptian cotton leafworm (Spodoptera littoralis) and Western Flower Thrips (Frankliniella occidentalis). Implications: Although the original hypothesis that pyramiding these two trasgenes could improve drought tolerance was not supported, the unexpected positive impact on herbivore deterring, as well as the changes in dynamics of JA biosynthesis in response to wounding and the profound changes in expression of wound response genes calls for deciphering the exact linolenic acid derived signaling molecule mediating this response. This will further facilitate breeding for herbivore pest and mechanical stress tolerance based on this pathway.