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The Journal of Physiology May 2023The Transient Receptor Potential Vanilloid 4 (TRPV4) channel has been shown to function in many physiological and pathophysiological processes. Despite abundant...
The Transient Receptor Potential Vanilloid 4 (TRPV4) channel has been shown to function in many physiological and pathophysiological processes. Despite abundant information on its importance in physiology, very few endogenous agonists for this channel have been described, and very few underlying mechanisms for its activation have been clarified. TRPV4 is expressed by several types of cells, such as vascular endothelial, and skin and lung epithelial cells, where it plays pivotal roles in their function. In the present study, we show that TRPV4 is activated by lysophosphatidic acid (LPA) in both endogenous and heterologous expression systems, pinpointing this molecule as one of the few known endogenous agonists for TRPV4. Importantly, LPA is a bioactive glycerophospholipid, relevant in several physiological conditions, including inflammation and vascular function, where TRPV4 has also been found to be essential. Here we also provide mechanistic details of the activation of TRPV4 by LPA and another glycerophospholipid, lysophosphatidylcholine (LPC), and show that LPA directly interacts with both the N- and C-terminal regions of TRPV4 to activate this channel. Moreover, we show that LPC activates TRPV4 by producing an open state with a different single-channel conductance to that observed with LPA. Our data suggest that the activation of TRPV4 can be finely tuned in response to different endogenous lipids, highlighting this phenomenon as a regulator of cell and organismal physiology. KEY POINTS: The Transient Receptor Potential Vaniloid (TRPV) 4 ion channel is a widely distributed protein with important roles in normal and disease physiology for which few endogenous ligands are known. TRPV4 is activated by a bioactive lipid, lysophosphatidic acid (LPA) 18:1, in a dose-dependent manner, in both a primary and a heterologous expression system. Activation of TRPV4 by LPA18:1 requires residues in the N- and C-termini of the ion channel. Single-channel recordings show that TRPV4 is activated with a decreased current amplitude (conductance) in the presence of lysophosphatidylcholine (LPC) 18:1, while LPA18:1 and GSK101 activate the channel with a larger single-channel amplitude. Distinct single-channel amplitudes produced by LPA18:1 and LPC18:1 could differentially modulate the responses of the cells expressing TRPV4 under different physiological conditions.
Topics: Transient Receptor Potential Channels; TRPV Cation Channels; Lysophosphatidylcholines; Lysophospholipids
PubMed: 36625071
DOI: 10.1113/JP284262 -
Journal of Lipid Research Oct 2016The accumulation of lipids is a histologic and biochemical hallmark of obesity-associated nonalcoholic fatty liver disease (NAFLD). A subset of NALFD patients develops... (Review)
Review
The accumulation of lipids is a histologic and biochemical hallmark of obesity-associated nonalcoholic fatty liver disease (NAFLD). A subset of NALFD patients develops progressive liver disease, termed nonalcoholic steatohepatitis, which is characterized by hepatocellular apoptosis and innate immune system-mediated inflammation. These responses are orchestrated by signaling pathways that can be activated by lipids, directly or indirectly. In this review, we discuss palmitate- and lysophosphatidylcholine (LPC)-induced upregulation of p53-upregulated modulator of apoptosis and cell-surface expression of the death receptor TNF-related apoptosis-inducing ligand receptor 2. Next, we review the activation of stress-induced kinases, mixed lineage kinase 3, and c-Jun N-terminal kinase, and the activation of endoplasmic reticulum stress response and its downstream proapoptotic effector, CAAT/enhancer binding homologous protein, by palmitate and LPC. Moreover, the activation of these stress signaling pathways is linked to the release of proinflammatory, proangiogenic, and profibrotic extracellular vesicles by stressed hepatocytes. This review discusses the signaling pathways induced by lethal and sublethal lipid overload that contribute to the pathogenesis of NAFLD.
Topics: Animals; CCAAT-Enhancer-Binding Proteins; Hepatocytes; Humans; JNK Mitogen-Activated Protein Kinases; Lysophosphatidylcholines; MAP Kinase Kinase Kinases; MAP Kinase Signaling System; Non-alcoholic Fatty Liver Disease; Palmitates; Stress, Physiological; TNF Receptor-Associated Factor 2; Tumor Suppressor Protein p53; Up-Regulation; Mitogen-Activated Protein Kinase Kinase Kinase 11
PubMed: 27049024
DOI: 10.1194/jlr.R066357 -
Life Science Alliance Feb 2023Autotaxin is primarily known for the formation of lysophosphatidic acid (LPA) from lysophosphatidylcholine. LPA is an important signaling phospholipid that can bind to...
Autotaxin is primarily known for the formation of lysophosphatidic acid (LPA) from lysophosphatidylcholine. LPA is an important signaling phospholipid that can bind to six G protein-coupled receptors (LPA). The ATX-LPA signaling axis is a critical component in many physiological and pathophysiological conditions. Here, we describe a potent inhibition of Δ--tetrahydrocannabinol (THC), the main psychoactive compound of medicinal cannabis and related cannabinoids, on the catalysis of two isoforms of ATX with nanomolar apparent EC values. Furthermore, we decipher the binding interface of ATX to THC, and its derivative 9(R)-Δ6a,10a-THC (6a10aTHC), by X-ray crystallography. Cellular experiments confirm this inhibitory effect, revealing a significant reduction of internalized LPA in the presence of THC with simultaneous ATX and lysophosphatidylcholine stimulation. Our results establish a functional interaction of THC with autotaxin-LPA signaling and highlight novel aspects of medicinal cannabis therapy.
Topics: Lysophosphatidylcholines; Lysophospholipids; Medical Marijuana; Receptors, Lysophosphatidic Acid; Dronabinol
PubMed: 36623871
DOI: 10.26508/lsa.202201595 -
Antimicrobial Agents and Chemotherapy Nov 2020Polymyxin B, used to treat infections caused by antibiotic-resistant Gram-negative bacteria, produces nephrotoxicity at its current dosage. We show that a combination of...
Polymyxin B, used to treat infections caused by antibiotic-resistant Gram-negative bacteria, produces nephrotoxicity at its current dosage. We show that a combination of nonbactericidal concentration of this drug and lysophosphatidylcholine (LPC) potently inhibits growth of and at least two other Gram-negative bacteria This combination makes bacterial membrane porous and causes degradation of DnaK, the regulator of protein folding. Polymyxin B-LPC combination may be an effective and safer regimen against drug-resistant bacteria.
Topics: Anti-Bacterial Agents; Gram-Negative Bacteria; Lysophosphatidylcholines; Microbial Sensitivity Tests; Polymyxin B
PubMed: 32988824
DOI: 10.1128/AAC.01337-20 -
Scientific Reports Nov 2022Drug-induced interstitial lung disease (DILD) occurs when drug exposure causes inflammation of the lung interstitium. DILD can be caused by different types of drugs, and...
Drug-induced interstitial lung disease (DILD) occurs when drug exposure causes inflammation of the lung interstitium. DILD can be caused by different types of drugs, and some DILD patterns results in a high mortality rate; hence, DILD poses a serious problem in clinical practice as well as drug development, and strategies to diagnose and distinguish DILD from other lung diseases are necessary. We aimed to identify novel biomarkers for DILD by performing lipidomics analysis on plasma samples from patients with acute and recovery phase DILD. Having identified lysophosphatidylcholines (LPCs) as candidate biomarkers for DILD, we determined their concentrations using validated liquid chromatography/mass spectrometry biomarker assays. In addition, we evaluated the ability of LPCs to discriminate patients with acute phase DILD from those with recovery phase DILD, DILD-tolerant, or other lung diseases, and characterized their association with clinical characteristics. Lipidomics analysis revealed a clear decrease in LPC concentrations in the plasma of patients with acute phase DILD. In particular, LPC(14:0) had the highest discriminative index against recovery phase and DILD-tolerant patients. LPC(14:0) displayed no clear association with causal drugs, or subjects' backgrounds, but was associated with disease severity. Furthermore, LPC(14:0) was able to discriminate between patients with DILD and other lung diseases, including idiopathic interstitial pneumonia and lung disease associated with connective tissue disease. LPC(14:0) is a promising biomarker for DILD that could improve the diagnosis of DILD and help to differentiate DILD from other lung diseases, such as idiopathic interstitial pneumonia and connective tissue disease.
Topics: Humans; Lysophosphatidylcholines; Lung Diseases, Interstitial; Idiopathic Interstitial Pneumonias; Biomarkers; Connective Tissue Diseases
PubMed: 36396675
DOI: 10.1038/s41598-022-24406-z -
Scientific Reports Sep 2017Docosahexaenoic acid (DHA) is uniquely concentrated in the brain, and is essential for its function, but must be mostly acquired from diet. Most of the current...
Docosahexaenoic acid (DHA) is uniquely concentrated in the brain, and is essential for its function, but must be mostly acquired from diet. Most of the current supplements of DHA, including fish oil and krill oil, do not significantly increase brain DHA, because they are hydrolyzed to free DHA and are absorbed as triacylglycerol, whereas the transporter at blood brain barrier is specific for phospholipid form of DHA. Here we show that oral administration of DHA to normal adult mice as lysophosphatidylcholine (LPC) (40 mg DHA/kg) for 30 days increased DHA content of the brain by >2-fold. In contrast, the same amount of free DHA did not increase brain DHA, but increased the DHA in adipose tissue and heart. Moreover, LPC-DHA treatment markedly improved the spatial learning and memory, as measured by Morris water maze test, whereas free DHA had no effect. The brain derived neurotrophic factor increased in all brain regions with LPC-DHA, but not with free DHA. These studies show that dietary LPC-DHA efficiently increases brain DHA content and improves brain function in adult mammals, thus providing a novel nutraceutical approach for the prevention and treatment of neurological diseases associated with DHA deficiency, such as Alzheimer's disease.
Topics: Animals; Ascorbic Acid; Brain; Brain Chemistry; Dietary Supplements; Docosahexaenoic Acids; Lysophosphatidylcholines; Memory; Mice; Spatial Learning
PubMed: 28900242
DOI: 10.1038/s41598-017-11766-0 -
MBio Feb 2021Lipids are biologically active molecules involved in a variety of cellular processes and immunological functions, including inflammation. It was recently shown that...
Lipids are biologically active molecules involved in a variety of cellular processes and immunological functions, including inflammation. It was recently shown that phospholipids and their derivatives, lysophospholipids, can reactivate latent (dormant) tumor cells, causing cancer recurrence. However, the potential link between lipids and HIV latency, persistence, and viral rebound after cessation of antiretroviral therapy (ART) has never been investigated. We explored the links between plasma lipids and the burden of HIV during ART. We profiled the circulating lipidome from plasma samples from 24 chronically HIV-infected individuals on suppressive ART who subsequently underwent an analytic treatment interruption (ATI) without concurrent immunotherapies. The pre-ATI viral burden was estimated as time-to-viral-rebound and viral load set points post-ATI. We found that higher pre-ATI levels of lysophospholipids, including the proinflammatory lysophosphatidylcholine, were associated with faster time-to-viral-rebound and higher viral set points upon ART cessation. Furthermore, higher pre-ATI levels of the proinflammatory by-product of intestinal lysophosphatidylcholine metabolism, trimethylamine--oxide (TMAO), were also linked to faster viral rebound post-ART. Finally, pre-ATI levels of several phosphatidylcholine species (lysophosphatidylcholine precursors) correlated strongly with higher pre-ATI levels of HIV DNA in peripheral CD4 T cells. Our proof-of-concept data point to phospholipids and lysophospholipids as plausible proinflammatory contributors to HIV persistence and rapid post-ART HIV rebound. The potential interplay between phospholipid metabolism and both the establishment and maintenance of HIV latent reservoirs during and after ART warrants further investigation. The likelihood of HIV rebound after stopping antiretroviral therapy (ART) is a combination of the size of HIV reservoirs that persist despite ART and the host immunological and inflammatory factors that control these reservoirs. Therefore, there is a need to comprehensively understand these host factors to develop a strategy to cure HIV infection and prevent viral rebound post-ART. Lipids are important biologically active molecules that are known to mediate several cellular functions, including reactivating latent tumor cells; however, their role in HIV latency, persistence, and post-ART rebound has never been investigated. We observed significant links between higher levels of the proinflammatory lysophosphatidylcholine and its intestinal metabolic by-product, trimethylamine--oxide, and both faster time-to-viral-rebound and higher viral load set point post-ART. These data highlight the need for further studies to understand the potential contribution of phosphatidylcholine and lysophosphatidylcholine metabolism in shaping host immunological and inflammatory milieu during and after ART.
Topics: Adult; Anti-Retroviral Agents; CD4-Positive T-Lymphocytes; Cohort Studies; DNA, Viral; Female; HIV Infections; Humans; Lysophosphatidylcholines; Male; Middle Aged; Phosphatidylcholines; Phospholipids; Proof of Concept Study; Viral Load; Virus Latency; Withholding Treatment; Young Adult
PubMed: 33622719
DOI: 10.1128/mBio.03444-20 -
AAPS PharmSciTech Sep 2010This study describes a simple chromatographic method for the simultaneous analyses of phosphatidylcholine (PC) and its hydrolytic degradation products:...
This study describes a simple chromatographic method for the simultaneous analyses of phosphatidylcholine (PC) and its hydrolytic degradation products: lysophosphatidylcholine (LPC) and free fatty acids (FFA). Quantitative determination of PC, LPC, and FFA is essential in order to assure safety and to accurately assess the shelf life of phospholipid-containing products. A single-run normal-phase high-performance liquid chromatography (HPLC) with evaporative light scattering detector has been developed. The method utilizes an Allsphere silica analytical column and a gradient elution with mobile phases consisting of chloroform: chloroform-methanol (70:30%, v/v) and chloroform-methanol-water-ammonia (45:45:9.5:0.5%, v/v/v/v). The method adequately resolves PC, LPC, and FFA within a run time of 25 min. The quantitative analysis of PC and LPC has been achieved with external standard method. The free fatty acids were analyzed as a group using linoleic acid as representative standard. Linear calibration curves were obtained for PC (1.64-16.3 μg, r(2) = 0.9991) and LPC (0.6-5.0 μg, r(2) = 0.9966), while a logarithmic calibration curve was obtained for linoleic acid (1.1-5.8 μg, r(2) = 0.9967). The detection and quantification limits of LPC and FFA were 0.04 and 0.1 μg, respectively. As a means of validating the applicability of the assay to pharmaceutical products, PC liposome was subjected to alkaline hydrolytic degradation. Quantitative HPLC analysis showed that 97% of the total mass balance for PC could be accounted for in liposome formulation. The overall results show that the HPLC method could be a useful tool for chromatographic analysis, stability studies, and formulation characterization of phospholipid-based pharmaceuticals.
Topics: Chromatography, High Pressure Liquid; Complex Mixtures; Equipment Design; Equipment Failure Analysis; Fatty Acids, Nonesterified; Lysophosphatidylcholines; Phosphatidylcholines; Reproducibility of Results; Sensitivity and Specificity
PubMed: 20585908
DOI: 10.1208/s12249-010-9470-4 -
Journal of Atherosclerosis and... Jun 2016
Topics: Fibromuscular Dysplasia; Humans; Lysophosphatidylcholines; Transforming Growth Factor beta
PubMed: 27009435
DOI: 10.5551/jat.ED040 -
Clinica Chimica Acta; International... Apr 2023Lipids take part in many pathophysiological processes of sepsis, thus, the variation of lipid composition may have clue on the severity and pathogen to sepsis. The...
BACKGROUND
Lipids take part in many pathophysiological processes of sepsis, thus, the variation of lipid composition may have clue on the severity and pathogen to sepsis. The objective of our study is to expand the profile of lipid compositions and screen potential biomarkers in intensive care unit (ICU) patients with sepsis.
METHODS
Patients admitted to the ICU clearly diagnosed with celiac sepsis were included in this prospective study. Age-matched healthy participants from the Physical Examination Center were used as the control group. Blood samples were obtained from patients within the first 12 h of admission. We analysed different components of the lipid metabolism between the sepsis patients and controls and described characteristic features during sepsis.
RESULTS
Thirty patients with celiac sepsis and 30 sex- and age-matched healthy controls were enrolled in this study. The lipid metabolic signature was obviously different between the sepsis patients and healthy controls and was mostly downregulated in sepsis patients. We identified 65 lipid species. Sixty-four lipid molecules were found to be significantly downregulated in sepsis patients, and only the level of one phosphatidylethanolamine (PE) molecule, PE (34:2) was higher in the sepsis patients with sepsis group comparing with the control group. The analysis of metabolic pathway illustrated the different lipid molecules were closely related to Phosphatidylcholine (PC), Lysophosphatidylcholine (LPC), and PE.
CONCLUSION
Sepsis contributes to impaired expression of most lipids, which mainly result in the disorder of glycerolipid metabolic pathway, including Phosphatidylcholine (PC), Lysophosphatidylcholine (LPC), and PE.
Topics: Humans; Tandem Mass Spectrometry; Lipidomics; Chromatography, High Pressure Liquid; Prospective Studies; Lysophosphatidylcholines; Sepsis; Phosphatidylcholines
PubMed: 37031781
DOI: 10.1016/j.cca.2023.117336