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Nature Communications Oct 2022The fatty acid composition of phosphatidylethanolamine (PE) determines cellular metabolism, oxidative stress, and inflammation. However, our understanding of how cells...
The fatty acid composition of phosphatidylethanolamine (PE) determines cellular metabolism, oxidative stress, and inflammation. However, our understanding of how cells regulate PE composition is limited. Here, we identify a genetic locus on mouse chromosome 11, containing two poorly characterized genes Tlcd1 and Tlcd2, that strongly influences PE composition. We generated Tlcd1/2 double-knockout (DKO) mice and found that they have reduced levels of hepatic monounsaturated fatty acid (MUFA)-containing PE species. Mechanistically, TLCD1/2 proteins act cell intrinsically to promote the incorporation of MUFAs into PEs. Furthermore, TLCD1/2 interact with the mitochondria in an evolutionarily conserved manner and regulate mitochondrial PE composition. Lastly, we demonstrate the biological relevance of our findings in dietary models of metabolic disease, where Tlcd1/2 DKO mice display attenuated development of non-alcoholic steatohepatitis compared to controls. Overall, we identify TLCD1/2 proteins as key regulators of cellular PE composition, with our findings having broad implications in understanding and treating disease.
Topics: Animals; Fatty Acids; Fatty Acids, Monounsaturated; Liver; Mice; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease; Phosphatidylethanolamines
PubMed: 36241646
DOI: 10.1038/s41467-022-33735-6 -
International Journal of Molecular... May 2022Phospholipids represent a crucial component for the structure of cell membranes. Phosphatidylcholine and phosphatidylethanolamine are two phospholipids that comprise the... (Review)
Review
Phospholipids represent a crucial component for the structure of cell membranes. Phosphatidylcholine and phosphatidylethanolamine are two phospholipids that comprise the majority of cell membranes. De novo biosynthesis of phosphatidylcholine and phosphatidylethanolamine occurs via the Kennedy pathway, and perturbations in the regulation of this pathway are linked to a variety of human diseases, including cancer. Altered phosphatidylcholine and phosphatidylethanolamine membrane content, phospholipid metabolite levels, and fatty acid profiles are frequently identified as hallmarks of cancer development and progression. This review summarizes the research on how phospholipid metabolism changes over oncogenic transformation, and how phospholipid profiling can differentiate between human cancer and healthy tissues, with a focus on colorectal cancer, breast cancer, and non-small cell lung cancer. The potential for phospholipids to serve as biomarkers for diagnostics, or as anticancer therapy targets, is also discussed.
Topics: Carcinoma, Non-Small-Cell Lung; Fatty Acids; Humans; Lung Neoplasms; Phosphatidylcholines; Phosphatidylethanolamines; Phospholipids
PubMed: 35563655
DOI: 10.3390/ijms23095266 -
Antioxidants & Redox Signaling May 2022Professor Valerian Kagan (PhD, 1972, MV Lomonosov Moscow State University; DSci, 1981, USSR, Academy of Sciences, Moscow) is recognized as a Redox Pioneer because he has...
Professor Valerian Kagan (PhD, 1972, MV Lomonosov Moscow State University; DSci, 1981, USSR, Academy of Sciences, Moscow) is recognized as a Redox Pioneer because he has published 4 articles in the field of redox biology that have been cited >1000 times and 138 articles in this field have been cited between 100 and 924 times. The central and most important impact of Dr. Kagan's research is in the field of redox lipidomics-a term coined for the first time by Dr. Kagan in 2004-and consequently the definition of signaling pathways by oxidatively modified phospholipids; this acquires further significance considering that oxygenated phospholipids play multifunctional roles as essential signals coordinating metabolism and physiology. Some examples are the selective oxidation of cardiolipin (CL) by a cytochrome peroxidase activity leading to the activation of the intrinsic apoptotic pathway; the hydroperoxy-arachidonoyl/adrenoyl phosphatidylethanolamine (PE) species, driven by 15-lipoxygenases (15-LOX), as death signals leading to ferroptotic cell death; the regulation of ferroptosis by iNOS/NO in pro-inflammatory conditions by a novel mechanism (realized interactions of 15-LOX reaction intermediates formed from arachidonoyl phosphatidylethanolamine [PE] species) and Ca-independent phospholipase A2 (iPLAβ; elimination of peroxidized PE); the involvement of oxygenated (phospho)lipids in immunosuppression by myeloid cells in the tumor microenvironment; hydrolysis of peroxidized CL by Ca-independent phospholipase A2 (iPLAγ) leading to pro- and anti-inflammatory signals and lipid mediators. Kagan continues his investigations to decipher the roles of enzyme-linked oxygenated phospholipids. 36, 813-823.
Topics: Ferroptosis; Humans; Male; Oxidation-Reduction; Phosphatidylethanolamines; Phospholipids; Valerian
PubMed: 35072541
DOI: 10.1089/ars.2021.0079 -
ACS Chemical Biology Aug 2023-Acyl-phosphatidylethanolamine hydrolyzing phospholipase D (NAPE-PLD) is a zinc metallohydrolase that hydrolyzes -acyl-phosphatidylethanolamines (NAPEs) to form...
-Acyl-phosphatidylethanolamine hydrolyzing phospholipase D (NAPE-PLD) is a zinc metallohydrolase that hydrolyzes -acyl-phosphatidylethanolamines (NAPEs) to form -acyl-ethanolamines (NAEs) and phosphatidic acid. Several lines of evidence suggest that reduced NAPE-PLD activity could contribute to cardiometabolic diseases. For instance, expression is reduced in human coronary arteries with unstable atherosclerotic lesions, defective efferocytosis is implicated in the enlargement of necrotic cores of these lesions, and NAPE-PLD products such as palmitoylethanolamide and oleoylethanolamide have been shown to enhance efferocytosis. Thus, enzyme activation mediated by a small molecule may serve as a therapeutic treatment for cardiometabolic diseases. As a proof-of-concept study, we sought to identify small molecule activators of NAPE-PLD. High-throughput screening followed by hit validation and primary lead optimization studies identified a series of benzothiazole phenylsulfonyl-piperidine carboxamides that variably increased activity of both mouse and human NAPE-PLD. From this set of small molecules, two NAPE-PLD activators ( and ) were shown to increase efferocytosis by bone-marrow derived macrophages isolated from wild-type mice, while efferocytosis was significantly reduced in BMDM or after Nape-pld inhibition. Together, these studies demonstrate an essential role for NAPE-PLD in the regulation of efferocytosis and the potential value of NAPE-PLD activators as a strategy to treat cardiometabolic diseases.
Topics: Mice; Humans; Animals; Phospholipase D; Phosphatidylethanolamines; Brain; Macrophages; Cardiovascular Diseases
PubMed: 37531659
DOI: 10.1021/acschembio.3c00401 -
Progress in Lipid Research Apr 2021Phospholipid biosynthesis is crucial for plant growth and development. It involves attachment of fatty acids to a phospho-diacylglycerol backbone and modification of the... (Review)
Review
Phospholipid biosynthesis is crucial for plant growth and development. It involves attachment of fatty acids to a phospho-diacylglycerol backbone and modification of the phospho-group into an amino alcohol. The biochemistry and molecular biology of the former has been well established, but a number of enzymes responsible for the latter have only recently been cloned and functionally characterized in Arabidopsis and some other model plant species. The metabolism involving the polar head groups of phospholipids established by past biochemical studies can now be validated by available gene knockout models. Moreover, gene knockout studies have revealed emerging functions of phospholipids in regulating plant growth and development. This review aims to revisit the old questions of polar headgroup biosynthesis of plant phosphatidylcholine and phosphatidylethanolamine by giving an overview of recent advances in the field and beyond.
Topics: Arabidopsis; Fatty Acids; Phosphatidylcholines; Phosphatidylethanolamines; Phospholipids
PubMed: 33503494
DOI: 10.1016/j.plipres.2021.101091 -
Chemistry and Physics of Lipids Jul 2021Liposomal systems are well known for playing an important role as drug carriers, presenting several therapeutic applications in different sectors, such as in drug... (Review)
Review
Liposomal systems are well known for playing an important role as drug carriers, presenting several therapeutic applications in different sectors, such as in drug delivery, diagnosis, and in many other academic areas. A novel class of this nanoparticle is the actively target liposome, which is constructed with the surface modified with appropriated molecules (or ligands) to actively bind a target molecule of certain cells, system, or tissue. There are many ways to functionalize these nanostructures, from non-covalent adsorption to covalent bond formation. In this review, we focus on the strategies of modifying liposomes by glycerophospholipid covalent chemical reaction. The approach used in this text summarizes the main reactions and strategies used in phospholipid modification that can be carried out by chemists and researchers from other areas. The knowledge of these methodologies is of great importance for planning new studies using this material and also for manipulating its properties.
Topics: Liposomes; Nanoparticles; Phosphatidylethanolamines; Phospholipids; Polyethylene Glycols; Surface Properties
PubMed: 33891960
DOI: 10.1016/j.chemphyslip.2021.105084 -
Proceedings of the National Academy of... Jun 2020Temporally harmonized elimination of damaged or unnecessary organelles and cells is a prerequisite of health. Under Type 2 inflammatory conditions, human airway...
Temporally harmonized elimination of damaged or unnecessary organelles and cells is a prerequisite of health. Under Type 2 inflammatory conditions, human airway epithelial cells (HAECs) generate proferroptotic hydroperoxy-arachidonoyl-phosphatidylethanolamines (HpETE-PEs) as proximate death signals. Production of 15-HpETE-PE depends on activation of 15-lipoxygenase-1 (15LO1) in complex with PE-binding protein-1 (PEBP1). We hypothesized that cellular membrane damage induced by these proferroptotic phospholipids triggers compensatory prosurvival pathways, and in particular autophagic pathways, to prevent cell elimination through programmed death. We discovered that PEBP1 is pivotal to driving dynamic interactions with both proferroptotic 15LO1 and the autophagic protein microtubule-associated light chain-3 (LC3). Further, the 15LO1-PEBP1-generated ferroptotic phospholipid, 15-HpETE-PE, promoted LC3-I lipidation to stimulate autophagy. This concurrent activation of autophagy protects cells from ferroptotic death and release of mitochondrial DNA. Similar findings are observed in Type 2 Hi asthma, where high levels of both 15LO1-PEBP1 and LC3-II are seen in HAECs, in association with low bronchoalveolar lavage fluid mitochondrial DNA and more severe disease. The concomitant activation of ferroptosis and autophagy by 15LO1-PEBP1 complexes and their hydroperoxy-phospholipids reveals a pathobiologic pathway relevant to asthma and amenable to therapeutic targeting.
Topics: Adult; Animals; Arachidonate 15-Lipoxygenase; Asthma; Autophagy; Bronchoalveolar Lavage Fluid; Cell Line; Cell Survival; Epithelial Cells; Female; Ferroptosis; Gene Knockout Techniques; Humans; Hydroxyeicosatetraenoic Acids; Interleukin-13; Male; Mice; Microtubule-Associated Proteins; Molecular Dynamics Simulation; Phosphatidylethanolamine Binding Protein; Phosphatidylethanolamines; Primary Cell Culture; Protein Binding; Severity of Illness Index
PubMed: 32513718
DOI: 10.1073/pnas.1921618117 -
Methods in Molecular Biology (Clifton,... 2023In animal tissues, N-acyltransferase (NAT) catalyzes the first reaction in the biosynthetic pathway of bioactive N-acylethanolamines, in which an acyl chain is...
In animal tissues, N-acyltransferase (NAT) catalyzes the first reaction in the biosynthetic pathway of bioactive N-acylethanolamines, in which an acyl chain is transferred from the sn-1 position of the donor phospholipid, such as phosphatidylcholine, to the amino group of phosphatidylethanolamine, resulting in the formation of N-acylphosphatidylethanolamine. NAT has long been known to be stimulated by Ca and hence referred to as Ca-dependent NAT. Later, this enzyme was identified as cPLAε (also referred to as PLA2G4E). On the other hand, members of the phospholipase A/acyltransferase (PLAAT) family (also known as HRAS-like suppressor family) show Ca-independent NAT activity. In this chapter, we describe (1) partial purification of Ca-dependent NAT from rat brain, (2) purification of recombinant cPLAε and PLAAT-2, and (3) NAT assay using radiolabeled substrate.
Topics: Acyltransferases; Animals; Phosphatidylcholines; Phosphatidylethanolamines; Phospholipases A; Phospholipids; Rats
PubMed: 36152189
DOI: 10.1007/978-1-0716-2728-0_17 -
European Review For Medical and... Apr 2021The objectives of this review are to explore the neuronal pathways and cellular and molecular mechanisms involved in both healthy and impaired cognitive function and to... (Review)
Review
OBJECTIVE
The objectives of this review are to explore the neuronal pathways and cellular and molecular mechanisms involved in both healthy and impaired cognitive function and to discuss the role of nootropics, in particular, those with cholinergic activity, as promising interventions to preserve and/or improve cognitive performance in patients in the symptomatic pre-dementia stage, known as mild cognitive impairment (MCI).
MATERIALS AND METHODS
Papers were retrieved by a PubMed search, using different combinations of keywords (e.g., cognitive function AND aging AND nootropics), without limitations in terms of publication date or language.
RESULTS
Nootropics modulate the activities of specific brain pathways involving neurotransmitters and neuromodulators that have distinct roles in the cognitive processes. The nootropic L-a-glyceryl-phosphoryl-ethanolamine (L-a GPE), by virtue of its action as a phospholipid (PL) precursor and acetylcholine (Ach) donor, targets neural stem cell aging, cholinergic depletion, oxidative stress and microglia activation, loss of entorhinal cortex neurons, and reduced hippocampal volume. Cognitive reserve levels may be linked to the resilience and adaptability of the brain to cope with age-related cognitive decline. L-a GPE may contribute to cognitive reserve preservation via its neuronal well-being promoting action.
CONCLUSIONS
The substantial burden of age-related cognitive decline demands effective long-term and well-tolerated interventions aimed at maximizing the span of effective functioning. The use of inappropriate medication may lower cognitive reserve, thus hastening the onset of symptomatic AD, while the use of nootropics, such as L-a GPE may contribute to cognitive reserve preservation via its neuronal well-being promoting action.
Topics: Aging; Cognition; Cognitive Dysfunction; Humans; Nootropic Agents; Phosphatidylethanolamines
PubMed: 33877665
DOI: 10.26355/eurrev_202104_25555 -
Biochimica Et Biophysica Acta.... Jan 2020The turnover of phospholipids plays an essential role in membrane lipid homeostasis by impacting both lipid head group and acyl chain composition. This review focusses... (Review)
Review
The turnover of phospholipids plays an essential role in membrane lipid homeostasis by impacting both lipid head group and acyl chain composition. This review focusses on the degradation and acyl chain remodeling of the major phospholipid classes present in the ER membrane of the reference eukaryote Saccharomyces cerevisiae, i.e. phosphatidylcholine (PC), phosphatidylinositol (PI) and phosphatidylethanolamine (PE). Phospholipid turnover reactions are introduced, and the occurrence and important functions of phospholipid remodeling in higher eukaryotes are briefly summarized. After presenting an inventory of established mechanisms of phospholipid acyl chain exchange, current knowledge of phospholipid degradation and remodeling by phospholipases and acyltransferases localized to the yeast ER is summarized. PC is subject to the PC deacylation-reacylation remodeling pathway (PC-DRP) involving a phospholipase B, the recently identified glycerophosphocholine acyltransferase Gpc1p, and the broad specificity acyltransferase Ale1p. PI is post-synthetically enriched in C18:0 acyl chains by remodeling reactions involving Cst26p. PE may undergo turnover by the phospholipid: diacylglycerol acyltransferase Lro1p as first step in acyl chain remodeling. Clues as to the functions of phospholipid acyl chain remodeling are discussed.
Topics: Acylation; Animals; Endoplasmic Reticulum; Humans; Phosphatidylcholines; Phosphatidylethanolamines; Phosphatidylinositols; Phospholipids; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 31146038
DOI: 10.1016/j.bbalip.2019.05.006