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Membrane lipid biosynthesis. Principal pathways for the production of sterols, sphingolipids and phospholipids in mammals, and the key biosynthetic enzymes (pale green) and rate-limiting enzymes (green) involved. AGPAT, 1-acylglycerol-3-phosphate-O-acyltransferase; CCT, CTP:phosphocholine cytidylyltransferase; CDP-Cho, cytidinediphosphate choline; CDP-DAG, cytidine diphosphate-diacylglycerol; CDP-Eth, cytidine diphosphate ethanolamine; CDS, cytidine diphosphate diacylglycerol synthase; CEPT, choline/ethanolaminephosphotransferase; CERS, ceramide synthase; Cho, choline; CL, cardiolipin; CLS, cardiolipin synthase; CPE, ceramide phosphoethanolamine; CPT, cholinephosphotransferase; FAS, fatty acid synthase; GCS, glucosylceramide synthase; HMGCS, hydroxymethylglutaryl coenzyme A (CoA) synthase; HMGCR, 3-hydroxy-3-methylglutaryl-CoA reductase; Ins, inositol; PA, phosphatidic acid; PAP (also known as LIPIN), phosphatidic acid phosphatase; P-Cho, phosphocholine; PG, phosphatidylglycerol; PGP, phosphatidylglycerolphosphate; PIP, phosphoinositide; PtdCho, phosphatidylcholine; PtdEtn, phosphatidylethanolamine; PtdInsS, phosphatidylinositol synthase; PtdSer, phosphatidylserine; SMS, sphingomyelin synthase; SMSr, sphingomyelin synthase-related enzyme; SPT, serine palmitoyltransferase; TAG/CE, triacylglycerol/cholesterol ester.
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The lipid composition of cellular organelles is tailored to suit their specialized tasks. A fundamental transition in the lipid landscape divides the secretory pathway in early and late membrane territories, allowing an adaptation from biogenic to barrier functions. Defending the contrasting features of these territories against erosion by vesicula...
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... endoplasmic reticulum (ER) is the gateway of the secretory pathway and the principal site for membrane protein insertion and folding 20 . It is also the cell's main lipid factory, in which the bulk of phospholipids and sterols, as well as substantial amounts of storage lipids such as triacylglycerol and steryl esters, are produced (Fig. 2). In addition, the ER synthesizes ceramide, the precursor of all sphin- golipids. Besides exporting ceramide, the ER supplies a large portion of membrane lipids to the Golgi and plasma membrane because these distal secretory organelles have little or no capacity to produce their The double bonds introduce kinks that lower the packing ...
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... PtdCho is a major membrane lipid, its production is a crucial point of control in global membrane homeostasis. The rate- limiting step in PtdCho biosynthesis is the formation of cytidine diphosphate-choline, a reaction catalysed by cytidine triphosphate (CTP):phosphocholine cytidylyltransferase (CCT; Fig. 2). CCT con- tains an amphipathic helix -called domain M -that silences the activity of the enzyme in its soluble form 50 . In the presence of PtdCho bilayers with a high content of conical lipids such as diacylglycerol or PtdEtn, domain M undergoes a conformational switch that creates a hydrophobic face for membrane binding 51 . ...
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... promotes delivery of ceramide for sphingomyelin synthesis to set up a thermodynamic trap for sterols. A related process probably occurs in yeast, although the ceramide carrier has yet to be identi- fied 77 . PtdCho is required in the PtdIns/PtdCho exchange process that restores Golgi PtdIns levels 37 , as well as for sphingomyelin bio- synthesis (Fig. 2); because PtdCho is a bulk lipid, its high levels in the trans-Golgi ensure that these seemingly antagonistic demands are easily met. Thus, a number of pipelines intersect to ensure that sphin- golipid precursors reach the trans-Golgi in synchrony with sterol arrival, allowing a fundamental transition in the lipid landscape that divides ...
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... levels: when sphingolipid lev- els are low, TORC2 phosphorylates the Ypk1 and Ypk2 kinases to generate two outcomes. The first is an increase in the production of sphingolipid precursors in the ER. The rate-limiting step in the synthesis of sphingolipid precursors is catalysed by serine palmi- toyltransferase (SPT; Lcb1 or Lcb2 in yeast; Fig. 2) and regulated by Orm proteins [79][80][81] . SPT, Orm proteins and the PtdIns(4)P phosphatase Sac1 form the SPOTS complex in the ER membrane. SPT activity in the SPOTS complex is auto-inhibited, but this inhibition is relieved on Ypk1-and Ypk2-mediated phosphorylation of the Orm proteins. The second result of TORC2-mediated ...
Citations
... The picture is even more complicated, since cholesterol-induced changes of membrane properties strongly depend on the acyl chain saturation 16 and protein composition 13,14 . Furthermore, lipid trafficking by vesicular and non-vesicular mechanisms as well as lipid synthesis constantly change the membrane composition in cells 17 . Together, this makes understanding lipid organization in cellular membranes particularly challenging. ...
Subcellular membranes have complex lipid and protein compositions, which give rise to organelle-specific membrane packing, fluidity, and permeability. Due to its exquisite solvent sensitivity, the lipophilic fluorescence dye Nile Red has been used extensively to study membrane packing and polarity. Further improvement of Nile Red can be achieved by introducing electron-donating or withdrawing functional groups. Here, we compare the potential of derivatives of Nile Red with such functional substitutions for super-resolution fluorescence microscopy of lipid packing in model membranes and living cells. All studied Nile Red derivatives exhibit cholesterol-dependent fluorescence changes in model membranes, as shown by spectrally resolved stimulated emission depletion (STED) microscopy. STED imaging of Nile Red probes in cells reveals lower membrane packing in fibroblasts from healthy subjects compared to those from patients suffering from Niemann Pick type C1 (NPC1) disease, a lysosomal storage disorder with accumulation of cholesterol and sphingolipids in late endosomes and lysosomes. We also find small but consistent changes in the fluorescence lifetime of the Nile Red derivatives in NPC1 cells, suggesting altered hydrogen-bonding capacity in their membranes. All Nile Red derivatives are essentially non-fluorescent in water but increase their brightness in membranes, allowing for their use in MINFLUX single molecule tracking experiments. Our study uncovers the potential of Nile Red probes with functional substitutions for nanoscopic membrane imaging.
... The picture is even more complicated, since cholesterol-induced changes of membrane properties strongly depend on the acyl chain saturation (16) and protein composition (13,14). Furthermore, lipid trafficking by vesicular and non-vesicular mechanisms as well as lipid synthesis constantly change the membrane composition in cells (17). Together, this makes understanding lipid organization in cellular membranes particularly challenging. ...
Subcellular membranes have complex lipid and protein compositions, which give rise to organelle-specific membrane packing, fluidity, and permeability. Due to its exquisite solvent sensitivity, the lipophilic fluorescence dye Nile Red has been used extensively to study membrane packing and polarity. Further improvement of Nile Red can be achieved by introducing electron-donating or withdrawing functional groups. Here, we compare the potential of derivatives of Nile Red with such functional substitutions for super-resolution fluorescence microscopy of lipid packing in model membranes and living cells. All studied Nile Red derivatives exhibit cholesterol-dependent fluorescence changes in model membranes, as shown by spectrally resolved stimulated emission depletion (STED) microscopy. STED imaging of Nile Red probes in cells reveals lower membrane packing in fibroblasts from healthy subjects compared to those from patients suffering from Niemann Pick type C1 (NPC1) disease, a lysosomal storage disorder with accumulation of cholesterol and sphingolipids in late endosomes and lysosomes. We also find small but consistent changes in the fluorescence lifetime of the Nile Red derivatives in NPC1 cells, suggesting altered hydrogen-bonding capacity in their membranes. All Nile Red derivatives are essentially non-fluorescent in water but increase their brightness in membranes, allowing for their use in MIN-FLUX single molecule tracking experiments. Our study uncovers the potential of Nile Red probes with functional substitutions for nanoscopic membrane imaging.
... To determine if plasma membrane phospholipid redistribution from the plasma membrane was a general phenomenon when choline kinase activity was decreased we also determined the localization of phosphatidylserine (PS). Like PI(4,5)P 2 , PS is highly enriched in inner leaflet of the plasma membrane, with PS also found in late endocytic compartments and recycling endosomes (44,45,46,47). To determine PS localization we used a well characterized PS binding probe consisting of the C2 domain of lactadherin (LactC2) linked with monomeric RFP (mRFP-Lact-C2). ...
Phosphatidylcholine (PC) is the major membrane phospholipid in most eukaryotic cells. Bi-allelic loss of function variants in CHKB , encoding the first step in the synthesis of PC, is the cause of a rostrocaudal muscular dystrophy in both humans and mice. Loss of sarcolemma integrity is a hallmark of muscular dystrophies; however, how this occurs in the absence of choline kinase function is not known. We determine that in Chkb −/− mice there is a failure of the α7β1 integrin complex that is specific to affected muscle. We observed that in Chkb −/− hindlimb muscles there is a decrease in sarcolemma association/abundance of the PI(4,5)P 2 binding integrin complex proteins vinculin, and α-actinin, and a decrease in actin association with the sarcolemma. In cells, pharmacological inhibition of choline kinase activity results in internalization of a fluorescent PI(4,5)P 2 reporter from discrete plasma membrane clusters at the cell surface membrane to cytosol, this corresponds with a decreased vinculin localization at plasma membrane focal adhesions that was rescued by overexpression of CHKB .
... Organisms can respond to environmental changes by regulating the levels of glycerophospholipids, which have significant effects on processes such as material transport, energy conversion and signal mediation (Mittler et al., 2012). The most abundant glycerophospholipid is phosphatidylcholine (PC), which is involved in assembling the bilayer structure of cell membranes and has a vital contribution to the stability and fluidity of cell membranes (Holthuis and Menon, 2014). Phosphatidylserine (PS) drives the stability of the cell membrane surface (Grinstein, 2010) and affects the integrity of membrane protein functions by interacting with cell membrane peripheral proteins; thus, the importance of PS to the cell membrane cannot be underestimated (Magalhaes and Glogauer, 2009). ...
Microcystins release from bloom-forming cyanobacteria is considered a way to gain competitive advantage in Microcystis populations, which threaten water resources security and aquatic ecological balance. However, the effects of microcystins on microalgae are still largely unclear. Through simulated culture experiments and the use of UHPLC-MS-based metabolomics, the effects of two microcystin-LR (MC-LR) concentrations (400 and 1,600 μg/L) on the growth and antioxidant properties of three algae species, the toxic Microcystis aeruginosa, a non-toxic Microcystis sp., and Chlorella vulgaris, were studied. The MC-LR caused damage to the photosynthetic system and activated the protective mechanism of the photosynthetic system by decreasing the chlorophyll-a and carotenoid concentrations. Microcystins triggered oxidative stress in C. vulgaris, which was the most sensitive algae species studied, and secreted more glycolipids into the extracellular compartment, thereby destroying its cell structure. However, C. vulgaris eliminated reactive oxygen species (ROS) by secreting terpenoids, thereby resisting oxidative stress. In addition, two metabolic pathways, the vitamin B6 and the sphingolipid pathways, of C. vulgaris were significantly disturbed by microcystins, contributing to cell membrane and mitochondrial damage. Thus, both the low (400 μg/L) and the high (1,600 μg/L) MC-LR concentration inhibited algae growth within 3 to 7 days, and the inhibition rates increased with the increase in the MC-LR concentration. The above results indicate that the toxin-producing Microcystis species have a stronger toxin tolerance under longer-term toxin exposure in natural water environments. Thus, microcystins participates in interspecific interaction and phytoplankton population regulation and creates suitable conditions for the toxin-producing M. aeruginosa to become the dominant species in algae blooms.
... The content of fatty acids undergoes a dramatic change, and this mutation has been proven to be a fatal tumor characteristic, which can seriously damage the cell structure, such as the accumulation of fat, water excretion, protein structure, and even the presence of fatty acids is activated during the process of information transmission, which triggers the development of tumors [13]. Despite the fact that it has been shown that the rapid multiplication of tumor cells leads to the impairment of lipid biosynthesis, in reality, they are activated only 3-5, i.e., when the number of cancer cells exceeds the normal level [14]. ...
There is a close relationship between abnormal lipid metabolism and tumor malignant behavior, and abnormal lipid metabolism plays a crucial role in developing malignant tumors. Based on BiLSTM model, combined with Transformer Encoder and CRF decoder, the article successfully constructed a joint extraction model of medical literature, and with the help of Neo4j technology, built the knowledge graph of lipid metabolism abnormality and tumor occurrence and development. The study used data sources from WOSCC, CNKI, Wanfang, VIP, and other databases as data sources. It used bibliometric analysis and tools like CiteSpace and VOS viewer to visualize and analyze related studies in-depth. The study results showed that Oral Oncology in the UK ranked first in abnormalities of lipid metabolism in the number of publications, with a total of 301 related papers and an impact factor of 5.118. The number of studies related to oncology increased from 11 in 2010 to 414 in 2023, with a growth of more than 36.64 times. By comprehensively analyzing the current situation of abnormal lipid metabolism and tumorigenesis and development, this paper provides new ideas and perspectives for the study of cancer prevention, diagnosis, treatment and mechanism. It helps to promote the in-depth research and development of related fields.
... Much less is known about the effects of water-soluble or "amphitropic" proteins (APs), i.e., water-soluble proteins that reversibly associate with cellular membranes. APs are a subfamily of peripheral membrane proteins that interact directly with the lipid membrane rather than with intrinsic membrane proteins; therefore, this interaction is strongly influenced by membrane lipid composition [11,12]. ...
Using the gramicidin A channel as a molecular probe, we show that tubulin binding to planar lipid membranes changes the channel kinetics—seen as an increase in the lifetime of the channel dimer—and thus points towards modification of the membrane’s mechanical properties. The effect is more pronounced in the presence of non-lamellar lipids in the lipid mixture used for membrane formation. To interpret these findings, we propose that tubulin binding redistributes the lateral pressure of lipid packing along the membrane depth, making it closer to the profile expected for lamellar lipids. This redistribution happens because tubulin perturbs the lipid headgroup spacing to reach the membrane’s hydrophobic core via its amphiphilic α-helical domain. Specifically, it increases the forces of repulsion between the lipid headgroups and reduces such forces in the hydrophobic region. We suggest that the effect is reciprocal, meaning that alterations in lipid bilayer mechanics caused by membrane remodeling during cell proliferation in disease and development may also modulate tubulin membrane binding, thus exerting regulatory functions. One of those functions includes the regulation of protein–protein interactions at the membrane surface, as exemplified by VDAC complexation with tubulin.
... al., 2014). The organisation of membranes can be disturbed by cellular perturbations such as Ros heat changes (Holthuis andMenon, 2014, Kobayashi andMenon, 2018). As a result, animals have created sophisticated methods to return biological membranes to their homeostatic states. ...
Research shown that the cell death, particularly apoptosis, can extend beyond single cell boundaries. Gap junctions IP3 diffusion, and sphingolipids play significant roles in membrane biology and regulation of cell function. S1P plays crucial role in the cardiovascular and immune systems, serving as a mediator of signaling during cell migration, differentiation, proliferation, and apoptosis. Intestinal phospholipid metabolism, including 1B phospholipase A2 and autotaxin-mediated pathways, contributes to cardiometabolic diseases through multiple mechanisms. A potential strategy for treating cardiovascular and metabolic diseases is the therapeutic suppression of1B phospholipase A2 and autotaxin in the gastrointestinal tract. Cellular stress signalling, inflammation, resolution, and host defence responses are all significantly influenced by lysophospholipids such LPA and S1P. New therapies for cancer, vascular diseases, fibrotic disorders, and autoimmune diseases have been made possible by developments in lysophospholipid research.
... Eukaryotic cells organize biochemistry in a variety of organelles with characteristic membrane properties and compositions (van Meer et al. 2008;Harayama and Riezman 2018). Organelles exchange membrane material via vesicular traffic and lipid transfer proteins (Prinz 2010;Holthuis and Menon 2014), and they adjust their composition in response to metabolic and physical stimuli. Hence, cells invest substantial resources for maintaining characteristic organelle mem-brane compositions that ultimately establish membrane identity (Bigay and Antonny 2012). ...
The endoplasmic reticulum (ER) is the key organelle for membrane biogenesis. Most lipids are synthesized in the ER, and most membrane proteins are first inserted into the ER membrane before they are transported to their target organelle. The composition and properties of the ER membrane must be carefully controlled to provide a suitable environment for the insertion and folding of membrane proteins. The unfolded protein response (UPR) is a powerful sig- naling pathway that balances protein and lipid production in the ER. Here, we summarize our current knowledge of how aberrant compositions of the ER membrane, referred to as lipid bilayer stress, trigger the UPR.
... Although our data showed that increased PE was not primarily responsible for the ectopic gut lipid accumulation phenotype of dAcsl knockdown flies ( Supplementary Fig. S5e and f) ER is an extensive membranous organelle that stores Ca 2+ and serves as the primary site for lipid biosynthesis and protein maturation [58]. The precise composition of ER membrane lipids is expected to modulate membrane morphology and function [59]. Organelle-mediated stress, particularly ER stress, plays an important pathophysiological role in several chronic metabolic diseases [60]. ...
Interorgan lipid transport is crucial for organism development and the maintenance of physiological function. Here, we demonstrate that Drosophila long-chain acyl-CoA synthetase (dAcsl), which catalyzes the conversion of fatty acids into acyl-coenzyme As (acyl-CoAs), plays a critical role in regulating systemic lipid homeostasis. dAcsl deficiency in the fat body leads to the ectopic accumulation of neutral lipids in the gut, along with significantly reduced lipoprotein contents in both the fat body and hemolymph. The aberrant phenotypes were rescued by fat body-specific overexpression of apolipophorin. A multi-omics investigation comprising lipidomics, metabolomics, and proteomics in conjunction with genetic screening revealed that glycosylation processes were suppressed in dAcsl knockdowns. Overexpression of CG9035, human ortholog of which is implicated in the congenital disorder of glycosylation, ameliorated gut lipid accumulation in Drosophila. Aberrant lipoprotein glycosylation led to accelerated proteasome-related degradation and induced ER stress in dAcsl knockdown flies, impairing lipoprotein release into the circulation which compromised interorgan lipid transport between the fat body and the gut. Inhibition of ubiquitin-proteasome-dependent degradation alleviated the phenotype of gut ectopic fat accumulation in dAcsl knockdowns. Finally, we verified that ACSL4, the human homolog of dAcsl, also regulated lipoprotein levels in HepG2 cells, indicating that the role of dAcsl in modulating lipoprotein secretion and systemic lipid homeostasis is possibly conserved in humans.
... It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted January 17, 2024. ; https://doi.org/10.1101/2024.01.16.575677 doi: bioRxiv preprint composition, influences membrane physicochemical properties and physiological functions (57,58). The role of unsaturated lipids in modulating membrane fluidity has been well described (38,(59)(60)(61)(62)(63). ...
We report a conserved transcriptomic signature of reduced fatty acid and lipid metabolism gene expression in human post-mortem ALS spinal cord and a Drosophila model of the most common genetic cause of FTD/ALS, a repeat expansion in C9orf72 . To investigate lipid alterations, we performed lipidomics on C9FTD/ALS iPSC-neurons and post-mortem FTLD brain tissue. This revealed a common and specific reduction in phospholipid species containing polyunsaturated fatty acids (PUFAs). To determine whether this PUFA deficit contributes to neurodegeneration, we fed C9FTD/ALS flies PUFAs, which yielded a modest increase in survival. However, increasing PUFA levels specifically in neurons of the C9orf72 flies, by overexpressing fatty acid desaturase enzymes, led to a substantial extension of lifespan. Neuronal overexpression of fatty acid desaturases also suppressed stressor induced neuronal death in C9FTD/ALS patient iPSC-neurons. These data implicate neuronal fatty acid saturation in the pathogenesis of FTD/ALS and suggest that interventions to increase PUFA levels specifically within neurons will be beneficial.
