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Jerold Chun - One of the best experts on this subject based on the ideXlab platform.
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Lysophospholipid receptor nomenclature review iuphar review 8
British Journal of Pharmacology, 2014Co-Authors: Yasuyuki Kihara, Sarah Spiegel, Michael Maceyka, Jerold ChunAbstract:Lysophospholipids encompass a diverse range of small, membrane-derived phospholipids that act as extracellular signals. The signalling properties are mediated by 7-transmembrane GPCRs, constituent members of which have continued to be identified after their initial discovery in the mid-1990s. Here we briefly review this class of receptors, with a particular emphasis on their protein and gene nomenclatures that reflect their cognate ligands. There are six Lysophospholipid receptors that interact with lysophosphatidic acid (LPA): protein names LPA1 – LPA6 and italicized gene names LPAR1-LPAR6 (human) and Lpar1-Lpar6 (non-human). There are five sphingosine 1-phosphate (S1P) receptors: protein names S1P1-S1P5 and italicized gene names S1PR1-S1PR5 (human) and S1pr1-S1pr5 (non-human). Recent additions to the Lysophospholipid receptor family have resulted in the proposed names for a lysophosphatidyl inositol (LPI) receptor – protein name LPI1 and gene name LPIR1 (human) and Lpir1 (non-human) – and three lysophosphatidyl serine receptors – protein names LyPS1, LyPS2, LyPS3 and gene names LYPSR1-LYPSR3 (human) and Lypsr1-Lypsr3 (non-human) along with a variant form that does not appear to exist in humans that is provisionally named LyPS2L. This nomenclature incorporates previous recommendations from the International Union of Basic and Clinical Pharmacology, the Human Genome Organization, the Gene Nomenclature Committee, and the Mouse Genome Informatix.
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International Union of Basic and Clinical Pharmacology. LXXVIII. Lysophospholipid Receptor Nomenclature
Pharmacological reviews, 2010Co-Authors: Jerold Chun, Timothy Hla, Kevin R. Lynch, Sarah Spiegel, Wouter H. MoolenaarAbstract:Lysophospholipids are cell membrane-derived lipids that include both glycerophospholipids such as lysophosphatidic acid (LPA) and sphingoid lipids such as sphingosine 1-phosphate (S1P). These and related molecules can function in vertebrates as extracellular signals by binding and activating G protein-coupled receptors. There are currently five LPA receptors, along with a proposed sixth (LPA1-LPA6), and five S1P receptors (S1P1-S1P5). A remarkably diverse biology and pathophysiology has emerged since the last review, driven by cloned receptors and targeted gene deletion (“knockout”) studies in mice, which implicate receptor-mediated Lysophospholipid signaling in most organ systems and multiple disease processes. The entry of various Lysophospholipid receptor modulatory compounds into humans through clinical trials is ongoing and may lead to new medicines that are based on this signaling system. This review incorporates IUPHAR Nomenclature Committee guidelines in updating the nomenclature for Lysophospholipid receptors (http://www.iuphar-db.org/DATABASE/FamilyMenuForward?familyId=36).
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Lysophospholipid Activation of G Protein-Coupled Receptors
Sub-cellular biochemistry, 2008Co-Authors: Tetsuji Mutoh, Jerold ChunAbstract:One of the major lipid biology discoveries in last decade was the broad range of physiological activities of Lysophospholipids that have been attributed to the actions of Lysophospholipid receptors. The most well characterized Lysophospholipids are lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). Documented cellular effects of these lipid mediators include growth-factor-like effects on cells, such as proliferation, survival, migration, adhesion, and differentiation. The mechanisms for these actions are attributed to a growing family of 7-transmembrane, G protein-coupled receptors (GPCRs). Their pathophysiological actions include immune modulation, neuropathic pain modulation, platelet aggregation, wound healing, vasopressor activity, and angiogenesis. Here we provide a brief introduction to receptor-mediated Lysophospholipid signaling and physiology, and then discuss potential therapeutic roles in human diseases.
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Potential therapeutic roles of Lysophospholipid signaling in autoimmune-related disease
Future Lipidology, 2007Co-Authors: Richard Rivera, Jerold ChunAbstract:Autoimmune disorders are characterized by lymphocyte infiltration and destruction of affected tissues. Lysophospholipids are small, relatively simple phospholipids derived from cell membranes that have been shown over the last decade to produce a wide range of effects through cognate G protein-coupled receptors, and include sphingosine 1-phosphate (S1P), which is the focus of this review, as well as lysophosphatidic acid (LPA). S1P1, a sphingosine 1-phosphate Lysophospholipid receptor, is essential for lymphocyte egress from the thymus and peripheral lymphoid tissues. Here we review how changes in S1P1-receptor expression and S1P concentration affect lymphocyte trafficking. In particular, we focus on mechanisms that involve S1P1 through its removal via genetic deletion and inhibition via pharmacological intervention, which provide a foundation for potentially useful approaches to the treatment of autoimmune disease based on Lysophospholipid signaling modulation. Recent advances in our understanding of how...
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Biological effects of Lysophospholipids.
Reviews of physiology biochemistry and pharmacology, 2006Co-Authors: Richard Rivera, Jerold ChunAbstract:Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P) are potent biologically active lipid mediators that exert a wide range of cellular effects through specific G protein-coupled receptors. To date, four LPA receptors and five S1P receptors have been identified. These receptors are expressed in a large number of tissues and cell types, allowing for a wide variety of cellular responses to Lysophospholipid signaling, including cell adhesion, cell motility, cytoskeletal changes, proliferation, angiogenesis, process retraction, and cell survival. In addition, recent studies in mice show that specific Lysophospholipid receptors are required for proper cardiovascular, immune, respiratory, and reproductive system development and function. Lysophospholipid receptors may also have specific roles in cancer and other diseases. This review will cover identification and expression of the Lysophospholipid receptors, as well as receptor signaling properties and function. Additionally, phenotypes of mice deficient for specific Lysophospholipid receptors will be discussed to demonstrate how these animals have furthered our understanding of the role Lysophospholipids play in normal biology and disease.
David A. Johnson - One of the best experts on this subject based on the ideXlab platform.
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Efficient tin-mediated synthesis of Lysophospholipid conjugates of a TLR7/8-active imidazoquinoline
Tetrahedron Letters, 2016Co-Authors: Sandra C Mwakwari, Laura S. Bess, Hélène G. Bazin, David A. JohnsonAbstract:Abstract The chemical synthesis of Lysophospholipids often involves multiple synthetic and chromatographic steps due to the incorporation of the fatty acyl group onto the glycerol scaffold early in the synthesis. We report herein a new protocol for the lysophosphatidylation of alcohols and its application to the synthesis of Lysophospholipid conjugates of TLR7/8-active imidazoquinoline 3 . This new procedure, which is based on the tin-mediated regioselective acylation of late-stage phosphoglycerol intermediate 17 , overcomes many of the drawbacks of conventional lysophosphatidylation methods and allows introduction of different fatty acyl groups in the penultimate step.
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efficient tin mediated synthesis of Lysophospholipid conjugates of a tlr7 8 active imidazoquinoline
Tetrahedron Letters, 2016Co-Authors: Sandra C Mwakwari, Laura S. Bess, Hélène G. Bazin, David A. JohnsonAbstract:The chemical synthesis of Lysophospholipids often involves multiple synthetic and chromatographic steps due to the incorporation of the fatty acyl group onto the glycerol scaffold early in the synthesis. We report herein a new protocol for the lysophosphatidylation of alcohols and its application to the synthesis of Lysophospholipid conjugates of TLR7/8-active imidazoquinoline 3. This new procedure, which is based on the tin-mediated regioselective acylation of late-stage phosphoglycerol intermediate 17, overcomes many of the drawbacks of conventional lysophosphatidylation methods and allows introduction of different fatty acyl groups in the penultimate step.
David Y. Hui - One of the best experts on this subject based on the ideXlab platform.
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Therapeutic reduction of Lysophospholipids in the digestive tract recapitulates the metabolic benefits of bariatric surgery and promotes diabetes remission
Elsevier, 2018Co-Authors: James G. Cash, Eddy Konaniah, Narasimha Hegde, David G. Kuhel, Miki Watanabe, Lindsey Romick-rosendale, David Y. HuiAbstract:Objective: Obesity and obesity-related metabolic disorders are major health problems worldwide. The most effective obesity intervention is bariatric surgery. This study tested the hypothesis that bariatric surgery alters phospholipid metabolism in the gastrointestinal tract to favor a metabolically healthy gut microbiota profile and therapeutic intervention of phospholipid metabolism in the gastrointestinal may have similar metabolic benefits. Methods: The first study compared plasma levels of the bioactive lipid metabolites Lysophospholipid and trimethylamine N-oxide (TMAO) as well as gut microbiota profile in high fat/carbohydrate (HFHC) diet-fed C57BL/6 mice with or without vertical sleeve gastrectomy (VSG) and in Pla2g1b−/− mice with group 1B phospholipase A2 gene inactivation. The second study examined the effectiveness of the non-absorbable secretory phospholipase A2 inhibitor methyl indoxam to reverse hyperglycemia and hyperlipidemia in HFHC diet-fed C57BL/6 mice after diabetes onset. Results: Both bariatric surgery and PLA2G1B inactivation were shown to reduce Lysophospholipid content in the gastrointestinal tract, resulting in resistance to HFHC diet-induced alterations of the gut microbiota, reduction of the cardiovascular risk factors hyperlipidemia and TMAO, decreased adiposity, and prevention of HFHC diet-induced diabetes. Importantly, treatment of wild type mice with methyl indoxam after HFHC diet-induced onset of hyperlipidemia and hyperglycemia effectively restored normal plasma lipid and glucose levels and replicated the metabolic benefits of VSG surgery with diabetes remission and TMAO reduction. Conclusion: These results provided pre-clinical evidence that PLA2G1B inhibition in the digestive tract may be a viable alternative option to bariatric surgery for obesity and obesity-related cardiometabolic disorder intervention. Keywords: Phospholipase A2, Gut microbiota, Cardiometabolic disease, Bariatric surgery, Lysophospholipi
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Liver-specific overexpression of LPCAT3 reduces postprandial hyperglycemia and improves lipoprotein metabolic profile in mice.
Nutrition & diabetes, 2016Co-Authors: James G. Cash, David Y. HuiAbstract:Previous studies have shown that group 1B phospholipase A2-mediated absorption of Lysophospholipids inhibits hepatic fatty acid β-oxidation and contributes directly to postprandial hyperglycemia and hyperlipidemia, leading to increased risk of cardiometabolic disease. The current study tested the possibility that increased expression of lysophosphatidylcholine acyltransferase-3 (LPCAT3), an enzyme that converts lysophosphatidylcholine to phosphatidylcholine in the liver, may alleviate the adverse effects of Lysophospholipids absorbed after a lipid-glucose mixed meal. The injection of an adenovirus vector harboring the human LPCAT3 gene into C57BL/6 mice increased hepatic LPCAT3 expression fivefold compared with mice injected with a control LacZ adenovirus. Postprandial glucose tolerance tests after feeding these animals with a bolus lipid-glucose mixed meal revealed that LPCAT3 overexpression improved postprandial hyperglycemia and glucose tolerance compared with control mice with LacZ adenovirus injection. Mice with LPCAT3 overexpression also showed reduced very low density lipoprotein production and displayed elevated levels of the metabolic- and cardiovascular-protective large apoE-rich high density lipoproteins in plasma. The mechanism underlying the metabolic benefits of LPCAT3 overexpression was shown to be due to the alleviation of Lysophospholipid inhibition of fatty acid β-oxidation in hepatocytes. Taken together, these results suggest that specific LPCAT3 induction in the liver may be a viable strategy for cardiometabolic disease intervention.
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group 1b phospholipase a2 mediated Lysophospholipid absorption directly contributes to postprandial hyperglycemia
Diabetes, 2006Co-Authors: Eric Labonte, Nicholas M. Schildmeyer, April M. Cannon, Kevin W. Huggins, Jason R Kirby, David Y. HuiAbstract:Postprandial hyperglycemia is an early indicator of abnormality in glucose metabolism leading to type 2 diabetes. However, mechanisms that contribute to postprandial hyperglycemia have not been identified. This study showed that mice with targeted inactivation of the group 1B phospholipase A2 (Pla2g1b) gene displayed lower postprandial glycemia than that observed in wild-type mice after being fed a glucose-rich meal. The difference was caused by enhanced postprandial glucose uptake by the liver, heart, and muscle tissues as well as altered postprandial hepatic glucose metabolism in the Pla2g1b-/- mice. These differences were attributed to a fivefold decrease in the amount of dietary phospholipids absorbed as Lysophospholipids in Pla2g1b-/- mice compared with that observed in Pla2g1b+/+ mice. Elevating plasma Lysophospholipid levels in Pla2g1b-/- mice via intraperitoneal injection resulted in glucose intolerance similar to that exhibited by Pla2g1b+/+ mice. Studies with cultured hepatoma cells revealed that Lysophospholipids dose-dependently suppressed insulin-stimulated glycogen synthesis. These results demonstrated that reduction of Lysophospholipid absorption enhances insulin-mediated glucose metabolism and is protective against postprandial hyperglycemia.
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Group 1B Phospholipase A2–Mediated Lysophospholipid Absorption Directly Contributes to Postprandial Hyperglycemia
Diabetes, 2006Co-Authors: Eric Labonte, R. Jason Kirby, Nicholas M. Schildmeyer, April M. Cannon, Kevin W. Huggins, David Y. HuiAbstract:Postprandial hyperglycemia is an early indicator of abnormality in glucose metabolism leading to type 2 diabetes. However, mechanisms that contribute to postprandial hyperglycemia have not been identified. This study showed that mice with targeted inactivation of the group 1B phospholipase A2 (Pla2g1b) gene displayed lower postprandial glycemia than that observed in wild-type mice after being fed a glucose-rich meal. The difference was caused by enhanced postprandial glucose uptake by the liver, heart, and muscle tissues as well as altered postprandial hepatic glucose metabolism in the Pla2g1b-/- mice. These differences were attributed to a fivefold decrease in the amount of dietary phospholipids absorbed as Lysophospholipids in Pla2g1b-/- mice compared with that observed in Pla2g1b+/+ mice. Elevating plasma Lysophospholipid levels in Pla2g1b-/- mice via intraperitoneal injection resulted in glucose intolerance similar to that exhibited by Pla2g1b+/+ mice. Studies with cultured hepatoma cells revealed that Lysophospholipids dose-dependently suppressed insulin-stimulated glycogen synthesis. These results demonstrated that reduction of Lysophospholipid absorption enhances insulin-mediated glucose metabolism and is protective against postprandial hyperglycemia.
Sandra C Mwakwari - One of the best experts on this subject based on the ideXlab platform.
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Efficient tin-mediated synthesis of Lysophospholipid conjugates of a TLR7/8-active imidazoquinoline
Tetrahedron Letters, 2016Co-Authors: Sandra C Mwakwari, Laura S. Bess, Hélène G. Bazin, David A. JohnsonAbstract:Abstract The chemical synthesis of Lysophospholipids often involves multiple synthetic and chromatographic steps due to the incorporation of the fatty acyl group onto the glycerol scaffold early in the synthesis. We report herein a new protocol for the lysophosphatidylation of alcohols and its application to the synthesis of Lysophospholipid conjugates of TLR7/8-active imidazoquinoline 3 . This new procedure, which is based on the tin-mediated regioselective acylation of late-stage phosphoglycerol intermediate 17 , overcomes many of the drawbacks of conventional lysophosphatidylation methods and allows introduction of different fatty acyl groups in the penultimate step.
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efficient tin mediated synthesis of Lysophospholipid conjugates of a tlr7 8 active imidazoquinoline
Tetrahedron Letters, 2016Co-Authors: Sandra C Mwakwari, Laura S. Bess, Hélène G. Bazin, David A. JohnsonAbstract:The chemical synthesis of Lysophospholipids often involves multiple synthetic and chromatographic steps due to the incorporation of the fatty acyl group onto the glycerol scaffold early in the synthesis. We report herein a new protocol for the lysophosphatidylation of alcohols and its application to the synthesis of Lysophospholipid conjugates of TLR7/8-active imidazoquinoline 3. This new procedure, which is based on the tin-mediated regioselective acylation of late-stage phosphoglycerol intermediate 17, overcomes many of the drawbacks of conventional lysophosphatidylation methods and allows introduction of different fatty acyl groups in the penultimate step.
Takao Shimizu - One of the best experts on this subject based on the ideXlab platform.
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an accurate and versatile method for determining the acyl group introducing position of Lysophospholipid acyltransferases
Biochimica et Biophysica Acta, 2019Co-Authors: Hiroki Kawana, Hideo Shindou, Takao Shimizu, Asuka Inoue, Kuniyuki Kano, Junken AokiAbstract:Lysophospholipid acyltransferases (LPLATs) incorporate a fatty acid into the hydroxyl group of Lysophospholipids (LPLs) and are critical for determining the fatty acid composition of phospholipids. Previous studies have focused mainly on their molecular identification and their substrate specificity regarding the polar head groups and acyl-CoAs. However, little is known about the positional specificity of the hydroxyl group of the glycerol backbone (sn-2 or sn-1) at which LPLATs introduce a fatty acid. This is mainly due to the instability of LPLs used as an acceptor, especially for LPLs with a fatty acid at the sn-2 position of the glycerol backbone (sn-2-LPLs), which are essential for the enzymatic assay to determine the positional specificity. In this study, we established a method to determine the positional specificity of LPLAT by preparing stable sn-2-LPLs in combination with PLA2 digestion, and applied the method for determining the positional specificity of several LPLATs including LPCAT1, LYCAT and LPCAT3. We found that LPCAT1 introduced palmitic acid both at the sn-1 and sn-2 positions of palmitoyl-LPC, while LYCAT and LPCAT3 specifically introduced stearic acid at the sn-1 position of LPG and arachidonic acid at the sn-2 position of LPC, respectively. The present method for evaluating the positional specificity could also be used for biochemical characterization of other LPLATs.
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cytosolic phospholipase a2 and Lysophospholipid acyltransferases
Biochimica et Biophysica Acta, 2019Co-Authors: Yoshihiro Kita, Hideo Shindou, Takao ShimizuAbstract:Phospholipase A2 (PLA2) enzymes catalyze the hydrolysis of ester bonds at sn-2 positions of glycerophospholipids (PL), producing free fatty acids and Lysophospholipids. In mammals, the PLA2 superfamily comprises more than 30 known enzymes, including various structurally and biochemically different enzymes with diverse biological functions. Some of the enzymes are involved in the production of lipid mediators, including eicosanoids and Lysophospholipid-related lipid mediators. Among them, cytosolic PLA2α (cPLA2α), a member of cPLA2 family, is one of the most important intracellular PLA2s. Upon cell activation, cPLA2α is activated and involved in eicosanoid production under various physiological and pathological conditions. PLA2s also play a role in membrane PL remodeling by coupling with re-acylation processes mediated by Lysophospholipid acyltransferases (LPLATs) to generate sn-1/sn-2 fatty acid asymmetry of PLs. This review summarizes the biochemical and in vivo roles of cPLA2 enzymes and LPLATs, including results from animal and human studies. This article is part of a Special Issue entitled Novel functions of phospholipase A2 Guest Editors: Makoto Murakami and Gerard Lambeau.
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lysophosphatidylcholine acyltransferase 4 is involved in chondrogenic differentiation of atdc5 cells
Scientific Reports, 2017Co-Authors: Shirou Tabe, Hisako Hikiji, Wataru Ariyoshi, Tomomi Hashidateyoshida, Hideo Shindou, Takao Shimizu, Toshinori Okinaga, Yuji Seta, Kazuhiro Tominaga, Tatsuji NishiharaAbstract:Glycerophospholipids have important structural and functional roles in cells and are the main components of cellular membranes. Glycerophospholipids are formed via the de novo pathway (Kennedy pathway) and are subsequently matured in the remodeling pathway (Lands’ cycle). Lands’ cycle consists of two steps: deacylation of phospholipids by phospholipases A2 and reacylation of Lysophospholipids by Lysophospholipid acyltransferases (LPLATs). LPLATs play key roles in the maturation and maintenance of the fatty acid composition of biomembranes, and cell differentiation. We examined whether LPLATs are involved in chondrogenic differentiation of ATDC5 cells, which can differentiate into chondrocytes. Lysophosphatidylcholine acyltransferase 4 (LPCAT4) mRNA expression and LPCAT enzymatic activity towards 18:1-, 18:2-, 20:4-, and 22:6-CoA increased in the late stage of chondrogenic differentiation, when mineralization occurred. LPCAT4 knockdown decreased mRNA and protein levels of chondrogenic markers as well as Alcian blue staining intensity and alkaline phosphatase activity in ATDC5 cells. These results suggest that LPCAT4 plays important roles during the transition of chondrocytes into hypertrophic chondrocytes and/or a mineralized phenotype.
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Diversity and function of membrane glycerophospholipids generated by the remodeling pathway in mammalian cells
Journal of lipid research, 2014Co-Authors: Daisuke Hishikawa, Tomomi Hashidate, Takao ShimizuAbstract:Cellular membranes are composed of numerous kinds of glycerophospholipids with different combinations of polar heads at the sn-3 position and acyl moieties at the sn-1 and sn-2 positions, respectively. The glycerophospholipid compositions of different cell types, organelles, and inner/outer plasma membrane leaflets are quite diverse. The acyl moieties of glycerophospholipids synthesized in the de novo pathway are subsequently remodeled by the action of phospholipases and Lysophospholipid acyltransferases. This remodeling cycle contributes to the generation of membrane glycerophospholipid diversity and the production of lipid mediators such as fatty acid derivatives and Lysophospholipids. Furthermore, specific glycerophospholipid transporters are also important to organize a unique glycerophospholipid composition in each organelle. Recent progress in this field contributes to understanding how and why membrane glycerophospholipid diversity is organized and maintained.
