Arabidopsis PROTODERMAL FACTOR2 binds lysophosphatidylcholines and transcriptionally regulates phospholipid metabolism.

Plant homeodomain leucine zipper IV (HD-Zip IV) transcription factors (TFs) contain an evolutionarily conserved steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) domain. While the START domain is required for TF activity, its presumed role as a lipid sensor is not clear. Here we used tandem affinity purification from Arabidopsis cell cultures to demonstrate that PROTODERMAL FACTOR2 (PDF2), a representative member that controls epidermal differentiation, recruits lysophosphatidylcholines (LysoPCs) in a START-dependent manner. Microscale thermophoresis assays confirmed that a missense mutation in a predicted ligand contact site reduces lysophospholipid binding. We additionally found that PDF2 acts as a transcriptional regulator of phospholipid- and phosphate (Pi) starvation-related genes and binds to a palindromic octamer with consensus to a Pi response element. Phospholipid homeostasis and elongation growth were altered in pdf2 mutants according to Pi availability. Cycloheximide chase experiments revealed a role for START in maintaining protein levels, and Pi starvation resulted in enhanced protein destabilization, suggesting a mechanism by which lipid binding controls TF activity. We propose that the START domain serves as a molecular sensor for membrane phospholipid status in the epidermis. Our data provide insights toward understanding how the lipid metabolome integrates Pi availability with gene expression.

Comparative analysis of lysophospholipid metabolism profiles and clinical characteristics in patients with high vs. low C-reactive protein levels in acute exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: The precise role of lysophospholipids (LysoPLs) in the pathogenesis of acute exacerbations of Chronic Obstructive Pulmonary Disease (AECOPD) remains unclear. In this study, we sought to elucidate the differences in serum LysoPL metabolite profiles and their correlation with clinical features between patients with low versus high CRP levels. METHODS: A total of 58 patients with AECOPD were enrolled in the study. Patients were classified into two groups: low CRP group (CRP < 20 mg/L, n = 34) and high CRP group (CRP ≥ 20 mg/L, n = 24). Clinical data were collected, and the LysoPL metabolite profiles were analyzed using Liquid Chromatography-Mass Spectrometry (LC-MS) and identified by matching with the LipidBlast library. RESULTS: Nineteen differential LysoPLs were initially identified through Student's t-test (p < 0.05 and VIP > 1). Subsequently, four LysoPLs, LPC(16:0), LPE(18:2), LPC(22:0), and LPC(24:0), were identified by FDR adjustment (adjusted p < 0.05). These four lysoPLs had a significant negative correlation with CRP. Integrative analysis revealed that LPC (16:0) and LPC (22:0) correlated with less hypercapnic respiratory failure and ICU admission. CONCLUSION: AECOPD patients with high CRP levels demonstrated a distinctive LysoPL metabolism profile, with LPC (16:0), LPE(18:2), LPC(22:0), and LPC(24:0) being the most significantly altered lipid molecules. These alterations were associated with poorer clinical outcomes.

The Role of Lysophospholipid Metabolites LPC and LPA in the Pathogenesis of Chronic Obstructive Pulmonary Disease.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition characterized by persistent respiratory symptoms and airflow limitation. While there are some available treatment options, the effectiveness of treatment varies depending on individual differences and the phenotypes of the disease. Therefore, exploring or identifying potential therapeutic targets for COPD is urgently needed. In recent years, there has been growing evidence showing that lysophospholipids, namely lysophosphatidylcholine (LPC) and lysophosphatidic acid (LPA), can play a significant role in the pathogenesis of COPD. Exploring the metabolism of lysophospholipids holds promise for understanding the underlying mechanism of COPD development and developing novel strategies for COPD treatment. This review primarily concentrates on the involvement and signaling pathways of LPC and LPA in the development and progression of COPD. Furthermore, we reviewed their associations with clinical manifestations, phenotypes, and prognosis within the COPD context and discussed the potential of the pivotal signaling molecules as viable therapeutic targets for COPD treatment.

The Role of Phospholipid Alterations in Mitochondrial and Brain Dysfunction after Cardiac Arrest.

The human brain possesses three predominate phospholipids, phosphatidylcholine (PC), phosphatidylethanolamine (PE) and phosphatidylserine (PS), which account for approximately 35-40%, 35-40%, and 20% of the brain's phospholipids, respectively. Mitochondrial membranes are relatively diverse, containing the aforementioned PC, PE, and PS, as well as phosphatidylinositol (PI) and phosphatidic acid (PA); however, cardiolipin (CL) and phosphatidylglycerol (PG) are exclusively present in mitochondrial membranes. These phospholipid interactions play an essential role in mitochondrial fusion and fission dynamics, leading to the maintenance of mitochondrial structural and signaling pathways. The essential nature of these phospholipids is demonstrated through the inability of mitochondria to tolerate alteration in these specific phospholipids, with changes leading to mitochondrial damage resulting in neural degeneration. This review will emphasize how the structure of phospholipids relates to their physiologic function, how their metabolism facilitates signaling, and the role of organ- and mitochondria-specific phospholipid compositions. Finally, we will discuss the effects of global ischemia and reperfusion on organ- and mitochondria-specific phospholipids alongside the novel therapeutics that may protect against injury.

The Effect of Lysophospholipids and Sex on Growth Performance and Small Intestine Morphology in Weanling Pigs, 7-30 kg.

Inclusion of lysophospholipids (LPL) has been proposed to increase growth performance in broilers and pigs, acting as emulsifiers through mixed micelle formation. The aim of this study was to investigate the effect of feeding LPL in weanling pig diets on growth performance and intestinal morphology. Eight hundred pigs (weight 6.96 kg ± SD 1.58 kg) were assigned to one of two dietary treatments, i.e., a basal diet (CON) or a basal diet + 0.05% lysophospholipids (LPL). The experimental period lasted for 42 days, and on days 40 and 41, 32 pigs in total were euthanized for intestinal tissue samples. From days 14 to 21, feed intake and average daily gain increased, as well as FCR, from days 28 to 42, in the LPL group compared with the CON group. In the overall period, no differences in growth performance were present between the groups. However, females displayed increased ADG from days 21 to 28 compared with castrates. The villous height tended (p = 0.051) to be lower in LPL in the proximal jejunum compared with CON. In the proximal jejunum, villus was higher (p > 0.01) in females, and in the distal jejunum, higher crypt cell proliferation (p < 0.01) and a tendency to deeper crypts (p = 0.064) were observed in female pigs as well. In conclusion, lysophospholipids did not increase growth performance in this study; however, the rate of recovery from a poorer starting point was noted, as growth rates recovered and increased faster in the LPL group. In conclusion, unlike the first phase, the LPL group recovered the growth from days 14 to 21 through higher feed intake and weight gain than the CON group. Eventually, the LPL group displayed improved FCR compared with the CON group from days 28 to 42. Further studies are needed to investigate whether this effect continues into the grower-finisher phase.

Phospholipid analyses of rabbit ocular surface tissues.

The tissues of the integument covering the ocular surface comprise a mucus membrane functioning as a protective physical barrier and has the ability to mount a defensive inflammatory response. Since lipid metabolism has a role in both of these functions, we studied normal membrane phospholipids (PL) of the cornea and bulbar conjunctiva to (1) determine baseline PL profiles of these tissues, (2) compare and contrast these individual PL metabolite profiles as well as groups of metabolites, and (3) describe pathway-specific metabolic interrelations among these tissues. Corneal and conjunctival tissue samples were isolated from rabbit eyes (n = 30) and extracted with chloroform-methanol using a modified Folch procedure. 31P nuclear magnetic resonance spectroscopy was used to qualitatively and quantitatively measure tissue PL profiles. The cornea and conjunctiva, respectively, have the following PL composition (mole % of total detected phospholipid): phosphatidylglycerol (PG) -, 0.4; lysophosphatidylethanolamine 1.2, -; phosphatidic acid -, 0.4; diPG (cardiolipin) 2.1, 3.5; unknown PL at the chemical shift of 0.13 δ 1.5, 0.9; ethanolamine plasmalogen 11.2, 13.0; phosphatidylethanolamine 11.5, 12.8; phosphatidylserine 8.9, 10.1; sphingomyelin 10.2, 10.7; lysophosphatidylcholine 0.9, 1.4; phosphatidylinositol 5.3, 5.3; phosphatidylcholine (PC) plasmalogen or alkylacylPC 2.2, 1.9; PC 45.1, 40.0. In addition, 28 PL metabolic indices were calculated from these data, which permitted pathway-specific lipid analyses. This study (1) establishes PL profiles of the two ocular tissues of the integument that cover the surface of the eye, (2) compares and contrasts indices comprised of ratios and combinations of PL, and (3) describes pathway-specific metabolic interrelations among these tissues to serve as baselines for studies involving the distribution of tissue phospholipids.

A comprehensive UHPLC-MS/MS method for metabolomics profiling of signaling lipids: Markers of oxidative stress, immunity and inflammation.

Signaling lipids (SLs) play a crucial role in various signaling pathways, featuring diverse lipid backbone structures. Emerging evidence showing the biological significance and biomedical values of SLs has strongly spurred the advancement of analytical approaches aimed at profiling SLs. Nevertheless, the dramatic differences in endogenous abundances across lipid classes as well as multiple isomers within the same lipid class makes the development of a generic analytical method challenging. A better analytical method that combines comprehensive coverage and high sensitivity is needed to enable us to gain a deeper understanding of the biochemistry of these molecules in health and disease. In this study, we developed a fast and comprehensive targeted ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method for profiling SLs. The platform enables analyses of 260 metabolites covering oxylipins (isoprostanes, prostaglandins and other oxidized lipids), free fatty acids, lysophospholipids, sphingoid bases (C16, C18), platelet activating factors (C16, C18), endocannabinoids and bile acids. Various validation parameters including linearity, limit of detection, limit of quantification, extraction recovery, matrix effect, intra-day and inter-day precision were used to characterize this method. Metabolite quantitation was successfully achieved in both NIST Standard Reference Material for human plasma (NIST SRM 1950) and pooled human plasma, with 109 and 144 metabolites quantitated. The quantitation results in NIST SRM 1950 plasma demonstrated good correlations with certified or previously reported values in published literature. This study introduced quantitative data for 37 SLs for the first time. Metabolite concentrations measured in NIST SRM 1950 will serve as essential reference data for facilitating interlaboratory comparisons. The methodology established here will be the cornerstone for in-depth profiling of signaling lipids across diverse biological samples and contexts.

Tracer-based lipidomics enables the discovery of disease-specific candidate biomarkers in mitochondrial ß-oxidation disorders.

Carnitine derivatives of disease-specific acyl-CoAs are the diagnostic hallmark for long-chain fatty acid ß-oxidation disorders (lcFAOD), including carnitine shuttle deficiencies, very-long-chain acyl-CoA dehydrogenase deficiency (VLCADD), long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) and mitochondrial trifunctional protein deficiency (MPTD). The exact consequence of accumulating lcFAO-intermediates and their influence on cellular lipid homeostasis is, however, still unknown. To investigate the fate and cellular effects of the accumulating lcFAO-intermediates and to explore the presence of disease-specific markers, we used tracer-based lipidomics with deuterium-labeled oleic acid (D9-C18:1) in lcFAOD patient-derived fibroblasts. In line with previous studies, we observed a trend towards neutral lipid accumulation in lcFAOD. In addition, we detected a direct connection between the chain length and patterns of (un)saturation of accumulating acylcarnitines and the various enzyme deficiencies. Our results also identified two disease-specific candidate biomarkers. Lysophosphatidylcholine(14:1) (LPC(14:1)) was specifically increased in severe VLCADD compared to mild VLCADD and control samples. This was confirmed in plasma samples showing an inverse correlation with enzyme activity, which was better than the classic diagnostic marker C14:1-carnitine. The second candidate biomarker was an unknown lipid class, which we identified as S-(3-hydroxyacyl)cysteamines. We hypothesized that these were degradation products of the CoA moiety of accumulating 3-hydroxyacyl-CoAs. S-(3-hydroxyacyl)cysteamines were significantly increased in LCHADD compared to controls and other lcFAOD, including MTPD. Our findings suggest extensive alternative lipid metabolism in lcFAOD and confirm that lcFAOD accumulate neutral lipid species. In addition, we present two disease-specific candidate biomarkers for VLCADD and LCHADD, that may have significant relevance for disease diagnosis, prognosis, and monitoring.

Synthesis of phospholipids in human placenta.

INTRODUCTION: Placental phospholipid synthesis is critical for the expansion of the placental exchange surface area and for production of signaling molecules. Despite their importance, it is not yet established which enzymes involved in the de novo synthesis and remodeling of placental phospholipids are expressed and active in the human placenta. METHODS: We identified phospholipid synthesis enzymes by immunoblotting in placental homogenates and immunofluorescence in placenta tissue sections. Primary human trophoblast (PHT) cells from term healthy placentas (n = 10) were cultured and exposed to 13C labeled fatty acids (16:0, 18:1 and 18:2 n-6, 22:6 n-3) for 2 and 24 h. Three phospholipid classes; phosphatidic acid, phosphatidylcholine, and lysophosphatidylcholine containing 13C fatty acids were quantified by Liquid Chromatography with tandem mass spectrometry (LC/MS-MS). RESULTS: Acyl transferase and phospholipase enzymes were detected in human placenta homogenate and primarily expressed in the syncytiotrophoblast. Three representative 13C fatty acids (16:0, 18:1 and 18:2 n-6) were incorporated rapidly into phosphatidic acid in trophoblasts, but 13C labeled docosahexaenoic acid (DHA; 22:6 n-3) incorporation was not detected. 13C DHA was incorporated into phosphatidylcholine. Lysophosphatidylcholine containing all four 13C labeled fatty acids were found in high abundance. CONCLUSIONS: Phospholipid synthesis and remodeling enzymes are present in the syncytiotrophoblast. 13C labeled fatty acids were rapidly incorporated into cellular phospholipids. 13C DHA was incorporated into phospholipids through the remodeling pathway rather than by de novo synthesis. These understudied pathways are highly active and critical for structure and function of the placenta.

Exploring Metabolic and Gut Microbiome Responses to Paraquat Administration in Male Wistar Rats: Implications for Oxidative Stress.

In this study, we examined the metabolic and gut microbiome responses to paraquat (PQ) in male Wistar rats, focusing on oxidative stress effects. Rats received a single intraperitoneal injection of PQ at 15 and 30 mg/kg, and various oxidative stress parameters (i.e., MDA, SOD, ROS, 8-isoprostanes) were assessed after three days. To explore the omic profile, GC-qTOF and UHPLC-qTOF were performed to assess the plasma metabolome; 1H-NMR was used to assess the urine metabolome; and shotgun metagenomics sequencing was performed to study the gut microbiome. Our results revealed reductions in body weight and tissue changes, particularly in the liver, were observed, suggesting a systemic effect of PQ. Elevated lipid peroxidation and reactive oxygen species levels in the liver and plasma indicated the induction of oxidative stress. Metabolic profiling revealed changes in the tricarboxylic acid cycle, accumulation of ketone body, and altered levels of key metabolites, such as 3-hydroxybutyric acid and serine, suggesting intricate links between energy metabolism and redox reactions. Plasma metabolomic analysis revealed alterations in mitochondrial metabolism, nicotinamide metabolism, and tryptophan degradation. The gut microbiome showed shifts, with higher PQ doses influencing microbial populations (e.g., Escherichia coli and Akkermansia muciniphila) and metagenomic functions (pyruvate metabolism, fermentation, nucleotide and amino acid biosynthesis). Overall, this study provides comprehensive insights into the complex interplay between PQ exposure, metabolic responses, and gut microbiome dynamics. These findings enhance our understanding of the mechanisms behind oxidative stress-induced metabolic alterations and underscore the connections between xenobiotic exposure, gut microbiota, and host metabolism.

Bioactive signalling lipids as drivers of chronic liver diseases.

Lipids are important in multiple cellular functions, with most having structural or energy storage roles. However, a small fraction of lipids exert bioactive roles through binding to G protein-coupled receptors and induce a plethora of processes including cell proliferation, differentiation, growth, migration, apoptosis, senescence and survival. Bioactive signalling lipids are potent modulators of metabolism and energy homeostasis, inflammation, tissue repair and malignant transformation. All these events are involved in the initiation and progression of chronic liver diseases. In this review, we focus specifically on the roles of bioactive lipids derived from phospholipids (lyso-phospholipids) and poly-unsaturated fatty acids (eicosanoids, pro-resolving lipid mediators and endocannabinoids) in prevalent chronic liver diseases (alcohol-associated liver disease, non-alcoholic fatty liver disease, viral hepatitis and hepatocellular carcinoma). We discuss the balance between pathogenic and beneficial bioactive lipids as well as potential therapeutic targets related to the agonism or antagonism of their receptors.

Lysophospholipids Are Associated With Outcomes in Hospitalized Patients With Mild Traumatic Brain Injury.

Mild traumatic brain injury (mTBI) accounts for 70-90% of all TBI cases. Lipid metabolites have important roles in plasma membrane biogenesis, function, and cell signaling. As TBI can compromise plasma membrane integrity and alter brain cell function, we sought to identify circulating phospholipid alterations after mTBI, and determine if these changes were associated with clinical outcomes. Patients with mTBI (Glasgow Coma Score [GCS] ≥13 and loss of consciousness <30 min) were recruited. A total of 84 mTBI subjects were enrolled after admission to a level I trauma center, with the majority having evidence of traumatic intracranial hemorrhage on brain computed tomography (CT). Plasma samples were collected within 24 h of injury with 32 mTBI subjects returning at 3 months after injury for a second plasma sample to be collected. Thirty-five healthy volunteers were enrolled as controls and had a one-time blood draw. Lipid metabolomics was performed on plasma samples from each subject. Fold change of selected lipid metabolites was determined. Multivariable regression models were created to test associations between lipid metabolites and discharge and 6-month Glasgow Outcomes Scale-Extended (GOSE) outcomes (dichotomized between "good" [GOSE ≥7] and "bad" [GOSE ≤6] functional outcomes). Plasma levels of 31 lipid metabolites were significantly associated with discharge GOSE using univariate models; three of these metabolites were significantly increased, while 14 were significantly decreased in subjects with good outcomes compared with subjects with poor outcomes. In multivariable logistic regression models, higher circulating levels of the lysophospholipids (LPL) 1-linoleoyl-glycerophosphocholine (GPC) (18:2), 1-linoleoyl-GPE (18:2), and 1-linolenoyl-GPC (18:3) were associated with both good discharge GOSE (odds ratio [OR] 12.2 [95% CI 3.35, 58.3], p = 5.23 × 10-4; OR 9.43 [95% CI 2.87, 39.6], p = 7.26 × 10-4; and OR 5.26 [95% CI 1.99, 16.7], p = 2.04 × 10-3, respectively) and 6-month (OR 4.67 [95% CI 1.49, 17.7], p = 0.013; OR 2.93 [95% CI 1.11, 8.87], p = 0.039; and OR 2.57 [95% CI 1.08, 7.11], p = 0.046, respectively). Compared with healthy volunteers, circulating levels of these three LPLs were decreased early after injury and had normalized by 3 months after injury. Logistic regression models to predict functional outcomes were created by adding each of the described three LPLs to a baseline model that included age and sex. Including 1-linoleoyl-GPC (18:2) (8.20% improvement, p = 0.009), 1-linoleoyl-GPE (18:2) (8.85% improvement, p = 0.021), or 1-linolenoyl-GPC (18:3) (7.68% improvement, p = 0.012), significantly improved the area under the curve (AUC) for predicting discharge outcomes compared with the baseline model. Models including 1-linoleoyl-GPC (18:2) significantly improved AUC for predicting 6-month outcomes (9.35% improvement, p = 0.034). Models including principal components derived from 25 LPLs significantly improved AUC for prediction of 6-month outcomes (16.0% improvement, p = 0.020). Our results demonstrate that higher plasma levels of LPLs (1-linoleoyl-GPC, 1-linoleoyl-GPE, and 1-linolenoyl-GPC) after mTBI are associated with better functional outcomes at discharge and 6 months after injury. This class of phospholipids may represent a potential therapeutic target.

Neurological Improvement via Lysophosphatidic Acid Administration in a Rodent Model of Cardiac Arrest-Induced Brain Injury.

Lysophosphatidic acid (LPA) serves as a fundamental constituent of phospholipids. While prior studies have shown detrimental effects of LPA in a range of pathological conditions, including brain ischemia, no studies have explored the impact of LPA in the context of cardiac arrest (CA). The aim of this study is to evaluate the effects of the intravenous administration of an LPA species containing oleic acid, LPA (18:1) on the neurological function of rats (male, Sprague Dawley) following 8 min of asphyxial CA. Baseline characteristics, including body weight, surgical procedure time, and vital signs before cardiac arrest, were similar between LPA (18:1)-treated (n = 10) and vehicle-treated (n = 10) groups. There was no statistically significant difference in 24 h survival between the two groups. However, LPA (18:1)-treated rats exhibited significantly improved neurological function at 24 h examination (LPA (18:1), 85.4% ± 3.1 vs. vehicle, 74.0% ± 3.3, p = 0.045). This difference was most apparent in the retention of coordination ability in the LPA (18:1) group (LPA (18:1), 71.9% ± 7.4 vs. vehicle, 25.0% ± 9.1, p < 0.001). Overall, LPA (18:1) administration in post-cardiac arrest rats significantly improved neurological function, especially coordination ability at 24 h after cardiac arrest. LPA (18:1) has the potential to serve as a novel therapeutic in cardiac arrest.

Tumor microenvironment-derived monoacylglycerol lipase provokes tumor-specific immune responses and lipid profiles.

We recently described that monoacylglycerol lipase (MGL) is present in the tumor microenvironment (TME), increasing tumor growth. In this study we compare the implications of MGL deficiency in the TME in different tumor types. We show that subcutaneous injection of KP (KrasLSL-G12D/p53fl/fl, mouse lung adenocarcinoma) or B16-F10 cells (mouse melanoma) induced tumor growth in MGL wild type (WT) and knockout (KO) mice. MGL deficiency in the TME attenuated the growth of KP cell tumors whereas tumors from B16-F10 cells increased in size. Opposite immune cell profiles were detected between the two tumor types in MGL KO mice. In line with their anti-tumorigenic function, the number of CD8+ effector T cells and eosinophils increased in KP cell tumors of MGL KO vs. WT mice whereas their presence was reduced in B16-F10 cell tumors of MGL KO mice. Differences were seen in lipid profiles between the investigated tumor types. 2-arachidonoylglycerol (2-AG) content significantly increased in KP, but not B16-F10 cell tumors of MGL KO vs. WT mice while other endocannabinoid-related lipids remained unchanged. However, profiles of phospho- and lysophospholipids, sphingomyelins and fatty acids in KP cell tumors were clearly distinct to those measured in B16-F10 cell tumors. Our data indicate that TME-localized MGL impacts tumor growth, as well as levels of 2-AG and other lipids in a tumor specific manner.

Effect of Genetically Reduced Maternal Myostatin on Late Gestation Maternal, Fetal, and Placental Metabolomes in Mice.

Myostatin (gene symbol: Mstn) is an autocrine and paracrine inhibitor of muscle growth. Pregnant mice with genetically reduced levels of myostatin give birth to offspring with greater adult muscle mass and bone biomechanical strength. However, maternal myostatin is not detectable in fetal circulations. Fetal growth is dependent on the maternal environment, and the provisioning of nutrients and growth factors by the placenta. Thus, this study examined the effect of reduced maternal myostatin on maternal and fetal serum metabolomes, as well as the placental metabolome. Fetal and maternal serum metabolomes were highly distinct, which is consistent with the role of the placenta in creating a specific fetal nutrient environment. There was no effect from myostatin on maternal glucose tolerance or fasting insulin. In comparisons between pregnant control and Mstn+/- mice, there were more significantly different metabolite concentrations in fetal serum, at 50, than in the mother's serum at 33, confirming the effect of maternal myostatin reduction on the fetal metabolic milieu. Polyamines, lysophospholipids, fatty acid oxidation, and vitamin C, in fetal serum, were all affected by maternal myostatin reduction.

Role of autotaxin in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by the production of various autoantibodies and deposition of immune complexes. SLE is a heterogenous disease, and the pattern of organ involvement and response to treatment differs significantly among patients. Novel biological markers are necessary to assess the extent of organ involvement and predict treatment response in SLE. Lysophosphatidic acid is a lysophospholipid involved in various biological processes, and autotaxin (ATX), which catalyzes the production of lysophosphatidic acid in the extracellular space, has gained attention in various diseases as a potential biomarker. The concentration of ATX is increased in the serum and urine of patients with SLE and lupus nephritis. Recent evidence suggests that ATX produced by plasmacytoid dendritic cells may play an important role in the immune system and pathogenesis of SLE. Furthermore, the production of ATX is associated with type I interferons, a key cytokine in SLE pathogenesis, and ATX may be a potential biomarker and key molecule in SLE.

Dietary lysophospholipids improves growth performance and hepatic lipid metabolism of largemouth bass (Micropterussalmoides).

This study was conducted to evaluate the influence of dietary lysophospholipids combined with 1% dietary fish oil reduction on the growth performance and hepatic lipid metabolism of largemouth bass (Micropterus salmoides). Five isonitrogenous feeds were prepared with lysophospholipids at 0% (fish oil group, FO), 0.05% (L-0.05), 0.1% (L-0.1), 0.15% (L-0.15) and 0.2% (L-0.2), respectively. The dietary lipid was 11% in the FO diet and 10% in the other diets. Largemouth bass were fed for 68 d (initial body weight = 6.04 ± 0.01 g) with 4 replicates per group and 30 fish per replicate. The results showed that the fish fed diet containing 0.1% lysophospholipids had higher digestive enzyme activity and obtained better growth performance compared to the fish fed FO diet (P < 0.05). The feed conversion rate in the L-0.1 group was significantly lower than that in the other groups. Serum total protein and triglyceride contents in L-0.1 group were significantly higher than those in other groups (P < 0.05) and the contents of total cholesterol and low-density lipoprotein cholesterol in L-0.1 group were significantly lower than those in FO group (P < 0.05). The activity and genes expression of hepatic glucolipid metabolizing enzymes in L-0.15 group were significantly increased compared to those in FO group (P < 0.05). Reducing 1% fish oil along with 0.1% lysophospholipids added to the feed could improve the digestion and absorption of nutrients, enhance the activity of liver glycolipid metabolizing enzymes, and thus effectively promote the growth of largemouth bass.

Lysophospholipids and their producing enzymes: Their pathological roles and potential as pathological biomarkers.

Accumulating evidence suggests that lysophospholipids (LPL) serve as lipid mediators that exert their diverse pathophysiological functions via G protein-coupled receptors. These include lysophosphatidic acid (LPA), sphingosine 1-phosphate (S1P), lysophosphatidylserine (LysoPS) and lysophosphatidylinositol (LPI). Unlike S1P, which is produced intracellularly and secreted from various cell types, some LPLs, such as LPA, LysoPS and LPI, are produced in lesions, especially under pathological conditions, where they positively or negatively regulate disease progression through their autacoid-like actions. Although these LPLs are minor components of the cell membrane, recent developments in mass spectrometry techniques have made it possible to detect and quantify them in a variety of biological fluids, including plasma, serum, urine and cerebrospinal fluid. The synthetic enzymes of LPA and LysoPS are also present in these biological fluids, which also can be detected by antibody-based methods. Importantly, their levels have been found to dramatically increase during various pathological conditions. Thus, LPLs and their synthetic enzymes in these biological fluids are potential biomarkers. This review discusses the potential of these LPLs and LPL-related molecules as pathological biomarkers, including methods and problems in their measurement.

Emerging roles of lysophosphatidylserine as an immune modulator.

In addition to direct activation by pathogens and antigens, immune cell functions are further modulated by factors in their environment. Recent studies have revealed that lysophospholipids (LPL) derived from membrane glycerophospholipids are such environmental factors. They are produced by the action of various phospholipases and modulate immune responses positively or negatively via G-protein-coupled receptor-type receptors. These include lysophosphatidic acid, lysophosphatidylserine (LysoPS), and lysophosphatidylinositol. Here, we summarize what is known about the synthetic pathways, receptors, and immunomodulatory functions of these LPLs. Particular focus is given to LysoPS, which have recently been identified, and recent findings on their immunomodulatory actions are presented.

Hepatitis B virus X protein induces ALDH2 ubiquitin-dependent degradation to enhance alcoholic steatohepatitis.

Background: Excessive alcohol intake with hepatitis B virus (HBV) infection accelerates chronic liver disease progression and patients with HBV infection are more susceptible to alcohol-induced liver disease. Hepatitis B virus X protein (HBx) plays a crucial role in disease pathogenesis, while its specific role in alcoholic liver disease (ALD) progression has not yet been elucidated. Here, we studied the role of HBx on the development of ALD. Methods: HBx-transgenic (HBx-Tg) mice and their wild-type littermates were exposed to chronic plus binge alcohol feeding. Primary hepatocytes, cell lines, and human samples were used to investigate the interaction between HBx and acetaldehyde dehydrogenase 2 (ALDH2). Lipid profiles in mouse livers and cells were assessed by using liquid chromatography-mass spectrometry. Results: We identified that HBx significantly aggravated alcohol-induced steatohepatitis, oxidative stress, and lipid peroxidation in mice. In addition, HBx induced worse lipid profiles with high lysophospholipids generation in alcoholic steatohepatitis, as shown by using lipidomic analysis. Importantly, serum and liver acetaldehyde were markedly higher in alcohol-fed HBx-Tg mice. Acetaldehyde induced lysophospholipids generation through oxidative stress in hepatocytes. Mechanistically, HBx directly bound to mitochondrial ALDH2 to induce its ubiquitin-proteasome degradation, resulting in acetaldehyde accumulation. More importantly, we also identified that patients with HBV infection reduced ALDH2 protein levels in the liver. Conclusions: Our study demonstrated that HBx-induced ubiquitin-dependent degradation of mitochondrial ALDH2 aggravates alcoholic steatohepatitis.