Lysophospholipid Research Articles

Tracing the Thermal History of Seafood Products through Lysophospholipid Analysis by Hydrophilic Interaction Liquid Chromatography⁻Electrospray Ionization Fourier Transform Mass Spectrometry.

Low temperature treatments commonly applied to seafood products have been shown to influence their phospholipid (PL) profile through enzymatic hydrolysis. In the present study, the generation of lysophospholipids (LPL) resulting from this process was systematically investigated for selected, commercially relevant seafood products, namely oysters, clams, octopuses, and shrimps. These products were subjected to thermal treatments like refrigeration or freezing after being purchased as fresh, defrozen, or frozen products depending on the case. The coupling between hydrophilic interaction liquid chromatography (HILIC) and electrospray ionization with high resolution/accuracy Fourier transform mass spectrometry (ESI-FTMS) was exploited to evaluate the PL profile of the cited products, especially the incidence of LPL related to the two main PL classes of seafood products—phosphatidylcholines (PC) and phosphatidylethanolamines (PE)—in the lipid extracts. The lyso forms of PE (LPE) were found to be generally more sensitive than those of PC (LPC) to thermal treatments, usually exhibiting a significant increase upon prolonged refrigeration at 4 °C in all types of investigated products except European flat oysters. Moreover, the distinction between fresh and frozen or defrozen products could be achieved in the case of octopuses and shrimps, respectively.

Unsaturated, low-abundant species of HDL (Lyso)phospholipids are most affected by ST segment elevation myocardial infarction

Unsaturated, low-abundant species of HDL (Lyso)phospholipids are most affected by ST segment elevation myocardial infarction

Changes in lysophospholipids and liver status after weight loss: the RESMENA study

BackgroundObesity and comorbidities such as non-alcoholic fatty liver disease (NAFLD) are major public health burdens. Alterations in lipid metabolism are involved in hepatic diseases. The objective of this study was to assess the influence of weight loss on lysophospholipid (LP) metabolism and liver status in obese subjects as well as to provide new evidence regarding the interaction of LP metabolism as a key factor in the onset and management of obesity-related diseases such as liver damage.MethodsThirty-three subjects from the RESMENA (Reduction of Metabolic Syndrome in Navarra, NCT01087086) study were selected based on their Fatty Liver Index (FLI). Plasma lipid species (lysophosphatidilcholine: LPC, lysophosphatidilethanolamines: LPE and lysophosphatidylinositols: LPI specifically) were determined by LC-MS, while waist circumference (WC) and other non-invasive liver markers such as, FLI and BAAT scores as well as dietary records, anthropometrical measurements, body composition by DXA and other metabolic determinants were analyzed before and after a six-month hypocaloric nutritional intervention.ResultsComputed Z-scores of total LP (LPC, LPE, and LPI) were significantly decreased after 6-months of following a hypocaloric diet. Specifically, LPC14:0, LPC15:0, LPC16:1, LPC18:4, LPC20:4, showed clear relationships with weight loss. Changes in FLI score, WC and BAAT score revealed associations with general changes in LPC score. Interestingly the BAAT score was statistically associated with the LPC score after adjustment for weight loss.ConclusionThe lipidomic LPC profile analysis revealed a generalized decrease in circulating lysophospholipids after weight loss. The involvement of particular LP in liver metabolism and obesity merit further attention, as some of these specific non-invasive liver markers were reduced independently of weight loss.Trial registrationNCT01087086. Registered 15 March 2010, retrospectively registry.

An evaluation of metabolizable energy content of main feed ingredients for growing pigs when adding dietary lysophospholipids

The present study was conducted to test whether the dietary supplementation of lysophospholipids (LPL) affects digestible energy (DE) content of feed ingredients, nutrient digestibility, and growth performance of growing pigs. In Exp. 1, 8 growing pigs were alternatively used for 8 dietary treatments including 4 feed ingredients (corn, soybean meal, distiller's dried grains with solubles, and animal fat), and 2 LPL concentrations (0% and 0.1%) in 6 periods to determine DE and metabolizable energy (ME) content. In Exp. 2, 200 growing pigs were randomly allotted to 4 treatments on the basis of body weight with 2 concentrations of fat (high and low) and 2 concentrations of LPL (0% and 0.1%). The experimental diets were fed for 42 d in 2 phases. In Exp. 1, gross energy (GE) digestibility, feed DE, and ME were increased in animal fat when LPL were added to the diet. In Exp. 2, the pigs fed LPL showed greater (P < .05) digestibility of EE, GE, crude protein (CP), and DM In phase 2. Pigs fed a high-fat diet had greater (P < .05) digestibility of EE, and GE. Gross energy retention was greater (P < .05) in pigs fed the high-fat diet compared with those fed the low-fat diet in phase 2. During phase 1, the average daily gain (ADG) of pigs fed the high-fat diet was greater (P < .05) than that for pigs fed the low-energy diet. During the second phase, ADG was increased in LPL and high-fat diets (P < .05). The overall results showed that pigs fed the LPL or high-fat treatments had greater ADG and feed to gain ratio (F/G). Considering the 2 experiments, it can be concluded that LPL increase the ME of animal fat and improves ADG and F/G in pigs.

Biomarkers in Spinal Cord Injury: from Prognosis to Treatment.

Spinal cord injury (SCI) is considered an incurable condition, having a heterogenous recovery and uncertain prognosis. Therefore, a reliable prediction of the improvement in the acute phase could benefit patients. Physicians are unanimous in insisting that at the initial damage of the spinal cord (SC), the patient should be carefully evaluated in order to help selecting an appropriate neuroprotective treatment. However, currently, neurologic impairment after SCI is measured and classified by functional examination. The identification of prognostic biomarkers of SCI would help to designate SC injured patients and correlate to diagnosis and correct treatment. Some proteins have already been identified as good potential biomarkers of central nervous system injury, both in cerebrospinal fluid (CSF) and blood serum. However, the problem for using them as biomarkers is the way they should be collected, as acquiring CSF through a lumbar puncture is significantly invasive. Remarkably, microRNAs (miRNAs) have emerged as interesting biomarker candidates because of their stability in biological fluids and their tissue specificity. Several miRNAs have been identified to have their expressions altered in SCI in many animal models, making them promising candidates as biomarkers after SCI. Moreover, there are yet no effective therapies for SCI. It is already known that altered lysophospholipids (LPs) signaling are involved in the biology of disorders, such as inflammation. Reports have demonstrated that LPs when locally distributed can regulate SCI repair and key secondary injury processes such as apoptosis and inflammation, and so could become in the future new therapeutic approaches for treating SCI.

Bioactive lipids in gintonin-enriched fraction from ginseng

BackgroundGinseng is a traditional herbal medicine for human health. Ginseng contains a bioactive ligand named gintonin. The active ingredient of gintonin is lysophosphatidic acid C18:2 (LPA C18:2). We previously developed a method for gintonin-enriched fraction (GEF) preparation to mass-produce gintonin from ginseng. However, previous studies did not show the presence of other bioactive lipids besides LPAs. The aim of this study was to quantify the fatty acids, lysophospholipids (LPLs), and phospholipids (PLs) besides LPAs in GEF. MethodsWe prepared GEF from white ginseng. We used gas chromatography-mass spectrometry for fatty acid analysis and liquid chromatography-tandem mass spectrometry for PL analysis, and quantified the fatty acids, LPLs, and PLs in GEF using respective standards. We examined the effect of GEF on insulin secretion in INS-1 cells. ResultsGEF contains about 7.5% linoleic (C18:2), 2.8% palmitic (C16:0), and 1.5% oleic acids (C18:1). GEF contains about 0.2% LPA C18:2, 0.06% LPA C16:0, and 0.02% LPA C18:1. GEF contains 0.08% lysophosphatidylcholine, 0.03% lysophosphatidylethanolamine, and 0.13% lysophosphatidylinositols. GEF also contains about 1% phosphatidic acid (PA) 16:0-18:2, 0.5% PA 18:2-18:2, and 0.2% PA 16:0-18:1. GEF-mediated insulin secretion was not blocked by LPA receptor antagonist. ConclusionWe determined four characteristics of GEF through lipid analysis and insulin secretion. First, GEF contains a large amount of linoleic acid (C18:2), PA 16:0-18:2, and LPA C18:2 compared with other lipids. Second, the main fatty acid component of LPLs and PLs is linoleic acid (C18:2). Third, GEF stimulates insulin secretion not through LPA receptors. Finally, GEF contains bioactive lipids besides LPAs.

Inhibition of Cytosolic Phospholipase A2α Impairs an Early Step of Coronavirus Replication in Cell Culture.

Coronavirus replication is associated with intracellular membrane rearrangements in infected cells, resulting in the formation of double-membrane vesicles (DMVs) and other membranous structures that are referred to as replicative organelles (ROs). The latter provide a structural scaffold for viral replication/transcription complexes (RTCs) and help to sequester RTC components from recognition by cellular factors involved in antiviral host responses. There is increasing evidence that plus-strand RNA (+RNA) virus replication, including RO formation and virion morphogenesis, affects cellular lipid metabolism and critically depends on enzymes involved in lipid synthesis and processing. Here, we investigated the role of cytosolic phospholipase A2α (cPLA2α) in coronavirus replication using a low-molecular-weight nonpeptidic inhibitor, pyrrolidine-2 (Py-2). The inhibition of cPLA2α activity, which produces lysophospholipids (LPLs) by cleaving at the sn-2 position of phospholipids, had profound effects on viral RNA and protein accumulation in human coronavirus 229E-infected Huh-7 cells. Transmission electron microscopy revealed that DMV formation in infected cells was significantly reduced in the presence of the inhibitor. Furthermore, we found that (i) viral RTCs colocalized with LPL-containing membranes, (ii) cellular LPL concentrations were increased in coronavirus-infected cells, and (iii) this increase was diminished in the presence of the cPLA2α inhibitor Py-2. Py-2 also displayed antiviral activities against other viruses representing the Coronaviridae and Togaviridae families, while members of the Picornaviridae were not affected. Taken together, the study provides evidence that cPLA2α activity is critically involved in the replication of various +RNA virus families and may thus represent a candidate target for broad-spectrum antiviral drug development.IMPORTANCE Examples of highly conserved RNA virus proteins that qualify as drug targets for broad-spectrum antivirals remain scarce, resulting in increased efforts to identify and specifically inhibit cellular functions that are essential for the replication of RNA viruses belonging to different genera and families. The present study supports and extends previous conclusions that enzymes involved in cellular lipid metabolism may be tractable targets for broad-spectrum antivirals. We obtained evidence to show that a cellular phospholipase, cPLA2α, which releases fatty acid from the sn-2 position of membrane-associated glycerophospholipids, is critically involved in coronavirus replication, most likely by producing lysophospholipids that are required to form the specialized membrane compartments in which viral RNA synthesis takes place. The importance of this enzyme in coronavirus replication and DMV formation is supported by several lines of evidence, including confocal and electron microscopy, viral replication, and lipidomics studies of coronavirus-infected cells treated with a highly specific cPLA2α inhibitor.

Effect of green tea on hepatic lipid metabolism in mice fed a high-fat diet

Green tea (GT) is a widely consumed beverage with health benefits, including antiobesity effects; however, the efficacy of GT on lipid levels associated with obesity is not clearly understood. Here, we examined the impact of GT consumption on lipid metabolism in the livers of high-fat diet (HFD)-induced obese mice. We performed lipid profiling using ultraperformance liquid chromatography quadrupole time-of-flight mass spectrometry in C57BL/6J mice fed a normal diet (ND), HFD and HFD with GT for 12 weeks. The partial least squares discriminant analysis score plot showed a difference among the groups and revealed that the levels of several lipid metabolites were altered in mice fed HFD with GT. The decreased levels of lysophospholipids (LPLs), such as lysophosphatidylcholine, lysophosphatidylethanolamine and lysophosphatidylserine, in HFD mice compared to those of the ND group were recovered by supplementation of GT. In agreement with these lipid metabolites changes, hepatic lysophosphatidylcholine acyltransferase 2/4 was significantly increased in HFD mice. This study showed abnormal changes in lipid species associated with obesity, and these levels were attenuated by GT intake, suggesting a relationship between the reduction of hepatic LPL levels and inflammation in obesity.

Solvent-free enzymatic hydrolysis of non-polar lipids in crude sunflower lecithin using phospholipase A1 (Lecitase® Ultra)

In this contribution, a new chromatographic method was applied to study the hydrolysis of non-polar lipids, i.e. triacylglicerols (TAG), diacylglycerols (DAG) and monoacylglycerols (MAG), when crude sunflower lecithin is treated with Lecitase® Ultra, an enzymatic preparation with phospholipase A1 (PLA1) activity. Results not only proved the enzyme lipase activity toward non-polar lipids in selected reaction conditions (aqueous system, T = 50 °C, pH = 5) but also suggested the occurrence of acyl-migration phenomenon observed by other authors in similar systems. Results showed that 1 h of reaction was enough to decrease the content of TAG in 54%, while DAG and MAG concentration increased from 0.4 to 3.5 and from 1.9 to 6.5 g/100 g of crude lecithin, respectively. Along the reaction, different contents of glycerides could be achieved, obtaining products with different composition which, in combination with the presence of phospholipids (PL) and/or lysophospholipids (LPL), could present specific emulsifying/stabilizing properties with a wide range of applications in food and pharmaceutical industry.

A pilot study of the opposing effects of hyperinsulinemia and hyperandrogenenism on serum lipid profiles and bioactive lipids in women with polycystic ovary syndrome

Objective To investigate serum lipid profiles in newly diagnosed patients with polycystic ovary syndrome (PCOS) using lipidomics and correlate these features with hyperinsulinemia and hyperandrogenism associated with PCOS and obesity. Methods 32 newly-diagnosed PCOS women and 34 controls were enrolled and divided into obese and lean subgroups according to the body mass index (BMI). Anthropometric, biochemical, and hormonal parameters were collected. Serum lipid profiles including phospholipids, free fatty acids (FFAs), and bioactive lipids were analyzed using GC-MS and LC-MS. Results PCOS patients, in particular, the obese ones with fatty liver, have abnormal phosphatidylcholine (PC)/lysophospholipid (LPC) metabolism. PC was increased (16∶0, 18∶0, 18∶1, 18∶2, and 20∶4), while LPC was decreased (16∶0, 18∶0, and 18∶1; all P<0.05). Serum polyunsaturated fatty acids (PUFAs), were decreased significantly, and the long chain saturated fatty acid was increased. We also found that insulin stimulated the metabolism of PUFAs, but the androgen inhibits the metabolism of PUFAs by measuring their metabolites. Conclusion PCOS patients have metabolic disorders of phospholipids and PUFAs. Insulin stimulated while androgen inhibited PUFAs metabolism. (Chin J Endocrinol Metab, 2017, 33: 644-650) Key words: Polycystic ovary syndrome; Lipidomics; Insulin resistance; Hyperandrogenism; Obesity

Structural insights into ligand recognition by the lysophosphatidic acid receptor LPA6.

Lysophosphatidic acid (LPA) is a bioactive lipid composed of a phosphate group, a glycerol backbone, and a single acyl chain that varies in length and saturation. LPA activates six class A G-protein-coupled receptors to provoke various cellular reactions. Because LPA signalling has been implicated in cancer and fibrosis, the LPA receptors are regarded as promising drug targets. The six LPA receptors are subdivided into the endothelial differentiation gene (EDG) family (LPA1-LPA3) and the phylogenetically distant non-EDG family (LPA4-LPA6). The structure of LPA1 has enhanced our understanding of the EDG family of LPA receptors. By contrast, the functional and pharmacological characteristics of the non-EDG family of LPA receptors have remained unknown, owing to the lack of structural information. Although the non-EDG LPA receptors share sequence similarity with the P2Y family of nucleotide receptors, the LPA recognition mechanism cannot be deduced from the P2Y1 and P2Y12 structures because of the large differences in the chemical structures of their ligands. Here we determine the 3.2 Å crystal structure of LPA6, the gene deletion of which is responsible for congenital hair loss, to clarify the ligand recognition mechanism of the non-EDG family of LPA receptors. Notably, the ligand-binding pocket of LPA6 is laterally open towards the membrane, and the acyl chain of the lipid used for the crystallization is bound within this pocket, indicating the binding mode of the LPA acyl chain. Docking and mutagenesis analyses also indicated that the conserved positively charged residues within the central cavity recognize the phosphate head group of LPA by inducing an inward shift of transmembrane helices 6 and 7, suggesting that the receptor activation is triggered by this conformational rearrangement.

Analysis of oxylipins in human plasma: Comparison of ultrahigh-performance liquid chromatography and ultrahigh-performance supercritical fluid chromatography coupled to mass spectrometry

The potential of ultrahigh-performance liquid chromatography–mass spectrometry (UHPLC/MS) and ultrahigh-performance supercritical fluid chromatography (UHPSFC) coupled to negative-ion electrospray ionization mass spectrometry (ESI–MS) for the analysis of 46 oxylipins and 2 fatty acid standards is compared in terms of their chromatographic resolution with the emphasis on distinguishing isobaric interferences and the method sensitivity. UHPLC provides the baseline separation of 24 isobaric oxylipins within 13min, while UHPSFC enables the separation of only 20 isobaric oxylipins within 8min. Moreover, the UHPLC/ESI–MS method provides an average improvement of sensitivity by 3.5-fold. A similar trend is observed in the analysis of human plasma samples, but lower ion suppression effects caused by lysophospholipids (LPL) are observed in case of UHPSFC/ESI–MS due to better separation of LPL. Both methods are fully applicable for the analysis of oxylipins, but UHPLC/ESI–MS method is preferred due to better separation and higher sensitivity, which results in the identification of 31 oxylipins in human plasma based on available standards and additional tentative 20 identifications based on accurate m/z values and the fragmentation behavior known from the literature.

Analysis of Lysophospholipid Content in Low Phytate Rice Mutants.

As a fundamental component of nucleic acids, phospholipids, and adenosine triphosphate, phosphorus (P) is critical to all life forms, however, the molecular mechanism of P translocation and distribution in rice grains are still not understood. Here, with the use of five different low phytic acid (lpa) rice mutants, the redistribution in the main P-containing compounds in rice grain, phytic acid (PA), lysophospholipid (LPL), and inorganic P (Pi), was investigated. The lpa mutants showed a significant decrease in PA and phytate-phosphorus (PA-P) concentration with a concomitant increase in Pi concentration. Moreover, defects in the OsST and OsMIK genes result in a great reduction of specific LPL components and LPL-phosphorus (LPL-P) contents in rice grain. In contrast, defective OsMRP5 and Os2-PGK genes led to a significant increase in individual LPL components. The effect of the Os2-PGK gene on the LPL accumulation was validated using breeding lines derived from a cross between KBNT-lpa (Os2-PGK mutation) and Jiahe218. This study demonstrates that these rice lpa mutants lead to the redistribution of Pi in endosperm and modify LPL biosynthesis. Increase LPLs in the endosperm in the lpa mutants may have practical applications in rice breeding to produce "healthier" rice.

Sphingosine 1-Phosphate Receptors: Do They Have a Therapeutic Potential in Cardiac Fibrosis?

Sphingosine 1-phosphate (S1P) is a bioactive lipid that is characterized by a peculiar mechanism of action. In fact, S1P, which is produced inside the cell, can act as an intracellular mediator, whereas after its export outside the cell, it can act as ligand of specific G-protein coupled receptors, which were initially named endothelial differentiation gene (Edg) and eventually renamed sphingosine 1-phosphate receptors (S1PRs). Among the five S1PR subtypes, S1PR1, S1PR2 and S1PR3 isoforms show broad tissue gene expression, while S1PR4 is primarily expressed in immune system cells, and S1PR5 is expressed in the central nervous system. There is accumulating evidence for the important role of S1P as a mediator of many processes, such as angiogenesis, carcinogenesis and immunity, and, ultimately, fibrosis. After a tissue injury, the imbalance between the production of extracellular matrix (ECM) and its degradation, which occurs due to chronic inflammatory conditions, leads to an accumulation of ECM and, consequential, organ dysfunction. In these pathological conditions, many factors have been described to act as pro- and anti-fibrotic agents, including S1P. This bioactive lipid exhibits both pro- and anti-fibrotic effects, depending on its site of action. In this review, after a brief description of sphingolipid metabolism and signaling, we emphasize the involvement of the S1P/S1PR axis and the downstream signaling pathways in the development of fibrosis. The current knowledge of the therapeutic potential of S1PR subtype modulators in the treatment of the cardiac functions and fibrinogenesis are also examined.

Genotypic Variation in Wheat Flour Lysophospholipids.

Lysophospholipids (LPLs) are the most abundant polar lipids in wheat endosperm and naturally complex with amylose, affecting starch physicochemical properties. We analyzed LPLs in wheat flour from 58 cultivars which differ by grain hardness using liquid chromatography mass spectrometry (LCMS). There were significant differences in LPL content between cultivars, demonstrating that genotype rather than environment contributes most to the total variance in wheat endosperm LPLs. Polar lipids such as LPLs may play a role in grain hardness through their interaction with puroindoline proteins, however, no strong correlation between kernel hardness and LPLs was detected. This may reflect the location of LPLs within the starch granule as opposed to the puroindoline proteins outside starch granules. LPLs may have an indirect relationship with kernel hardness as they could share the same origin as polar lipids that interact with puroindoline on the starch granule surface.

Abstract 161: Diet-Induced Obesity Links to Breast Cancer Progression via LPA/PKD-1-CD36 Signaling Axis-Mediated Microvascular Remodeling

Background: Obesity increases breast cancer (BC) risk. However, the molecular links by which obesity promotes BC progression remain largely unknown. Lysophosphatidic acid (LPA) produced excessively in obesity is a lipid signaling mediator essential for vascular remodeling, angiogenesis and BC progression, in which protein kinase D1 (PKD-1) and angiogenic regulator CD36 play an important role. Hypothesis: Obesity promotes microvascular remodeling and angiogenesis for BC progression via LPA/PKD-1-CD36 signaling axis. Methods: The hypothesis was tested in tumor-associated endothelial cells (TAECs), BC cells and a diet-induced obesity (DIO) mouse model. Lentiviral transduction, qPCR, Western blotting and Halo pull-down assays, angiogenesis profiling and immunofluorescence and immunohistochemical assays were applied for analysis of gene and protein expression, and relevant signaling pathways. Seahorse Bioscience Extracellular Flux Analyzer was used to detect cellular mitochondrial respiration. Results: LPA/PKD-1-CD36 signaling was a bona fide BC promoter via stimulating microvascular remodeling in chronic DIO. ER + breast cancer grew faster and larger in the DIO mice than in the lean control, specifically accompanied by enhanced microvascular remodeling in a syngeneic ER + BC model. The expression of vascular endothelial cell growth receptor 2, and endothelial differentiation gene 2/LPA receptor 1 (Edg2/LPA 1 ), and phospho-PKD-1 also increased, accompanied by CD36 downregulation in the tumor endothelium. TAECs exposed to LPA showed sustained nuclear PKD-1 phosphorylation, and elevated mRNA levels of ephrin B2, and reduced CD36 mRNA expression, along with increased proliferation, which was inhibited by a selective PKD inhibitor. Finally, LPA/PKD-1 signaling changed mitochondrial respiration in ECs and breast adenocarcinoma cells. Conclusion: These studies suggest that LPA/PKD-1-CD36 signaling axis links DIO to BC progression via stimulation of arteriolar remodeling of microvasculature in the tumor microenvironment. The axis-mediated changes in cellular metabolism may promote the microvascular remodeling process. Targeting this signaling axis could provide an additional novel therapeutic strategy against breast cancer.

Review of the Third Domain Receptor Binding Fragment of Alphafetoprotein (AFP): Plausible Binding of AFP to Lysophospholipid Receptor Targets.

Alpha-fetoprotein (AFP) is a 69 kD fetal- and tumor-associated single-chain glycoprotein belonging to the albuminoid gene family. AFP functions as a carrier/transport molecule as well as a growth regulator and has been utilized as a clinical biomarker for both fetal defects and cancer growth. Lysophospholipids (LPLs) are plasma membrane-derived bioactive lipid signaling mediators composed of a small molecular weight single acyl carbon chain (palmitic, oleic acid) attached to a polar headgroup; they range in molecular mass from 250-750 daltons. The LPLs consist of either sphingosine-1-phosphate or lysophosphatidic acid, and mostly their choline, ethanolamine, serine or inositol derivatives. They are present only in vertebrates. These bioactive paracrine lipid mediators are ubiquitously distributed in tissues and are released from many different cell types (platelets, macrophages, monocytes, etc.) involved in developmental, physiological, and pathological processes. The LPLs bind to four different classes of G-protein coupled receptors described herein which transduce a multiple of cell effects encompassing activities such as morphogenesis, neural development, angiogenesis, and carcinogenesis. The identification of potential binding sites of LPL receptors on the AFP third domain receptor binding fragment was derived by computer modeling analysis. It is conceivable, but not proven, that AFP might bind not only to the LPL receptors, but also to LPLs themselves since AFP binds medium and long chain fatty acids. It is proposed that some of the activities ascribed to AFP in the past might be due in part to the presence of bound LPLs and/or their receptors.

Lysophospholipids and Their Receptors Serve as Conditional DAMPs and DAMP Receptors in Tissue Oxidative and Inflammatory Injury.

Significance: We proposed lysophospholipids (LPLs) and LPL-G-protein-coupled receptors (GPCRs) as conditional danger-associated molecular patterns (DAMPs) and conditional DAMP receptors as a paradigm shift to the widely accepted classical DAMP and DAMP receptor model. Recent Advances: The aberrant levels of LPLs and GPCRs activate pro-inflammatory signal transduction pathways, trigger innate immune response, and lead to tissue oxidative and inflammatory injury. Critical Issues: Classical DAMP model specifies only the endogenous metabolites that are released from damaged/dying cells as DAMPs, but fails to identify elevated endogenous metabolites secreted from viable/live cells during pathologies as DAMPs. The current classification of DAMPs also fails to clarify the following concerns: (i) Are molecules, which bind to pattern recognition receptors (PRRs), the only DAMPs contributing to inflammation and tissue injury? (ii) Are all DAMPs acting only via classical PRRs during cellular stress? To answer these questions, we reviewed the molecular characteristics and signaling mechanisms of LPLs, a group of endogenous metabolites and their specific receptors and analyzed the significant progress achieved in characterizing oxidative stress mechanisms of LPL mediated tissue injury. Future Directions: Further LPLs and LPL-GPCRs may serve as potential therapeutic targets for the treatment of pathologies induced by sterile inflammation. Antioxid. Redox Signal. 28, 973-986.

LplT‐Aas system: The primary mechanism for lysophospholipid remodeling in E. coli

Lysophospholipids (LPLs) are metabolic intermediates in phospholipid turnover and are derived from multiple endogenous and exogenous sources in bacterial membrane envelope. Distinct from their diacyl counterparts, these detergent‐like lipid molecules alter the local membrane properties and their accumulation may lead to severe membrane disruption and eventually cell lysis. LplT and Aas form a novel lysophospholipid remodeling system found exclusively in Gram‐negative bacteria. LplT is a member of Major Facilitator Superfamily and facilitates energy‐independent lipid flipping across the bacterial inner membrane. Aas catalyzes acyl transfer to LPL from acyl‐ACP on the cytoplasmic surface. The biological function and molecular mechanism of this lipid remodeling system remain largely unknown. We found that LplT‐Aas effectively facilitate remodeling of all three major bacterial phospholipids, PE, PG and cardiolipin, in E.coli. LplT imports lyso‐PE, lyso‐PG into the cells, which are subsequently acylated by the action of Aas to form their respective diacyl forms. We also identified a novel cardiolipin hydrolysis reaction by venom phospholipase A2 to form diacyl cardiolipin progressing to the completely deacylated headgroup. These two distinct cardiolipin derivatives are both translocated by LplT and then remodeled by Aas to form a triacyl form of cardiolipin. These results reveal the first cardiolipin remodeling mechanism in bacteria. LplT cannot transport lyso‐PC or lyso‐PA, suggesting its primary role in phospholipid repairing mechanism in the bacterial membrane envelope. To understand this novel LPL transport mechanism, we found that the substrate fatty acid chain is not required for LplT transport and its substrate binding was not inhibited by either orthophosphate or glycerol 3‐phosphate, suggesting that either a glycerol or ethanolamine headgroup is the chemical determinant for substrate recognition. Membrane phospholipids could not serve as a competitive inhibitor in vitro. This strict selectivity for lyso lipids allows LplT‐Aas to fulfill their efficient lipid repairing function in a membrane environment. Based on a structural model, we propose a “sideway sliding” mechanism to explain how a conserved membrane‐embedded α‐helical interface excludes membrane from the LplT binding site to facilitate efficient flipping of LPL across the cell membrane. Very recently, we found that LplT‐Aas play a potent role in maintaining membrane stability and integrity in the bacterial envelope and may be involved in the bacterial resistance against secretory phospholipase A2‐mediated host immune attack. These data demonstrate the first evidence for the biological function of this novel LPL remodeling system in E.coli.Support or Funding InformationNIH grant R01GM098572

Effects of lysophospholipid supplementation to lower nutrient diets on growth performance, intestinal morphology, and blood metabolites in broiler chickens

The purpose of this research was to investigate the effects of dietary lysophospholipid (LPL) supplementation on low-energy, crude protein, and selected amino acids on growth performance, intestinal morphology, blood metabolites, inflammatory response, and carcass traits in broiler chickens. A total of 300 one-day-old male chicks (Ross 308) were assigned to 5 treatments, with 6 replications of 10 birds each in a completely randomized design. The 5 treatments were: positive control (PC) without LPL supplementation and adequate in all nutrients, negative control (NC) without LPL, and reduced 150 kcal/kg of metabolizable energy and reduced 5 to 6% of crude protein and selected amino acids including Lys, Met, Thr, and Trp in a calculated amount relative to the PC, NC + 0.05% LPL (LPL05), NC + 0.10% LPL (LPL10), and NC + 0.15% LPL (LPL15). Feeding LPL linearly improved growth performance, feed conversion ratio, ether extract, and protein digestibility. LPL supplementation on low-energy and nitrogenous diets showed significant enhancements in metabolic profiles of blood glucose, protein utilization, and immune system functions. These improvements influenced carcass composition, especially in relative weights of pancreas and breast muscle. In contrast, LPL addition showed no significant effects on relative weights of immune organs, gizzard, and abdominal fat. The NC birds were more susceptible to inflammation via modulating the secretion of interleukin-1 (IL-1) and increasing crypt depth in the jejunal and duodenal segments. However, the inclusion of 0.05% LPL to the NC diet could alleviate inflammation with increased jejunal villi height, ratio of villi height to crypt depth, and decreased IL-1 level. Overall, LPL promotes growth performance, nutrient utilization, gut health, anti-inflammation, and muscle yields when applied to diets of broiler chickens with lower levels of energy, crude protein, and selected amino acids.