Alterations In Membrane Lipid Composition Research Articles

Lipotoxicity as a therapeutic target in obesity and diabetic cardiomyopathy.

Unhealthy sources of fats, ultra-processed foods with added sugars, and a sedentary lifestyle make humans more susceptible to developing overweight and obesity. While lipids constitute an integral component of the organism, excessive and abnormal lipid accumulation that exceeds the storage capacity of lipid droplets disrupts the intracellular composition of fatty acids and results in the release of deleterious lipid species, thereby giving rise to a pathological state termed lipotoxicity. This condition induces endoplasmic reticulum stress, mitochondrial dysfunction, inflammatory responses, and cell death. Recent advances in omics technologies and analytical methodologies and clinical research have provided novel insights into the mechanisms of lipotoxicity, including gut dysbiosis, epigenetic and epitranscriptomic modifications, dysfunction of lipid droplets, post-translational modifications, and altered membrane lipid composition. In this review, we discuss the recent knowledge on the mechanisms underlying the development of lipotoxicity and lipotoxic cardiometabolic disease in obesity, with a particular focus on lipotoxic and diabetic cardiomyopathy.

Altered fatty acid composition confers improved drought acclimation in maize

Drought induces alteration in membrane lipid composition in plants; however, still little is known about whether membrane lipid remodeling plays a role in plant drought acclimation, including both drought tolerance and recovery, especially in crops. Here, we imposed natural progressive drought and re-watering in 18 maize genotypes at the seedling stage, and analyzed the physiological responses, drought tolerance and drought acclimation capabilities, contents of lipids, and fatty acid compositions. The results showed that drought caused significant reductions in shoot dry weight, relative water content, Fv/Fm, total lipid content, and double bond index (DBI) in most genotypes, while re-watering partially recovered these reductions. Meanwhile, the total lipid content, fatty acid composition, and DBI were also changed obviously in response to drought and re-watering. In order to explore the relationship between membrane lipid change and plant drought response, we did a principal component analysis. The results showed that C18:3 fatty acid contributed greatly to drought tolerance, and C16:2 and C16:3 fatty acids were more responsible for drought recovery. Meanwhile, DBI showed significant positive correlations with shoot dry weight and relative water content, but a negative association with lipid peroxidation, and more importantly, DBI was important for both drought tolerance and recovery. These alterations in membrane lipid composition may facilitate increasing membrane fluidity and decreasing membrane damage, thus maintaining the high photosynthetic capability under drought. Our results suggest that lipid remodeling is important for drought tolerance and recovery in crops, and different fatty acid species have different roles in crop drought acclimation.

EHD2 regulates plasma membrane integrity and downstream insulin receptor signaling events.

Adipocyte dysfunction is a crucial driver of insulin resistance and type 2 diabetes. We identified EH domain-containing protein2(EHD2) as one of the most highly upregulated genes at the early stage of adipose-tissue expansion. EHD2 is a dynamin-related ATPase influencing several cellular processes, including membrane recycling, caveolae dynamics, and lipid metabolism. Here, we investigated the role of EHD2 in adipocyte insulin signaling and glucose transport. Using C57BL6/N EHD2 knockout mice under short-term high-fat diet conditions and 3T3-L1 adipocytes we demonstrate that EHD2 deficiency is associated with deterioration of insulin signal transduction and impaired insulin-stimulated GLUT4 translocation. Furthermore, we show that lack of EHD2 is linked with altered plasma membrane lipid and protein composition, reduced insulin receptor expression, and diminished insulin-dependent SNARE protein complex formation. In conclusion, these data highlight the importance of EHD2 for the integrity of the plasma membrane milieu, insulin receptor stability, and downstream insulin receptor signaling events, involved in glucose uptake and ultimately underscore its role in insulin resistance and obesity.

CPNE1 regulates myogenesis through the PERK-eIF2α pathway mediated by endoplasmic reticulum stress

Sarcopenia is characterized by a progressive reduction in muscle mass or muscle physiological function associated with aging, but the relevant molecular mechanisms are not clear. Here, we identify the role of the myogenesis modifier CPNE1 in sarcopenia. CPNE1 is upregulated in aged skeletal muscles and young skeletal muscle satellite cells with palmitate-induced atrophy. The overexpression of CPNE1 hinders proliferation and differentiation and increases muscle atrophy characteristics in young skeletal muscle-derived satellite cells. In addition, CPNE1 overexpression disrupts the balance of mitochondrial fusion and division and causes endoplasmic reticulum stress. We found that the effects of CPNE1 on mitochondrial function are dependent on the PERK/eIF2α/ATF4 pathway. The overexpression of CPNE1 in young muscles alters membrane lipid composition, reduces skeletal muscle fibrosis regeneration, and exercise capacity in mice. These effects were reversed by PERK inhibitor GSK2606414. Moreover, immunoprecipitation indicates that CPNE1 overexpression greatly increased the acetylation of PERK. Therefore, CPNE1 is an important modifier that drives mitochondrial homeostasis to regulate myogenic cell proliferation and differentiation via the PERK-eIF2α pathway, which could be a valuable target for age-related sarcopenia.

Cell Membrane Features as Potential Breeding Targets to Improve Cold Germination Ability of Seeds

Cold stress breeding that focuses on the improvement of chilling tolerance at the germination stage is constrained by the complexities of the trait which involves integrated cellular, biochemical, hormonal and molecular responses. Biological membrane serves as the first line of plant defense under stress. Membranes receive cold stress signals and transduce them into intracellular responses. Low temperature stress, in particular, primarily and effectively affects the structure, composition and properties of cell membranes, which ultimately disturbs cellular homeostasis. Under cold stress, maintenance of membrane integrity through the alteration of membrane lipid composition is of prime importance to cope with the stress. This review describes the critical role of cell membranes in cold stress responses as well as the physiological and biochemical manifestations of cold stress in plants. The potential of cell membrane properties as breeding targets in developing strategies to improve cold germination ability is discussed using cotton (Gossypium hirsutum L.) as a model.

Transcriptome and Metabolome Analyses Reveal Potential Salt Tolerance Mechanisms Contributing to Maintenance of Water Balance by the Halophytic Grass Puccinellia nuttalliana.

Elevated soil salinity exacerbated by human activities and global climate change poses serious threats to plant survival. Although halophytes provide many important clues concerning salt tolerance in plants, some unanswered questions remain to be addressed, including the processes of water and solute transport regulation. We performed high-throughput RNA-sequencing in roots and metabolome characterizations in roots and leaves of Puccinellia nuttalliana halophytic grass subjected to 0 (control) and 150 mM NaCl. In RNAseq, a total of 31 Gb clean bases generated were de novo assembled into 941,894 transcripts. The PIP2;2 and HKT1;5 transcript levels increased in response to the NaCl treatment implying their roles in water and ion homeostasis. Several transcription factors, including WRKY39, DEK3, HY5, and ABF2, were also overexpressed in response to NaCl. The metabolomic analysis revealed that proline and dopamine significantly increased due to the upregulation of the pathway genes under salt stress, likely contributing to salt tolerance mechanisms. Several phosphatidylcholines significantly increased in roots suggesting that the alterations of membrane lipid composition may be an important strategy in P. nuttalliana for maintaining cellular homeostasis and membrane integrity under salt stress. In leaves, the TCA cycle was enriched suggesting enhanced energy metabolism to cope with salt stress. Other features contributing to the ability of P. nuttalliana to survive under high salinity conditions include salt secretion by the salt glands and enhanced cell wall lignification of the root cells. While most of the reported transcriptomic, metabolomics, and structural alterations may have consequences to water balance maintenance by plants under salinity stress, the key processes that need to be further addressed include the role of the changes in the aquaporin gene expression profiles in the earlier reported enhancement of the aquaporin-mediated root water transport.

Lipidomic Profiling of Clinical Prostate Cancer Reveals Targetable Alterations in Membrane Lipid Composition.

Dysregulated lipid metabolism is a prominent feature of prostate cancer that is driven by androgen receptor (AR) signaling. Here we used quantitative mass spectrometry to define the "lipidome" in prostate tumors with matched benign tissues (n = 21), independent unmatched tissues (n = 47), and primary prostate explants cultured with the clinical AR antagonist enzalutamide (n = 43). Significant differences in lipid composition were detected and spatially visualized in tumors compared with matched benign samples. Notably, tumors featured higher proportions of monounsaturated lipids overall and elongated fatty acid chains in phosphatidylinositol and phosphatidylserine lipids. Significant associations between lipid profile and malignancy were validated in unmatched samples, and phospholipid composition was characteristically altered in patient tissues that responded to AR inhibition. Importantly, targeting tumor-related lipid features via inhibition of acetyl-CoA carboxylase 1 significantly reduced cellular proliferation and induced apoptosis in tissue explants. This characterization of the prostate cancer lipidome in clinical tissues reveals enhanced fatty acid synthesis, elongation, and desaturation as tumor-defining features, with potential for therapeutic targeting. SIGNIFICANCE: This study identifies malignancy and treatment-associated changes in lipid composition of clinical prostate cancer tissues, suggesting that mediators of these lipidomic changes could be targeted using existing metabolic agents.

Lipid-mediated impairment of axonal lysosome transport contributing to autophagic stress

ABSTRACT Efficient degradation of autophagic vacuoles (AVs) generated at axon terminals by mature lysosomes enriched in the cell body represents an exceptional challenge that neurons face in maintaining cellular homeostasis. Here, we discuss our recent findings revealing a lipid-mediated impairment of lysosome transport to distal axons contributing to axonal AV accumulation in the neurodegenerative lysosomal storage disorder Niemann-Pick disease type C (NPC). Using transmission electron microscopy, we observed a striking buildup of endocytic and autophagic organelles in NPC dystrophic axons, indicating defects in the clearance of organelles destined for lysosomal degradation. We further revealed that elevated cholesterol on NPC lysosome membranes abnormally sequesters motor-adaptors of axonal lysosome delivery, resulting in impaired anterograde lysosome transport into distal axons that disrupts maturation of axonal AVs during their retrograde transport route. Together, our study demonstrates a mechanism by which altered membrane lipid composition compromises axonal lysosome trafficking and positioning and shows that lowering lysosomal lipid levels rescues lysosome transport into NPC axons, thus reducing axonal autophagic stress at early stages of NPC disease.

Lipid-mediated motor-adaptor sequestration impairs axonal lysosome delivery leading to autophagic stress and dystrophy in Niemann-Pick type C.

Niemann-Pick disease type C (NPC) is a neurodegenerative lysosomal storage disorder characterized by lipid accumulation in endolysosomes. An early pathologic hallmark is axonal dystrophy occurring at presymptomatic stages in NPC mice. However, the mechanisms underlying this pathologic change remain obscure. Here, we demonstrate that endocytic-autophagic organelles accumulate in NPC dystrophic axons. Using super-resolution and live-neuron imaging, we reveal that elevated cholesterol on NPC lysosome membranes sequesters kinesin-1 and Arl8 independent of SKIP and Arl8-GTPase activity, resulting in impaired lysosome transport into axons, contributing to axonal autophagosome accumulation. Pharmacologic reduction of lysosomal membrane cholesterol with 2-hydroxypropyl-β-cyclodextrin (HPCD) or elevated Arl8b expression rescues lysosome transport, thereby reducing axonal autophagic stress and neuron death in NPC. These findings demonstrate a pathological mechanism by which altered membrane lipid composition impairs lysosome delivery into axons and provide biological insights into the translational application of HPCD in restoring axonal homeostasis at early stages of NPC disease.

A systematic framework for using membrane metrics for strain engineering

The cell membrane plays a central role in the fitness and performance of microbial cell factories and therefore it is an attractive engineering target. The goal of this work is to develop a systematic framework for identifying membrane features for use as engineering targets. The metrics that describe the composition of the membrane can be visualized as “knobs” that modulate various “outcomes”, such as physical properties of the membrane and metabolic activity in the form of growth and productivity, with these relationships varying depending on the condition. We generated a set of strains with altered membrane lipid composition via expression of des, fabA and fabB and performed a rigorous characterization of these knobs and outcomes across several individual inhibitory conditions. Here, the knobs are the relative abundance of unsaturated lipids and lipids containing cyclic rings; the average lipid length, and the ratio of linear and non-linear lipids (L/nL ratio). The outcomes are membrane permeability, hydrophobicity, fluidity, and specific growth rate. This characterization identified significant correlations between knobs and outcomes that were specific to individual inhibitors, but also were significant across all tested conditions. For example, across all conditions, the L/nL ratio is positively correlated with the cell surface hydrophobicity, and the average lipid length is positively correlated with specific growth rate. A subsequent analysis of the data with the individual inhibitors identified pairs of lipid metrics and membrane properties that were predicted to impact cell growth in seven modeled scenarios with two or more inhibitors. The L/nL ratio and the membrane hydrophobicity were predicted to impact cell growth with the highest frequency. We experimentally validated this prediction in the combined condition of 42 °C, 2.5 mM furfural and 2% v/v ethanol in minimal media. Membrane hydrophobicity was confirmed to be a significant predictor of ethanol production. This work demonstrates that membrane physical properties can be used to predict the performance of biocatalysts in single and multiple inhibitory conditions, and possibly as an engineering target. In this manner, membrane properties can possibly be used as screening or selection metrics for library- or evolution-based strain engineering.

Blood donor obesity is associated with changes in red blood cell metabolism and susceptibility to hemolysis in cold storage and in response to osmotic and oxidative stress.

Obesity is a global pandemic characterized by multiple comorbidities, including cardiovascular and metabolic diseases. The aim of this study was to define the associations between blood donor body mass index (BMI) and RBC measurements of metabolic stress and hemolysis. The associations between donor BMI (<25 kg/m2 , normal weight; 25-29.9 kg/m2 , overweight; and ≥30 kg/m2 , obese) and hemolysis (storage, osmotic, and oxidative; n = 18 donors) or posttransfusion recovery (n = 14 donors) in immunodeficient mice were determined in stored leukocyte-reduced RBC units. Further evaluations were conducted using the National Heart, Lung, and Blood Institute RBC-Omics blood donor databases of hemolysis (n = 13 317) and metabolomics (n = 203). Evaluations in 18 donors revealed that BMI was significantly (P < 0.05) and positively associated with storage and osmotic hemolysis. A BMI of 30 kg/m2 or greater was also associated with lower posttransfusion recovery in mice 10 minutes after transfusion (P = 0.026). Multivariable linear regression analyses in RBC-Omics revealed that BMI was a significant modifier for all hemolysis measurements, explaining 4.5%, 4.2%, and 0.2% of the variance in osmotic, oxidative, and storage hemolysis, respectively. In this cohort, obesity was positively associated (P < 0.001) with plasma ferritin (inflammation marker). Metabolomic analyses on RBCs from obese donors (44.1 ± 5.1 kg/m2 ) had altered membrane lipid composition, dysregulation of antioxidant pathways (eg, increased oxidized lipids, methionine sulfoxide, and xanthine), and dysregulation of nitric oxide metabolism, as compared to RBCs from nonobese (20.5 ± 1.0 kg/m2 ) donors. Obesity is associated with significant changes in RBC metabolism and increased susceptibility to hemolysis under routine storage of RBC units. The impact on transfusion efficacy warrants further evaluation.

Abstract 2076: Phospholipid profiling of clinical prostate tissues reveals targetable alterations in membrane lipid composition accompanying tumorigenesis

Abstract Membranes are unique phospholipid (PL) interfaces that play a central role in cancer cell biology. However, PL composition of clinical tumors, and its dynamic regulation, remains a critical gap in the molecular profiling of this disease. Here, we used mass spectrometry-based spatial imaging and lipidomics to generate PL profiles of clinical prostate tissues upon cancer development and in patient-derived tumor explants (PDEs; n=43) cultured with the current clinical agent enzalutamide. Analysis of more than 100 PL species in tumors and matched normal tissues from 21 patients revealed a complexity of cancer-related changes in the tissue PL landscape. Phosphatidylcholine (PC)-based PLs were the most abundant PL class, and their relative abundance was increased in tumors compared to matched benign tissues. A greater proportion of monounsaturated fatty acid chains was characteristic of PLs in tumors, most evident in the PC and phosphatidylethanolamine (PE) PLs, as was striking elongation of fatty acid chains in the phosphatidylinositol (PI) and phosphatidylserine (PS) classes. The abundance of specific PL species and saturation groups was significantly associated with malignancy in both this and an independent cohort of unmatched patient tissues (n=47). Notably, the PL profile was significantly associated with the ERG molecular subtype and basal proliferative index (Ki67) in tumors. Furthermore, we identified individual PL species that were associated with the antiproliferative response to enzalutamide, in cultured PDEs. In light of these PL features, we proposed acetyl coA carboxylase (ACC) as a novel therapeutic target in prostate cancer. Indeed, blocking lipid biosynthesis and elongation in prostate tumors with an ACC inhibitor (ACCi, PF-05175157) significantly reduced tumor cell proliferation in PDE tissues (n=13), concomitant with increased pACC1 staining and a decreased proportion of longer chain PLs. Our findings suggest that the clinical PCa lipidome is not only a marker of malignant transformation and aggressiveness, but also therapeutic response to enzalutamide. Moreover, defining this unique biology identified further clinically actionable targets that may improve prostate cancer outcomes. Citation Format: Lisa M. Butler, Chui Yan Mah, Jonas Dehairs, Andrew Vincent, Shadrack Mutuku, Xander Spotbeen, Rajdeep Das, Zeyad Nassar, Luke Selth, Paul Trim, Marten Snel, David Lynn, Lisa Horvath, Wayne Tilley, Margaret Centenera, Johannes Swinnen. Phospholipid profiling of clinical prostate tissues reveals targetable alterations in membrane lipid composition accompanying tumorigenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2076.

The Role of Triacylglycerol in Plant Stress Response.

Vegetable oil is mainly composed of triacylglycerol (TAG), a storage lipid that serves as a major commodity for food and industrial purposes, as well as an alternative biofuel source. While TAG is typically not produced at significant levels in vegetative tissues, emerging evidence suggests that its accumulation in such tissues may provide one mechanism by which plants cope with abiotic stress. Different types of abiotic stress induce lipid remodeling through the action of specific lipases, which results in various alterations in membrane lipid composition. This response induces the formation of toxic lipid intermediates that cause membrane damage or cell death. However, increased levels of TAG under stress conditions are believed to function, at least in part, as a means of sequestering these toxic lipid intermediates. Moreover, the lipid droplets (LDs) in which TAG is enclosed also function as a subcellular factory to provide binding sites and substrates for the biosynthesis of bioactive compounds that protect against insects and fungi. Though our knowledge concerning the role of TAG in stress tolerance is expanding, many gaps in our understanding of the mechanisms driving these processes are still evident. In this review, we highlight progress that has been made to decipher the role of TAG in plant stress response, and we discuss possible ways in which this information could be utilized to improve crops in the future.

Bacterial Cyclopropane Fatty Acid Synthase mRNA Is Targeted by Activating and Repressing Small RNAs.

Altering membrane protein and lipid composition is an important strategy for maintaining membrane integrity during environmental stress. Many bacterial small RNAs (sRNAs) control membrane protein production, but sRNA-mediated regulation of membrane fatty acid composition is less well understood. The sRNA RydC was previously shown to stabilize cfa (cyclopropane fatty acid synthase) mRNA, resulting in higher levels of cyclopropane fatty acids in the cell membrane. Here, we report that additional sRNAs, ArrS and CpxQ, also directly regulate cfa posttranscriptionally. RydC and ArrS act through masking an RNase E cleavage site in the cfa mRNA 5' untranslated region (UTR), and both sRNAs posttranscriptionally activate cfa In contrast, CpxQ binds to a different site in the cfa mRNA 5' UTR and represses cfa expression. Alteration of membrane lipid composition is a key mechanism for bacteria to survive low-pH environments, and we show that cfa translation increases in an sRNA-dependent manner when cells are subjected to mild acid stress. This work suggests an important role for sRNAs in the acid stress response through regulation of cfa mRNA.IMPORTANCE Small RNAs (sRNAs) in bacteria are abundant and play important roles in posttranscriptional regulation of gene expression, particularly under stress conditions. Some mRNAs are targets for regulation by multiple sRNAs, each responding to different environmental signals. Uncovering the regulatory mechanisms governing sRNA-mRNA interactions and the relevant conditions for these interactions is an ongoing challenge. In this study, we discovered that multiple sRNAs control membrane lipid composition by regulating stability of a single mRNA target. The sRNA-dependent regulation occurred in response to changing pH and was important for cell viability under acid stress conditions. This work reveals yet another aspect of bacterial physiology controlled at the posttranscriptional level by sRNA regulators.

Hypoxia-induced remodelling of goldfish membranes

Hypoxia-tolerant animals use metabolic suppression as an essential strategy to survive low oxygen. Ectotherms can alter membrane lipid composition in response to changes in environmental temperature, but it is currently unknown whether chronic hypoxia can also elicit membrane restructuring. The goal of this study was to investigate a possible physiological link between membrane remodelling and metabolic suppression in goldfish exposed to prolonged hypoxia (4 weeks at 10% air saturation). We have tested the hypothesis that chronic hypoxia would modulate membrane lipid composition in ways that are consistent with known mechanisms of ion pump inhibition. Because homeoviscous membrane restructuring could interfere with the response to hypoxia, measurements were made at 2 temperatures. Results show that hypoxic goldfish suppress metabolic rate by 74% (at 13 °C) and 63% (at 20 °C). This study is the first to reveal that cold-acclimated animals undergo extensive, tissue-specific restructuring of membrane lipids as they reach minimal metabolic rates. However, hypoxia does not affect membrane composition in fish acclimated to 20 °C. The strong membrane response of cold-acclimated fish involves increases in cholesterol abundance (in white muscle and gills) and in fatty acid saturation, mainly caused by a reduction in %22:6 (docosahexaenoic acid in gills and liver). Major ion pumps like Na+/K+-ATPase are known to be inhibited by cholesterol and activated by 22:6. Because ion pumping by membrane-bound ATPases accounts for a large fraction of basal cellular energy use, we propose that the membrane responses reported here could be a novel mechanism to promote metabolic suppression in cold-acclimated animals.

Chronic and Intermittent Ethanol Treatment Differentially Regulates Membrane Compartmentalization of G‐protein Subunits in Rat Brain

IntroductionEthanol exposure produces profound changes in the trafficking and activity of many G‐protein coupled receptors (GPCRs) which are associated with alcohol preference, tolerance, and dependence. However, the molecular mechanism involved in ethanol‐induced changes in receptor function remains unclear. Our lab previously found that ethanol treatment increases cholesterol content in rat brain, altering membrane lipid composition. Cholesterol, enriched in lipid rafts of membranes, plays an important role in membrane integrity and promotes the recruitment of signaling molecules. Ethanol‐induced disruption of brain cholesterol homeostasis would influence the signaling of many membrane‐bound GPCRs and channels. This study aimed to examine whether CIE also causes changes in the membrane localization of G‐protein subunits which are tightly associated with many GPCRs and channels.MethodsMale Sprague Dawley rats were exposed to 7 cycles of 12 hours of ethanol vapor inhalation followed by 12 hours of normal air. Rats were sacrificed 24 hours after the final ethanol exposure and the prefrontal cortex (PFC) tissue was dissected. Samples were homogenized followed by discontinuous sucrose density (5%–40%) ultracentrifugation and separated by density into 15 fractions. Western blotting was performed to determine the localization of G‐protein subunits on in lipid raft and non‐lipid raft fractions.ResultsCIE selectively altered membrane compartmentalization of certain subunits of G‐protein. There was an increase in localization of Gαo subunit from lipid rafts to non‐lipid rafts in CIE‐treated rat PFC. In contrast, CIE caused Gβ subunit to translocate from non‐lipid rafts to lipid rafts. Moreover, CIE had no effect on membrane compartmentalization of Gαi3 and Gαq. These results indicate selective changes in location of certain G‐protein subunits, altering proximal microdomain interaction with membrane channels and receptors and thus downstream signaling. This provides a possible mechanism underlying cholesterol‐mediated changes in GPCR signaling in rat brain tissue.Support or Funding InformationThis project is supported by NIH R01DA042862, P50DA006634, F31AA025532.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Sphingolipid/Pkh1/2-TORC1/Sch9 Signaling Regulates Ribosome Biogenesis in Tunicamycin-Induced Stress Response in Yeast.

Reduced ribosome biogenesis in response to environmental conditions is a key feature of cell adaptation to stress. For example, ribosomal genes are transcriptionally repressed when cells are exposed to tunicamycin, a protein glycosylation inhibitor that induces endoplasmic reticulum stress and blocks vesicular trafficking in the secretory pathway. Here, we describe a novel regulatory model, in which tunicamycin-mediated stress induces the accumulation of long-chain sphingoid bases and subsequent activation of Pkh1/2 signaling, which leads to decreased expression of ribosomal protein genes via the downstream effectors Pkc1 and Sch9. Target of rapamycin complex 1 (TORC1), an upstream activator of Sch9, is also required. This pathway links ribosome biogenesis to alterations in membrane lipid composition under tunicamycin-induced stress conditions. Our results suggest that sphingolipid/Pkh1/2-TORC1/Sch9 signaling is an important determinant for adaptation to tunicamycin-induced stress.

The Significance of Lipids to Biofilm Formation in Candida albicans: An Emerging Perspective.

Candida albicans, the dimorphic opportunistic human fungal pathogen, is capable of forming highly drug-resistant biofilms in the human host. Formation of biofilm is a multistep and multiregulatory process involving various adaptive mechanisms. The ability of cells in a biofilm to alter membrane lipid composition is one such adaptation crucial for biofilm development in C. albicans. Lipids modulate mixed species biofilm formation in vivo and inherent antifungal resistance associated with these organized communities. Cells in C. albicans biofilms display phase-dependent changes in phospholipid classes and in levels of lipid raft formation. Systematic studies with genetically modified strains in which the membrane phospholipid composition can be manipulated are limited in C. albicans. In this review, we summarize the knowledge accumulated on the impact that alterations in phospholipids may have on the biofilm forming ability of C. albicans in the human host. This review may provide the requisite impetus to analyze lipids from a therapeutic standpoint in managing C. albicans biofilms.

Exogenous application of gibberellic acid participates in up-regulation of lipid biosynthesis under salt stress in rice

Alterations in membrane lipid composition lead to improved plant salt tolerance. Gibberellic acid (GA3) has also been widely reported to reduce growth inhibition induced by increased salinity. However, little is known about whether exogenous application of GA3 participates in up-regulation of lipid biosynthesis under salt stress. In this study, one of the major lipid biosynthesis genes in rice (Oryza sativa L. cv. Nipponbare), monogalactosyldiacylglycerol synthase (OsMGD) was found to be significantly up-regulated by GA3 treatment. Lipid analysis showed that after salt disturbance, the concentrations of all the measured lipids, including monogalactosyldiacylglycerol (MGDG), digalactosyldiacylglycerol (DGDG) and phospholipid lipids + sulfoquinovosyl diacylglycerol (PL + SQDG) were decreased significantly. However, GA3 treatment prior to salt disturbance caused those lipids to remain at high levels, as well as preserving a high DGDG/MGDG ratio. The desaturation of DGDG (DBI) was also increased in GA3 pre-treatment plants as compared with no GA3 pre-treatment, primarily due to a decrease of 16:0 fatty acids and an increase of 18:3 fatty acids in DGDG. Plants pre-treated with GA3 prior to salt disturbance had higher dry weights than those without pre-treatment. The chlorophyll concentration was also higher in GA3 treated plants than in untreated plants under salt disturbance. Taken together, these results indicate that exogenous application of GA3 participates in up-regulation of chloroplast lipid biosynthesis under salt disturbance in rice.

Cell membranes. Molecular lipid therapy

Membrane lipids, due to diverse molecular structures, electric charge and different functional characteristic, have a profound role in multiple cytophysiological processes. A better understanding of the membrane structure and changes of its function in a wide range of diseases gave rise to a new approach termed membrane lipid therapy and directed to modifying the membranes. The strategies directed to membrane involve a direct regulation of membrane lipid composition that causes a change of the transmembrane protein function and modifies the organization of membrane microdomains, or regulation of enzyme activity and gene expression to alter membrane lipid composition. Membrane therapy assumes the use of new molecules specifically designed to modify lipid composition and function of abnormal signaling proteins. Therefore, modifications of the lipid composition and organization of membrane microdomains become pharmacological targets to reverse pathological changes in the profile of enzymatically and non-enzymatically generated lipid derivatives or to modify signaling pathways in the cell. The present monography is an update of the canonical membrane model by Singer-Nicolson and describes the therapeutic targets related to the regulation of the composition and organization of the lipids in the plasma membrane.