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Purpose of Review: To provide an update on the diagnosis of non-specific Lipid Transfer Protein (nsLTP) allergy. Recent Findings: More publications report the presence of nsLTP allergy in Northern European countries and nsLTP sensitisation in children. Individuals are more likely to have severe reactions if there is recognition of increasing numbers of LTP components. Diagnosis is problematic; not all those with nsLTP allergy will have a positive test to a peach extract containing Pru p 3, the peach nsLTP. Summary: Sensitisation to nsLTP is being reported in more countries, including to the nsLTP in Cannabis Sativa in North America. Meals containing multiple nsLTP foods are more likely to be involved in co-factor reactions. Component-resolved diagnostics are superior to skin prick tests, to determine sensitisation to the individual nsLTP allergens causing symptoms and, in the future, the Basophil Activation test may best discriminate between sensitization and clinical allergy. [ABSTRACT FROM AUTHOR]

Various lipid transfer proteins (LTPs) mediate the inter‐organelle transport of lipids. By working at membrane contact zones between donor and acceptor organelles, LTPs achieve rapid and accurate inter‐organelle transfer of lipids. This article will describe the emerging paradigm that the action of LTPs at organelle contact zones generates metabolic channeling events in lipid metabolism, mainly referring to how ceramide synthesized in the endoplasmic reticulum is preferentially metabolized to sphingomyelin in the distal Golgi region, how cholesterol and phospholipids receive specific metabolic reactions in mitochondria, and how the hijacking of host LTPs by intracellular pathogens may generate new channeling‐like events. In addition, the article will discuss how the function of LTPs is regulated, exemplified by a few representative LTP systems, and will briefly touch on experiments that will be necessary to establish the paradigm that LTP‐mediated inter‐organelle transport of lipids is one of the mechanisms of compartmentalization‐based metabolic channeling events. [ABSTRACT FROM AUTHOR]

The adaption of plants to stressful environments depends on long-distance responses in plant organs, which themselves are remote from sites of perception of external stimuli. Jasmonic acid (JA) and its derivatives are known to be involved in plants' adaptation to salinity. However, to our knowledge, the transport of JAs from roots to shoots has not been studied in relation to the responses of shoots to root salt treatment. We detected a salt-induced increase in the content of JAs in the roots, xylem sap, and leaves of pea plants related to changes in transpiration. Similarities between the localization of JA and lipid transfer proteins (LTPs) around vascular tissues were detected with immunohistochemistry, while immunoblotting revealed the presence of LTPs in the xylem sap of pea plants and its increase with salinity. Furthermore, we compared the effects of exogenous MeJA and salt treatment on the accumulation of JAs in leaves and their impact on transpiration. Our results indicate that salt-induced changes in JA concentrations in roots and xylem sap are the source of accumulation of these hormones in leaves leading to associated changes in transpiration. Furthermore, they suggest the possible involvement of LTPs in the loading/unloading of JAs into/from the xylem and its xylem transport. [ABSTRACT FROM AUTHOR]

Food allergy (FA) has shown an increasing prevalence in the last decades, becoming a major public health problem. However, data on the prevalence of FA across the world are heterogeneous because they are influenced by several factors. Among IgE-mediated FA, an important role is played by FA related to plant-derived food which can result from the sensitization to a single protein (specific FA) or to homologous proteins present in different foods (cross-reactive FA) including non-specific lipid transfer proteins (nsLTPs), profilins, and pathogenesis-related class 10 (PR-10). In addition, the clinical presentation of FA is widely heterogeneous ranging from mild symptoms to severe reactions up to anaphylaxis, most frequently associated with nsLTP-related FA (LTP syndrome). Considering the potential life-threatening nature of nsLTP-related FA, the patient's geographical setting should always be taken into account; thereby, it is highly recommended to build a personalized approach for managing FA across the world in the precision medicine era. For this reason, in this review, we aim to provide an overview of the prevalence of nsLTP-mediated allergies in the Mediterranean area and to point out the potential reasons for the different geographical significance of LTP-driven allergies with a particular focus on the allergenic properties of food allergens and their cross reactivity. [ABSTRACT FROM AUTHOR]

Over the past two decades, we have witnessed a growing appreciation for the importance of membrane contact sites (CS) in facilitating direct communication between organelles. CS are tiny regions where the membranes of two organelles meet but do not fuse and allow the transfer of metabolites between organelles, playing crucial roles in the coordination of cellular metabolic activities. The significant advancements in imaging techniques and molecular and cell biology research have revealed that CS are more complex than what originally thought, and as they are extremely dynamic, they can remodel their shape, composition, and functions in accordance with metabolic and environmental changes and can occur between more than two organelles. Here, we describe how recent studies led to the identification of a three‐way mitochondria–ER–lipid droplet CS and discuss the emerging functions of these contacts in maintaining lipid storage, homeostasis, and balance. We also summarize the properties and functions of key protein components localized at the mitochondria–ER–lipid droplet interface, with a special focus on lipid transfer proteins. Understanding tripartite CS is essential for unraveling the complexities of inter‐organelle communication and cooperation within cells. [ABSTRACT FROM AUTHOR]

Numerous lipids are heterogeneously distributed among organelles. Most lipid trafficking between organelles is achieved by a group of lipid transfer proteins (LTPs) that carry lipids using their hydrophobic cavities. The human genome encodes many intracellular LTPs responsible for lipid trafficking and the function of many LTPs in defining cellular lipid levels and distributions is unclear. Here, we created a gene knockout library targeting 90 intracellular LTPs and performed whole-cell lipidomics analysis. This analysis confirmed known lipid disturbances and identified new ones caused by the loss of LTPs. Among these, we found major sphingolipid imbalances in ORP9 and ORP11 knockout cells, two proteins of previously unknown function in sphingolipid metabolism. ORP9 and ORP11 form a heterodimer to localize at the ER-trans-Golgi membrane contact sites, where the dimer exchanges phosphatidylserine (PS) for phosphatidylinositol-4-phosphate (PI(4)P) between the two organelles. Consequently, loss of either protein causes phospholipid imbalances in the Golgi apparatus that result in lowered sphingomyelin synthesis at this organelle. Overall, our LTP knockout library toolbox identifies various proteins in control of cellular lipid levels, including the ORP9-ORP11 heterodimer, which exchanges PS and PI(4)P at the ER-Golgi membrane contact site as a critical step in sphingomyelin synthesis in the Golgi apparatus.

Phosphatidylinositol 4-monophosphate (PtdIns(4)P) is one of the key membrane components which mark the membrane contact sites. In the mammalian Golgi complex, PtdIns(4)P is produced at various subregions via specific mechanisms for each site. Particularly, PtdIns(4)P pools generated at the distal Golgi regions are pivotal for the determination of membrane contacts between the endoplasmic reticulum (ER) and Golgi, at which inter-organelle lipid transport takes place. In this short review, we will focus on C10orf76 (or ARMH3), which we propose to rename as DGARM after a d istal G olgi arm adillo repeat protein, for its function in generating a PtdIns(4)P pool crucial for ER-to-distal Golgi ceramide transport. We further discuss from the viewpoint of the evolutionary conservation of DGARM. [ABSTRACT FROM AUTHOR]

This work reports analysis of lipid transfer protein (LTPs) mRNA levels in rat soleus muscle after 12-h and 14-day hindlimb suspension (HS). The LTP genes of interest were as follows: ceramide transporter 1 (CERT1), ceramide-1-phosphate transporter protein (CPTP), sphingosine-1-phosphate transporter (Protein spinster homolog 2—SPNS2), four-phosphate adaptor protein 2 (FAPP2) transferring glucosylceramide, and oxysterol-binding proteins OSBP and ORP4 (family I of OSBP-related proteins). LTP mRNA expression was analyzed using RT-PCR. Early changes in the expression of LTP genes after 12-h HS were characterized by the dramatic decrease in mRNA content of CERT1, CPTP, SPNS2 and ORP4 genes. In contrast, the expression of the FAPP2 gene was increased, whereas OSBP mRNA content did not change as compared to the control level. After the 14-day HS only CERT1 and CPTP mRNA levels remained decreased while expression of other LTP genes did not significantly differ from the control values. Clomipramine treatment did not affect sphingolipid transporters and OSBPs at the early period of HS, but notably enhanced the expression of CERT1, CPTP, FAPP2, and both OSBPs genes in soleus muscle of rats subjected to 14-day unloading. Our data indicate that short-term and long-term muscle unloading differently affects the expression of genes encoding LTPs for sphingolipid and cholesterol intracellular transport. Only ceramide and ceramide-1-phosphate transporters were decreased at both periods of disuse. Taking into account our previous data about acid sphingomyelinase (aSMase) and ceramide up-regulation in the unloaded soleus muscle, as well as a normalizing effect of clomipramine on both high ceramide level and low expression of its transporters at 14-day HS, we can assume that there must be a feedback mechanism in regulation of CERT1 and CPTP genes expression in case of ceramide accumulation caused by disuse. [ABSTRACT FROM AUTHOR]

The lipid phosphatidylinositol 4-phosphate (PI4P) plays a master regulatory role at Golgi membranes, orchestrating membrane budding, non-vesicular lipid transport and membrane organization. It follows that harmonious Golgi function requires strictly maintained PI4P homeostasis. One of the most abundant PI4P effector proteins is the oxysterol binding protein (OSBP), a lipid transfer protein that exchanges trans-Golgi PI4P for ER cholesterol. Although this protein consumes PI4P as part of its lipid anti-porter function, whether it actively contributes to Golgi PI4P homeostasis has been questioned. Here, we employed a series of acute and chronic genetic manipulations, together with orthogonal targeting of OSBP, to interrogate its control over Golgi PI4P abundance. Modulating OSBP levels at ER:Golgi membrane contact sites produces reciprocal changes in PI4P levels. Additionally, we observe that OSBP has a high capacity for PI4P turnover, even at orthogonal organelle membranes. However, despite also visiting the plasma membrane, endogenous OSBP makes no impact on PI4P levels in this compartment. We conclude that OSBP is a major determinant of Golgi PI4P homeostasis. [ABSTRACT FROM AUTHOR]

Oxysterol-binding protein (OSBP)-related proteins (ORPs) 5 and 8 have been shown to deplete the lipid phosphatidylinositol 4-phosphate (PI4P) at sites of membrane contact between the endoplasmic reticulum (ER) and plasma membrane (PM). This is believed to be caused by transport of PI4P from the PM to the ER, where PI4P is degraded by an ER-localized SAC1 phosphatase. This is proposed to power the anti-port of phosphatidylserine (PS) lipids from ER to PM, up their concentration gradient. Alternatively, ORPs have been proposed to sequester PI4P, dependent on the concentration of their alternative lipid ligand. Here, we aimed to distinguish these possibilities in living cells by orthogonal targeting of PI4P transfer and degradation to PM-mitochondria contact sites. Surprisingly, we found that orthogonal targeting of SAC1 to mitochondria enhanced PM PI4P turnover independent of targeting to contact sites with the PM. This turnover could be slowed by knock-down of soluble ORP2, which also has a major impact on PM PI4P levels even without SAC1 over-expression. The data reveal a role for contact site-independent modulation of PM PI4P levels and lipid antiport. [ABSTRACT FROM AUTHOR]

As an important cereal crop, barley occupies an important position in feed production and food processing. Proteins in barley grains have significant effects on the beer brewing process and beer quality, especially in terms of its foaming capacity and turbidity. However, little research has been conducted on the important proteins in barley such as hordeins and heat-stable proteins (protein Z and lipid transfer proteins). Information on their structure is lacking, and the development of their functions is still in its early stages. This review paper focuses on the structure, functional properties and application of important proteins in barley, and outlines their roles and changes in beer brewing with the aim of providing theoretical references for their processing and utilization.

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The adaption of plants to stressful environments depends on long-distance responses in plant organs, which themselves are remote from sites of perception of external stimuli. Jasmonic acid (JA) and its derivatives are known to be involved in plants’ adaptation to salinity. However, to our knowledge, the transport of JAs from roots to shoots has not been studied in relation to the responses of shoots to root salt treatment. We detected a salt-induced increase in the content of JAs in the roots, xylem sap, and leaves of pea plants related to changes in transpiration. Similarities between the localization of JA and lipid transfer proteins (LTPs) around vascular tissues were detected with immunohistochemistry, while immunoblotting revealed the presence of LTPs in the xylem sap of pea plants and its increase with salinity. Furthermore, we compared the effects of exogenous MeJA and salt treatment on the accumulation of JAs in leaves and their impact on transpiration. Our results indicate that salt-induced changes in JA concentrations in roots and xylem sap are the source of accumulation of these hormones in leaves leading to associated changes in transpiration. Furthermore, they suggest the possible involvement of LTPs in the loading/unloading of JAs into/from the xylem and its xylem transport.

Accurate intracellular cholesterol traffic plays crucial roles. Niemann Pick type C (NPC) proteins NPC1 and NPC2, are two lysosomal cholesterol transporters that mediate the cholesterol exit from lysosomes. However, other proteins involved in this process remain poorly defined. Here, we find that the previously unannotated protein TMEM241 is required for cholesterol egressing from lysosomes through amphotericin B-based genome-wide CRISPR-Cas9 KO screening. Ablation of TMEM241 caused impaired sorting of NPC2, a protein utilizes the mannose-6-phosphate (M6P) modification for lysosomal targeting, resulting in cholesterol accumulation in the lysosomes. TMEM241 is a member of solute transporters 35 nucleotide sugar transporters family and localizes on the cis-Golgi network. Our data indicate that TMEM241 transports UDP-N-acetylglucosamine (UDP-GlcNAc) into Golgi lumen and UDP-GlcNAc is used for the M6P modification of proteins including NPC2. Furthermore, Tmem241-deficient mice display cholesterol accumulation in pulmonary cells and behave pulmonary injury and hypokinesia. Taken together, we demonstrate that TMEM241 is a Golgi-localized UDP-GlcNAc transporter and loss of TMEM241 causes cholesterol accumulation in lysosomes because of the impaired M6P-dependent lysosomal targeting of NPC2.

Introduction: Lipid transfer proteins (LTPs) are allergens found in a wide range of plant-foods. Specifically, Pru p 3, the major allergen of peach, is commonly responsible for severe allergic reactions. The need for new alternatives to conventional food allergy treatments, like restrictive diets, suggests allergen immunotherapy as a promising option. It has been demonstrated that sublingual immunotherapy (SLIT) with synthetic glycodendropeptides, such as D1ManPrup3, containing mannose and Pru p 3 peptides induced tolerance in mice and that the persistence of this effect depends on treatment dose (2nM or 5nM). Moreover, it produces changes associated with differential gene expression and methylation profile of dendritic cells, as well as phenotypical changes in regulatory T cells (Treg). However, there are no works addressing the study of epigenetic changes in terms of methylation in the cell subsets that sustain tolerant responses, Treg. Therefore, in this work, DNA methylation changes in splenic-Treg from Pru p 3 anaphylactic mice were evaluated. Methods: It was performed by whole genome bisulphite sequencing comparing SLIT-D1ManPrup3 treated mice: tolerant (2nM D1ManPrup3), desensitized (5nM D1ManPrup3), and sensitized but not treated (antigenonly), with anaphylactic mice. Results: Most of the methylation changes were found in the gene promoters from both SLIT-treated groups, desensitized (1,580) and tolerant (1,576), followed by the antigen-only (1,151) group. Although tolerant and desensitized mice showed a similar number of methylation changes, only 445 genes were shared in both. Remarkably, interesting methylation changes were observed on the promoter regions of critical transcription factors for Treg function like Stat4, Stat5a, Stat5b, Foxp3, and Gata3. In fact, Foxp3 was observed exclusively as hypomethylated in tolerant group, whereas Gata3 was only hypomethylated in the desensitized mice. Discussion: In conclusion, diverse D1ManPrup3 doses induce different responses (tolerance or desensitization) in mice, which are reflected by differential methylation changes in Tregs. [ABSTRACT FROM AUTHOR]

Somatic embryogenesis (SE) is a process that scientists have been trying to understand for many years because, on the one hand, it is a manifestation of the totipotency of plant cells, so it enables the study of the mechanisms regulating this process, and, on the other hand, it is an important method of plant propagation. Using SE in basic research and in practice is invaluable. This article describes the latest, but also historical, information on changes in the chemical composition of the cell wall during the transition of cells from the somatic to embryogenic state, and the importance of symplasmic communication during SE. Among wall chemical components, different pectic, AGP, extensin epitopes, and lipid transfer proteins have been discussed as potential apoplastic markers of explant cells during the acquisition of embryogenic competence. The role of symplasmic communication/isolation during SE has also been discussed, paying particular attention to the formation of symplasmic domains within and between cells that carry out different developmental processes. Information about the number and functionality of plasmodesmata (PD) and callose deposition as the main player in symplasmic isolation has also been presented. [ABSTRACT FROM AUTHOR]

Abstract Background The detoxification of very long-chain and branched-chain fatty acids and the metabolism of cholesterol to form bile acids occur largely through a process called peroxisomal β-oxidation. Mutations in several peroxisomal proteins involved in β-oxidation have been reported, resulting in diseases characterized by neurological defects. The final step of the peroxisomal β-oxidation pathway is catalyzed by sterol carrier protein-x (SCPx), which is encoded by the SCP2 gene. Previously, there have been two reports of SCPx deficiency, which resulted from a homozygous or compound heterozygous SCP2 mutation. We report herein the first patient with a heterozygous SCP2 mutation leading to SCPx deficiency. Results Clinical presentations of the patient included progressive brainstem neurodegeneration, cardiac dysrhythmia, muscle wasting, and azoospermia. Plasma fatty acid analysis revealed abnormal values of medium-, long-, and very long-chain fatty acids. Protein expression of SCPx and other enzymes involved in β-oxidation were altered between patient and normal fibroblasts. RNA sequencing and lipidomic analyses identified metabolic pathways that were altered between patient and normal fibroblasts including PPAR signaling, serotonergic signaling, steroid biosynthesis, and fatty acid degradation. Treatment with fenofibrate or 4-hydroxytamoxifen increased SCPx levels, and certain fatty acid levels in patient fibroblasts. Conclusions These findings suggest that the patient’s SCP2 mutation resulted in decreased protein levels of SCPx, which may be associated with many metabolic pathways. Increasing SCPx levels through pharmacological interventions may reverse some effects of SCPx deficiency. Collectively, this work provides insight into many of the clinical consequences of SCPx deficiency and provides evidence for potential treatment strategies.

IntroductionLipid transfer proteins (LTPs) are allergens found in a wide range of plant-foods. Specifically, Pru p 3, the major allergen of peach, is commonly responsible for severe allergic reactions. The need for new alternatives to conventional food allergy treatments, like restrictive diets, suggests allergen immunotherapy as a promising option. It has been demonstrated that sublingual immunotherapy (SLIT) with synthetic glycodendropeptides, such as D1ManPrup3, containing mannose and Pru p 3 peptides induced tolerance in mice and that the persistence of this effect depends on treatment dose (2nM or 5nM). Moreover, it produces changes associated with differential gene expression and methylation profile of dendritic cells, as well as phenotypical changes in regulatory T cells (Treg). However, there are no works addressing the study of epigenetic changes in terms of methylation in the cell subsets that sustain tolerant responses, Treg. Therefore, in this work, DNA methylation changes in splenic-Treg from Pru p 3 anaphylactic mice were evaluated.MethodsIt was performed by whole genome bisulphite sequencing comparing SLIT-D1ManPrup3 treated mice: tolerant (2nM D1ManPrup3), desensitized (5nM D1ManPrup3), and sensitized but not treated (antigen-only), with anaphylactic mice.ResultsMost of the methylation changes were found in the gene promoters from both SLIT-treated groups, desensitized (1,580) and tolerant (1,576), followed by the antigen-only (1,151) group. Although tolerant and desensitized mice showed a similar number of methylation changes, only 445 genes were shared in both. Remarkably, interesting methylation changes were observed on the promoter regions of critical transcription factors for Treg function like Stat4, Stat5a, Stat5b, Foxp3, and Gata3. In fact, Foxp3 was observed exclusively as hypomethylated in tolerant group, whereas Gata3 was only hypomethylated in the desensitized mice.DiscussionIn conclusion, diverse D1ManPrup3 doses induce different responses (tolerance or desensitization) in mice, which are reflected by differential methylation changes in Tregs.

Plant lipid transfer proteins (LTPs) play essential roles in various biological processes, including anther and pollen development, vegetative organ development, seed development and germination, and stress response, but the research progress varies greatly among Arabidopsis, rice and maize. Here, we presented a preliminary introduction and characterization of the whole 65 LTP genes in maize, and performed a phylogenetic tree and gene ontology analysis of the LTP family members in maize. We compared the research progresses of the reported LTP genes involved in male fertility and other biological processes in Arabidopsis and rice, and thus provided some implications for their maize orthologs, which will provide useful clues for the investigation of LTP transporters in maize. We predicted the functions of LTP genes based on bioinformatic analyses of their spatiotemporal expression patterns by using RNA-seq and qRT-PCR assays. Finally, we discussed the advances and challenges in substrate identification of plant LTPs, and presented the future research directions of LTPs in plants. This study provides a basic framework for functional research and the potential application of LTPs in multiple plants, especially for male sterility research and application in maize. [ABSTRACT FROM AUTHOR]

Vesicular trafficking and membrane fusion are well-characterized, versatile, and sophisticated means of 'long range' intracellular protein and lipid delivery. Membrane contact sites (MCS) have been studied in far less detail, but are crucial for 'short range' (10–30 nm) communication between organelles, as well as between pathogen vacuoles and organelles. MCS are specialized in the non-vesicular trafficking of small molecules such as calcium and lipids. Pivotal MCS components important for lipid transfer are the VAP receptor/tether protein, oxysterol binding proteins (OSBPs), the ceramide transport protein CERT, the phosphoinositide phosphatase Sac1, and the lipid phosphatidylinositol 4-phosphate (PtdIns(4) P). In this review, we discuss how these MCS components are subverted by bacterial pathogens and their secreted effector proteins to promote intracellular survival and replication. [ABSTRACT FROM AUTHOR]

Lipid transfer proteins mediate nonvesicular transport of lipids at membrane contact sites to regulate the lipid composition of organelle membranes. Recently, a new type of bridge-like lipid transfer protein has emerged; these proteins contain a long hydrophobic groove and can mediate bulk transport of lipids between organelles. Here, we review recent insights into the structure of these proteins and identify a repeating modular unit that we propose to name the repeating β-groove (RBG) domain. This new structural understanding conceptually unifies all the RBG domain-containing lipid transfer proteins as members of an RBG protein superfamily. We also examine the biological functions of these lipid transporters in normal physiology and disease and speculate on the evolutionary origins of RBG proteins in bacteria. VPS13, ATG2, SHIP164, Csf1, and the Hob proteins comprise a novel superfamily of conserved lipid transfer proteins with long hydrophobic grooves. All these long hydrophobic grooves are built from multiple repeating modules that consist of five β-sheets followed by a loop, for which we propose the name the 'repeating β-groove' (RBG) domain. RBG proteins carry out lipid transport at membrane contact sites, with functions in lipid homeostasis and membrane biogenesis. Some of these processes require bulk lipid transfer, which appears to be one of the primary molecular functions of RBG proteins. Eukaryotic RBG proteins likely evolved from structurally related prokaryotic proteins that transfer lipids between the inner and outer membranes in Gram-negative bacteria. [ABSTRACT FROM AUTHOR]

IntroductionAllergen-specific immunotherapy (AIT) is applied as treatment to rise tolerance in patients with food allergies. Although AIT is thoroughly used, the underlying epigenetic events related to tolerant induction are still unknown. Thus, we aim to investigate epigenetic changes that could be related to tolerance in dendritic cells (DCs) from anaphylactic mice to lipid transfer proteins, Pru p 3, in the context of a sublingual immunotherapy (SLIT) with a glycodendropeptide (D1ManPrup3) that has demonstrated tolerant or desensitization responses depending on the treatment dose.MethodsChanges in DNA methylation in CpG context were determined comparing Sensitized (Antigen-only) animals and two groups receiving SLIT with the D1ManPrup3 nanostructure (D1ManPrup3-SLIT): Tolerant (2nM D1ManPrup3) and Desensitized (5nM D1ManPrup3), against anaphylactic animals. DNA from lymph nodes-DCs were isolated and then, Whole Genome Bisulphite Sequencing was performed to analyze methylation.ResultsMost differentially methylated regions were found on the area of influence of gene promoters (DMPRs). Compared to the Anaphylactic group, the highest value was found in Desensitized mice (n = 7,713 DMPRs), followed by Tolerant (n = 4,091 DMPRs) and Sensitized (n = 3,931 DMPRs) mice. Moreover, many of these epigenetic changes were found in genes involved in immune and tolerance responses (Il1b, Il12b, Il1a, Ifng, and Tnf) as shown by functional enrichment (DCs regulation, B cell-mediated immunity, and effector mechanisms).DiscussionIn conclusion, different doses of D1ManPrup3-SLIT induce different DNA methylation changes, which are reflected in the induction of distinct responses, tolerance, or desensitization.

Cannabis is the most widely consumed illicit drug in the world and carries a risk of severe IgE-mediated allergic reactions, requiring appropriate diagnostic management. Currently available diagnostics are still relatively limited and require careful interpretation of results to avoid harmful over- and underdiagnosis. This review focuses on the most up-to-date understandings of cannabis allergy diagnosis, starting with the main clinical features of the disease and the allergenic characteristics of Cannabis sativa, and then providing insights into in vivo, in vitro, and ex vivo diagnostic tests. At present, the diagnosis of IgE-mediated cannabis allergy is based on a three-step approach that starts with accurate history taking and ends with a confirmation of sensitization to the whole extract and, finally, molecular components. Although much has been discovered since its first description in 1971, the diagnosis of cannabis allergy still has many unmet needs. The lack of commercial standardized and validated extracts and in vitro assays makes a harmonized workup of cannabis allergy difficult. Furthermore, the epidemiological characteristics, and clinical implications of sensitization to different molecular components are not yet fully known. Future research will complete the picture and likely result in an individualized and standardized approach. [ABSTRACT FROM AUTHOR]

Plant molecules are continuously investigated to prevent and treat inflammatory and ulcerative disorders associated with the gastrointestinal tract, such as gastritis, colitis, mucositis, and ulcers. However, most of the published work is devoted to investigating the therapeutic properties of secondary plant metabolites. This work investigated the gastroprotective activity of a lipid transfer protein isolated from Morinda citrifolia L., named McLTP1, when orally administered to mice from the perspective of its use as a novel peptide-based drug for the prevention and treatment of ulcerative gastric lesions. Pretreatment with McLTP1 at different doses (4, 8, or 16 mg/kg) reduced ethanol-induced gastric lesions (p < 0.05) by 40%, 84%, and 88%, respectively. In ethanol-induced gastric lesions, alterations in the levels of glutathione (GSH) (↑100%; p < 0.05) and a reduction of 45% (p < 0.05) in the levels of malondialdehyde (MDA) were demonstrated after McLTP1 administration (8 mg/kg). McLTP1 showed an anti-inflammatory effect through modulation of the cytokines IL-10 (↑33%) and TNF-α (↓54%) and was able to reduce myeloperoxidase (MPO) levels (↓95%) in gastric tissue. In addition, the gastroprotective effect of McLTP1 also involves the production of nitric oxide. The present findings reveal that McLTP1 has a gastroprotective effect dependent, at least in part, on its anti-inflammatory and antioxidant effects.Please confirm if the author names are presented accurately and in the correct sequence (given name, middle name/initial, family name). Also, kindly confirm the details in the metadata are correct.I confirm that the author names are presented accurately and in the correct sequence. [ABSTRACT FROM AUTHOR]

Background: The detoxification of very long-chain and branched-chain fatty acids and the metabolism of cholesterol to form bile acids occur largely through a process called peroxisomal β-oxidation. Mutations in several peroxisomal proteins involved in β-oxidation have been reported, resulting in diseases characterized by neurological defects. The final step of the peroxisomal β-oxidation pathway is catalyzed by sterol carrier protein-x (SCPx), which is encoded by the SCP2 gene. Previously, there have been two reports of SCPx deficiency, which resulted from a homozygous or compound heterozygous SCP2 mutation. We report herein the first patient with a heterozygous SCP2 mutation leading to SCPx deficiency. Results: Clinical presentations of the patient included progressive brainstem neurodegeneration, cardiac dysrhythmia, muscle wasting, and azoospermia. Plasma fatty acid analysis revealed abnormal values of medium-, long-, and very long-chain fatty acids. Protein expression of SCPx and other enzymes involved in β-oxidation were altered between patient and normal fibroblasts. RNA sequencing and lipidomic analyses identified metabolic pathways that were altered between patient and normal fibroblasts including PPAR signaling, serotonergic signaling, steroid biosynthesis, and fatty acid degradation. Treatment with fenofibrate or 4-hydroxytamoxifen increased SCPx levels, and certain fatty acid levels in patient fibroblasts. Conclusions: These findings suggest that the patient's SCP2 mutation resulted in decreased protein levels of SCPx, which may be associated with many metabolic pathways. Increasing SCPx levels through pharmacological interventions may reverse some effects of SCPx deficiency. Collectively, this work provides insight into many of the clinical consequences of SCPx deficiency and provides evidence for potential treatment strategies. [ABSTRACT FROM AUTHOR]

Invasion of human red blood cells by the malaria parasite Plasmodium falciparum is followed by dramatic modifications of erythrocytes properties, including de novo formation of new membrane systems. Lipid transfer proteins from both the parasite and the host cell are most likely an important part of those membrane remodeling processes. Using bioinformatics and in silico structural analysis, we have identified five P. falciparum potential lipid transfer proteins containing cellular retinaldehyde binding - triple functional domain (CRAL-TRIO). Two of these proteins, C6KTD4, encoded by the PF3D7&#95;0629900 gene and Q8II87, encoded by the PF3D7&#95;1127600 gene, were studied in more detail. In vitro lipid transfer assays using recombinant C6KTD4 and Q8II87 confirmed that these proteins are indeed bona fide lipid transfer proteins. C6KTD4 transfers sterols, phosphatidylinositol 4,5 bisphosphate, and, to some degree, also phosphatidylcholine between two membrane compartments. Q8II87 possesses phosphatidylserine transfer activity in vitro. In the yeast model, the expression of P. falciparumQ8II87 protein partially complements the absence of Sec14p and its closest homologue, Sfh1p. C6KTD4 protein can substitute for the collective essential function of oxysterol-binding related proteins. According to published whole genome studies in P. falciparum, absence of C6KTD4 and Q8II87 proteins has severe consequences for parasite viability. Therefore, CRAL-TRIO lipid transfer proteins of P. falciparum are potential targets of novel antimalarials, in search for which the yeast model expressing these proteins could be a valuable tool., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Numerous lipids are heterogeneously distributed among organelles. Most lipid trafficking between organelles is achieved by a group of lipid transfer proteins (LTPs) that carry lipids using their hydrophobic cavities. The human genome encodes many intracellular LTPs responsible for lipid trafficking and the function of many LTPs in defining cellular lipid levels and distributions is unclear. Here, we created a gene knockout library targeting 90 intracellular LTPs and performed whole-cell lipidomics analysis. This analysis confirmed known lipid disturbances and identified new ones caused by the loss of LTPs. Among these, we found major sphingolipid imbalances in ORP9 and ORP11 knockout cells, two proteins of previously unknown function in sphingolipid metabolism. ORP9 and ORP11 form a heterodimer to localize at the ER- trans -Golgi membrane contact sites, where the dimer exchanges phosphatidylserine (PS) for phosphatidylinositol-4-phosphate (PI(4)P) between the two organelles. Consequently, loss of either protein causes phospholipid imbalances in the Golgi apparatus that result in lowered sphingomyelin synthesis at this organelle. Overall, our LTP knockout library toolbox identifies various proteins in control of cellular lipid levels, including the ORP9-ORP11 heterodimer, which exchanges PS and PI(4)P at the ER-Golgi membrane contact site as a critical step in sphingomyelin synthesis in the Golgi apparatus., Competing Interests: BC, SB, JA, NB, AM, RK, MG, JN No competing interests declared, (© 2023, Cabukusta et al.)

Somatic embryogenesis (SE) is a process that scientists have been trying to understand for many years because, on the one hand, it is a manifestation of the totipotency of plant cells, so it enables the study of the mechanisms regulating this process, and, on the other hand, it is an important method of plant propagation. Using SE in basic research and in practice is invaluable. This article describes the latest, but also historical, information on changes in the chemical composition of the cell wall during the transition of cells from the somatic to embryogenic state, and the importance of symplasmic communication during SE. Among wall chemical components, different pectic, AGP, extensin epitopes, and lipid transfer proteins have been discussed as potential apoplastic markers of explant cells during the acquisition of embryogenic competence. The role of symplasmic communication/isolation during SE has also been discussed, paying particular attention to the formation of symplasmic domains within and between cells that carry out different developmental processes. Information about the number and functionality of plasmodesmata (PD) and callose deposition as the main player in symplasmic isolation has also been presented.

Phosphoinositide lipids (PPIn) are enriched in stearic‐ and arachidonic acids (38:4) but how this enrichment is established and maintained during phospholipase C (PLC) activation is unknown. Here we show that the metabolic fate of newly synthesized phosphatidic acid (PA), the lipid precursor of phosphatidylinositol (PI), is influenced by the fatty acyl‐CoA used with preferential routing of the arachidonoyl‐enriched species toward PI synthesis. Furthermore, during agonist stimulation the unsaturated forms of PI(4,5P)2 are replenished significantly faster than the more saturated ones, suggesting a favored recycling of the unsaturated forms of the PLC‐generated hydrolytic products. Cytidine diphosphate diacylglycerol synthase 2 (CDS2) but not CDS1 was found to contribute to increased PI resynthesis during PLC activation. Lastly, while the lipid transfer protein, Nir2 is found to contribute to rapid PPIn resynthesis during PLC activation, the faster re‐synthesis of the 38:4 species does not depend on Nir2. Therefore, the fatty acid side‐chain composition of the lipid precursors used for PI synthesis is an important determinant of their metabolic fates, which also contributes to the maintenance of the unique fatty acid profile of PPIn lipids. Synopsis: This study describes how the unique fatty acyl side‐chain profile of phosphatidylinositol and phosphatidylinositol 4,5‐bisphosphate are maintained during activation of phospholipase C and suggests that the metabolic fate of phosphatidic acid within the ER may be different depending on whether it is synthesized de novo or generated as the result of PLC or PLD activation. Utilization of fatty acyl‐CoA for de novo phospholipid synthesis or lipid storage depends on the chain length and unsaturation.PLC‐mediated PI(4,5)P2 hydrolysis leads to increased PI synthesis that requires CDS2, but not CDS1 or DGKε.Resynthesis of PI(4,5)P2 during PLC activation is faster for species containing unsaturated fatty acids. [ABSTRACT FROM AUTHOR]

Introduction: Wheat is the most important cereal for human nutrition but its high consumption is associated to an increasing complaint of wheat-related disorders, many of which are allergic in nature and different in respect to the involved allergens. In this study, we compared the clinical aspects of wheat allergy presented by patients sensitized to Tri a 19 in respect to those presented by patients sensitized to Tri a 14. Methods: With this aim, we selected patients sensitized to 1 or both of the 2 allergens, and among these we identified those who were really wheat allergic and reactive on the basis of a standardized methodology. We evaluated the clinical features such as the kind and severity of symptoms, the coexistence of triggering factors such as physical exercise and NSAIDs and alcohol consumption, and the association with other allergens and with various immunologic parameters. Wheat allergy in Tri a 19 sensitized patients was confirmed through a questionnaire while the patients sensitized to Tri a 14 underwent wheat challenge with 100 g of pasta followed by exercise on a treadmill. Results: Seventy-nine patients sensitized to Tri a 14 and 40 patients sensitized to Tri a 19 were recruited. The 2 sensitizations were independent with a significant inverse relation (p < 0.00001). The Tri a 19 sensitized patients presented, in respect to the Tri a 14 sensitized ones, an older age (p = 0.0017), a higher risk to be wheat allergic (p < 0.0001), a higher severity of the reactions (p < 0.00001) and a higher association with some cofactors, namely alcohol (p < 0.0005) and physical exercise (p = 0.003). On the contrary, Tri a 14 sensitization was associated with atopy (p < 0.0001), with a higher probability of patients being asymptomatic (p < 0.0001) and being sensitized to other foods, in particular to nuts and cereals (p < 0.00001). Conclusions: Sensitization to Tri a 19 or Tri a 14 determines different clinical pictures. In particular, sensitization to Tri a 19 implies a higher probability of severe reactions, even dependent on daily triggers, while that to Tri a 14 implies a higher cross-reactivity with other foods but it's more frequently asymptomatic, making a food challenge necessary to prevent useless food avoidance. [ABSTRACT FROM AUTHOR]

Abstract Antimicrobial peptides (AMPs) are a class of short, usually positively charged polypeptides that exist in humans, animals, and plants. Considering the increasing number of drug-resistant pathogens, the antimicrobial activity of AMPs has attracted much attention. AMPs with broad-spectrum antimicrobial activity against many gram-positive bacteria, gram-negative bacteria, and fungi are an important defensive barrier against pathogens for many organisms. With continuing research, many other physiological functions of plant AMPs have been found in addition to their antimicrobial roles, such as regulating plant growth and development and treating many diseases with high efficacy. The potential applicability of plant AMPs in agricultural production, as food additives and disease treatments, has garnered much interest. This review focuses on the types of plant AMPs, their mechanisms of action, the parameters affecting the antimicrobial activities of AMPs, and their potential applications in agricultural production, the food industry, breeding industry, and medical field.

Allergy to fruits and vegetables is the most common primary food allergy in Mediterranean countries, especially the lipid transfer proteins (LTPs) syndrome. This study is the first research that studies multiple clinical, allergological and therapeutics characteristics of allergies to plants in the South-East of Spain, and assessing whether these characteristics differ in emergency room or outpatient clinic. This is a prospective study of patients who consult for the first time for allergy to vegetables at Granada, Spain. We record demographic data, symptoms, allergological study and indicated therapy. The characteristics obtained agree with the current bibliographic except the higher prevalence than other areas of positive sensitization of Pru p 3, Cor a 9 and Ara h 9, which predisposes to severe allergic reactions. We conclude: Allergy to plant food in Granada is a more severe phenotype than other geographic areas from Spain, especially in young adults sensitized by different LTPs and pollinosis to olive pollen. [ABSTRACT FROM AUTHOR]

The myelin sheath, which is wrapped around axons, is a lipid-enriched structure produced by mature oligodendrocytes. Disruption of the myelin sheath is observed in several neurological diseases, such as multiple sclerosis. A crucial component of myelin is sphingomyelin, levels of which can be increased by ABCA8, a member of the ATP-binding cassette transporter family. ABCA8 is highly expressed in the cerebellum, specifically in oligodendroglia. However, whether ABCA8 plays a role in myelination and mechanisms that would underlie this role remain unknown. Here, we found that the absence of Abca8b, a mouse ortholog of ABCA8, led to decreased numbers of cerebellar oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes in mice. We show that in oligodendrocytes, ABCA8 interacts with chondroitin sulfate proteoglycan 4 (CSPG4), a molecule essential for OPC proliferation, migration, and myelination. In the absence of Abca8b, localization of CSPG4 to the plasma membrane was decreased, contributing to reduced cerebellar CSPG4 expression. Cerebellar CSPG4+ OPCs were also diminished, leading to decreased mature myelinating oligodendrocyte numbers and cerebellar myelination levels in Abca8b−/− mice. In addition, electron microscopy analyses showed that the number of nonmyelinated cerebellar axons was increased, whereas cerebellar myelin thickness (g-ratio), myelin sheath periodicity, and axonal diameter were all decreased, indicative of disordered myelin ultrastructure. In line with disrupted cerebellar myelination, Abca8b−/− mice showed lower cerebellar conduction velocity and disturbed locomotion. In summary, ABCA8 modulates cerebellar myelination, in part through functional regulation of the ABCA8-interacting protein CSPG4. Our findings suggest that ABCA8 disruption may contribute to the pathophysiology of myelin disorders.

Plant lipid transfer proteins (LTPs) play essential roles in various biological processes, including anther and pollen development, vegetative organ development, seed development and germination, and stress response, but the research progress varies greatly among Arabidopsis, rice and maize. Here, we presented a preliminary introduction and characterization of the whole 65 LTP genes in maize, and performed a phylogenetic tree and gene ontology analysis of the LTP family members in maize. We compared the research progresses of the reported LTP genes involved in male fertility and other biological processes in Arabidopsis and rice, and thus provided some implications for their maize orthologs, which will provide useful clues for the investigation of LTP transporters in maize. We predicted the functions of LTP genes based on bioinformatic analyses of their spatiotemporal expression patterns by using RNA-seq and qRT-PCR assays. Finally, we discussed the advances and challenges in substrate identification of plant LTPs, and presented the future research directions of LTPs in plants. This study provides a basic framework for functional research and the potential application of LTPs in multiple plants, especially for male sterility research and application in maize.

Summary: Sublingual immunotherapy with Pru p3 extract (SLIT-peach ® ) is used in allergy patients to multiple plant foods to induce tolerance to nonspecific lipid transfer proteins (nsLTP). The aim of this paper is to communicate the efficacy of a new ultrafast regimen. Until now on the initiation regimen lasts four days. We present a number of 22 patients with LTP-syndrome due to ingestion of different vegetable foods sensitized to Pru p3. According to European Academy of Allergy position paper (1) food immunotherapy is indicated when avoidance measures are ineffective, undesirable, or cause serious limitations on patients quality of life. Our patients had an impact on their quality of life (score > 130) before SLIT measured with (2) EuroPrevall Food Allergy Quality of Life Questionnaire (FAQLQ). The ultrafast regimen in one day is achieved in the 95% of our patients. Mild adverse reactions were observed, such as oral pruritus presence in almost all patients. Only one patient (5%) achieved the maintenance dose in two days due to intense oral pruritus. No patients presented systemic reactions. The maintenance dose achieved consists of 4 drops (0,16 ml) from vial number 4 daily. The concentration of Pru p3 in vial nº4 is 50 cg/ml. Four drops a day equals 8 micrograms of Pru p3. This new ultrafast regimen in one day is secure in patients with LTP-Syndrome to induce tolerance to SLIT-peach ® (Pru p3 extract).

Viruses are obligate parasites that depend on the host cell machinery for their replication and dissemination. Cellular lipids play a central role in multiple stages of the viral life cycle such as entry, replication, morphogenesis, and egress. Most viruses reorganize the host cell membranes for the establishment of viral replication complex. These specialized structures allow the segregation of replicating viral RNA from ribosomes and protect it from host nucleases. They also facilitate localized enrichment of cellular components required for viral replication and assembly. The specific composition of the lipid membrane governs its ability to form negative or positive curvature and possess a rigid or flexible form, which is crucial for membrane rearrangement and establishment of viral replication complexes. In this review, we highlight how different viruses manipulate host lipid transfer proteins and harness their functions to enrich different membrane compartments with specific lipids in order to facilitate multiple aspects of the viral life cycle.

Viruses are obligate parasites that depend on the host cell machinery for their replication and dissemination. Cellular lipids play a central role in multiple stages of the viral life cycle such as entry, replication, morphogenesis, and egress. Most viruses reorganize the host cell membranes for the establishment of viral replication complex. These specialized structures allow the segregation of replicating viral RNA from ribosomes and protect it from host nucleases. They also facilitate localized enrichment of cellular components required for viral replication and assembly. The specific composition of the lipid membrane governs its ability to form negative or positive curvature and possess a rigid or flexible form, which is crucial for membrane rearrangement and establishment of viral replication complexes. In this review, we highlight how different viruses manipulate host lipid transfer proteins and harness their functions to enrich different membrane compartments with specific lipids in order to facilitate multiple aspects of the viral life cycle. [ABSTRACT FROM AUTHOR]

Background: Component-resolved diagnosis reveals the IgE response to many inhaled, food, and other allergens, improving the understanding and diagnosis of allergic diseases. Objective: The aims of the study are to study the recognition of different lipid transfer proteins (LTPs) and other allergen families in a large group of people sensitized to Pru p 3 and to analyze the relationship between the clinical entities and the allergens. Methods: This cross-sectional study included a large cohort of patients with positive skin tests to peach fruit and Pru p 3 specific IgE antibodies. Respiratory and food allergy symptoms were collected, and we performed prick tests with pollen, plant food, and other allergens plus the ImmunoCAP ISAC assay. Results: Our sample consisted of 421 people with a mean age of 33.25 years (range 16–68); 54.6% were women. Clinical entities included anaphylaxis (37.1%), urticaria (67.9%), and oral allergy syndrome (59.1%). Rhinitis, rhinoconjunctivitis, and/or asthma were diagnosed in 71.8% of the participants. The most pronounced correlation existed between sensitization to Pru p 3 and to Jug r 3, Pla a 3, Ara h 9, and Cor a 8. We found a higher incidence of anaphylaxis in people with 5 or more recognized LTPs. No association was observed between inhaled and food allergies. Conclusion: Most Pru p 3-sensitized participants were sensitized to additional allergens from the same family and, to a lesser extent, to other allergens, mainly in the profilin and PR-10 protein families. Anaphylaxis occurred in more than a third of the cases evaluated, and almost three-quarters of them had respiratory symptoms. Respiratory and food allergies involving LTPs do not seem to be associated. [ABSTRACT FROM AUTHOR]

Non-specific lipid transfer proteins (LTPs) constitute a large protein family in plants characterized by having a tunnel-like hydrophobic cavity, which allows them to transfer different lipid molecules. LTPs have been studied in various model plants including those of agronomic interest. Recent studies have demonstrated that LTPs play key functions in both biotic and abiotic stress. In plants-pathogen interaction, they act as either positive or negative regulators of defense responses. However, little is known about the roles of LTPs in symbiotic interactions, especially in root nodule symbiosis. Here, we performed a broad genome analysis of LTP family members in legumes and other important model plants, focusing on their possible roles in legume-rhizobium symbiosis. In silico analysis showed that legumes contain large LTP families, with at least 70 LTP members clustered into four clades. Although the structures of LTP genes and proteins are conserved among species, differences were observed between clades from different species. LTPs are widely expressed in different plant tissues. In general, genes of the LTP1 and LTP2 classes are highly expressed in shoot and reproductive tissues in all analyzed species. Furthermore, genes of the different classes are also expressed in roots inoculated with rhizobia and nodules of legumes. RT-qPCR expression profile analysis of seven PvLTP genes in common bean (Phaseolus vulgaris) revealed that these genes are differentially expressed during the early and late stages of nodulation and they are genetically regulated by PvRbohA. These findings provide insight into the putative roles of LTP family members in legume-rhizobium symbiosis and their possible interactions with RBOH-dependent ROS production.

Antimicrobial peptides (AMPs) are a class of short, usually positively charged polypeptides that exist in humans, animals, and plants. Considering the increasing number of drug-resistant pathogens, the antimicrobial activity of AMPs has attracted much attention. AMPs with broad-spectrum antimicrobial activity against many gram-positive bacteria, gram-negative bacteria, and fungi are an important defensive barrier against pathogens for many organisms. With continuing research, many other physiological functions of plant AMPs have been found in addition to their antimicrobial roles, such as regulating plant growth and development and treating many diseases with high efficacy. The potential applicability of plant AMPs in agricultural production, as food additives and disease treatments, has garnered much interest. This review focuses on the types of plant AMPs, their mechanisms of action, the parameters affecting the antimicrobial activities of AMPs, and their potential applications in agricultural production, the food industry, breeding industry, and medical field. [ABSTRACT FROM AUTHOR]

Background and Aims: Cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) are crucial proteins in reverse cholesterol transport. There are insufficient data on regulating these proteins by insulin therapy in type 1 diabetes mellitus (T1DM). We aimed to assess prospectively the impact of insulin therapy initiation on transfer proteins serum levels in adults with newly diagnosed T1DM.Methods and Results: 57 adults with newly diagnosed T1DM were enrolled in the InLipoDiab1 Study. All participants were treated with subcutaneous insulin in the model of intensive insulin therapy since the diagnosis of diabetes. Serum PLTP and CETP concentrations were measured at diagnosis, after three weeks, six months, and after one year of insulin treatment, using the immunoenzymatic method ELISA. A significant decrease in PLTP and CETP concentrations were demonstrated during twelve months of insulin therapy in newly diagnosed T1DM. The dynamics of changes in the level of these proteins varied depending on the occurrence of remission after a year of the disease. In the group without remission, a significant decrease in PLTP and CETP levels appeared after six months of follow-up. The remission group was characterized by a decrease in proteins concentration only after one year of treatment. In the non-remission group, significant negative correlations were found between the daily dose of insulin and levels of PLTP and CETP.Conclusion: Exogenous insulin is an inhibitor of lipid transfer proteins involved in high-density lipoprotein cholesterol metabolism in the first year of treatment. [ABSTRACT FROM AUTHOR]

Present in the small intestine, cellular retinol binding protein 2 (CRBP2) plays an important role in the uptake, transport, and metabolism of dietary retinoids. However, the recent discovery of the interactions of CRBP2 with 2-arachidonoylglycerol and other monoacylglycerols (MAGs) suggests the broader involvement of this protein in lipid metabolism and signaling. To better understand the physiological role of CRBP2, we determined its protein-lipid interactome using a fluorescence-based retinol replacement assay adapted for a high-throughput screening format. By examining chemical libraries of bioactive lipids, we provided evidence for the selective interaction of CRBP2 with a subset of nonretinoid ligands with the highest affinity for sn-1 and sn-2 MAGs that contain polyunsaturated C18-C20 acyl chains. We also elucidated the structure-affinity relationship for nonretinoid ligands of this protein. We further dissect the molecular basis for this ligand's specificity by analyzing high-resolution crystal structures of CRBP2 in complex with selected derivatives of MAGs. Finally, we identify T51 and V62 as key amino acids that enable the broadening of ligand selectivity to MAGs in CRBP2 as compared with retinoid-specific CRBP1. Thus, our study provides the molecular framework for understanding the lipid selectivity and diverse functions of CRBPs in controlling lipid homeostasis.

Lipid transfer proteins (LTPs) are recognized as key players in the inter-organelle trafficking of lipids and are rapidly gaining attention as a novel molecular target for medicinal products. In mammalian cells, ceramide is newly synthesized in the endoplasmic reticulum (ER) and converted to sphingomyelin in the trans-Golgi regions. The ceramide transport protein CERT, a typical LTP, mediates the ER-to-Golgi transport of ceramide at an ER-distal Golgi membrane contact zone. About 20 years ago, a potent inhibitor of CERT, named (1R,3S)-HPA-12, was found by coincidence among ceramide analogs. Since then, various ceramide-resembling compounds have been found to act as CERT inhibitors. Nevertheless, the inevitable issue remains that natural ligand-mimetic compounds might directly bind both to the desired target and to various undesired targets that share the same natural ligand. To resolve this issue, a ceramide-unrelated compound named E16A, or (1S,2R)-HPCB-5, that potently inhibits the function of CERT has recently been developed, employing a series of in silico docking simulations, efficient chemical synthesis, quantitative affinity analysis, protein–ligand co-crystallography, and various in vivo assays. (1R,3S)-HPA-12 and E16A together provide a robust tool to discriminate on-target effects on CERT from off-target effects. This short review article will describe the history of the development of (1R,3S)-HPA-12 and E16A, summarize other CERT inhibitors, and discuss their possible applications.

Lipids are amphiphilic molecules that self-assemble to form biological membranes. Thousands of lipid species coexist in the cell and, once combined, define organelle identity. Due to recent progress in lipidomic analysis, we now know how lipid composition is finely tuned in different subcellular regions. Along with lipid synthesis, remodeling and flip-flop, lipid transfer is one of the active processes that regulates this intracellular lipid distribution. It is mediated by Lipid Transfer Proteins (LTPs) that precisely move certain lipid species across the cytosol and between the organelles. A particular subset of LTPs from three families (Sec14, PITP, OSBP/ORP/Osh) act as lipid exchangers. A striking feature of these exchangers is that they use phosphatidylinositol or phosphoinositides (PIPs) as a lipid ligand and thereby have specific links with PIP metabolism and are thus able to both control the lipid composition of cellular membranes and their signaling capacity. As a result, they play pivotal roles in cellular processes such as vesicular trafficking and signal transduction at the plasma membrane. Recent data have shown that some PIPs are used as energy by lipid exchangers to generate lipid gradients between organelles. Here we describe the importance of lipid counter-exchange in the cell, its structural basis, and presumed links with pathologies.

Phospholipid transfer protein (PLTP) is one of the major modulators of lipoprotein metabolism and atherosclerosis development in humans; however, we still do not quite understand the mechanisms. In mouse models, PLTP overexpression induces atherosclerosis, while its deficiency reduces it. Thus, mouse models were used to explore the mechanisms. In this review, I summarize the major progress made in the PLTP research field and emphasize its impact on lipoprotein metabolism and atherosclerosis, as well as its regulation.