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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 -
Cell Chemical Biology Jul 2022Phospholipids are ligands for nuclear hormone receptors (NRs) that regulate transcriptional programs relevant to normal physiology and disease. Here, we demonstrate that...
Phospholipids are ligands for nuclear hormone receptors (NRs) that regulate transcriptional programs relevant to normal physiology and disease. Here, we demonstrate that mimicking phospholipid-NR interactions is a robust strategy to improve agonists of liver receptor homolog-1 (LRH-1), a therapeutic target for colitis. Conventional LRH-1 modulators only partially occupy the binding pocket, leaving vacant a region important for phospholipid binding and allostery. Therefore, we constructed a set of molecules with elements of natural phospholipids appended to a synthetic LRH-1 agonist. We show that the phospholipid-mimicking groups interact with the targeted residues in crystal structures and improve binding affinity, LRH-1 transcriptional activity, and conformational changes at a key allosteric site. The best phospholipid mimetic markedly improves colonic histopathology and disease-related weight loss in a murine T cell transfer model of colitis. This evidence of in vivo efficacy for an LRH-1 modulator in colitis represents a leap forward in agonist development.
Topics: Animals; Colitis; Ligands; Mice; Phospholipids; Receptors, Cytoplasmic and Nuclear
PubMed: 35316658
DOI: 10.1016/j.chembiol.2022.03.001 -
Cell Reports Sep 2023Ferroptosis is a form of regulated cell death with roles in degenerative diseases and cancer. Excessive iron-catalyzed peroxidation of membrane phospholipids, especially...
Ferroptosis is a form of regulated cell death with roles in degenerative diseases and cancer. Excessive iron-catalyzed peroxidation of membrane phospholipids, especially those containing the polyunsaturated fatty acid arachidonic acid (AA), is central in driving ferroptosis. Here, we reveal that an understudied Golgi-resident scaffold protein, MMD, promotes susceptibility to ferroptosis in ovarian and renal carcinoma cells in an ACSL4- and MBOAT7-dependent manner. Mechanistically, MMD physically interacts with both ACSL4 and MBOAT7, two enzymes that catalyze sequential steps to incorporate AA in phosphatidylinositol (PI) lipids. Thus, MMD increases the flux of AA into PI, resulting in heightened cellular levels of AA-PI and other AA-containing phospholipid species. This molecular mechanism points to a pro-ferroptotic role for MBOAT7 and AA-PI, with potential therapeutic implications, and reveals that MMD is an important regulator of cellular lipid metabolism.
Topics: Cell Line; Fatty Acids, Unsaturated; Ferroptosis; Phosphatidylinositols; Phospholipids; Humans
PubMed: 37691145
DOI: 10.1016/j.celrep.2023.113023 -
Biochemical Pharmacology Dec 2022In mammalian cells, phospholipids and cholesterol are assembled into bilayer membranes forming the plasma membrane, nuclear envelope, mitochondria, endoplasmic... (Review)
Review
In mammalian cells, phospholipids and cholesterol are assembled into bilayer membranes forming the plasma membrane, nuclear envelope, mitochondria, endoplasmic reticulum, Golgi apparatus, lysosomes, and endosomes. Phospholipids are divided into classes based on the molecular structures, including phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidic acid, phosphatidylinositol, phosphatidylglycerol, cardiolipin, and sphingomyelin. In addition to their structural roles, phospholipids play important roles in many cellular processes, such as membrane protein regulation, membrane trafficking, cell growth, apoptosis, and intracellular signaling. Thus, abnormal phospholipid metabolism is associated with various diseases. In mammalian cells, phospholipid classes are generated through several enzymatic steps, predominantly in the endoplasmic reticulum, mitochondria, and Golgi apparatus. In recent years, various enzymes involved in the biosynthesis of phospholipid classes have been identified. However, little is known about the regulatory mechanisms underlying the biosynthesis of phospholipid classes. Using our recently developed enzymatic fluorometric assays for all major phospholipid classes, we have demonstrated changes in phospholipid composition in intracellular organelles during cell growth. In this review, we summarize the current understanding of the properties and functions of phospholipid biosynthesis enzymes, and discuss their regulatory mechanisms.
Topics: Animals; Phospholipids; Endoplasmic Reticulum; Mitochondria; Cell Membrane; Phosphatidylserines; Mammals
PubMed: 36241095
DOI: 10.1016/j.bcp.2022.115296 -
Trends in Plant Science Apr 2021In plants, defense-associated signal transduction involves key membrane-related processes, such as phospholipid-based signaling and membrane trafficking. Coordination of... (Review)
Review
In plants, defense-associated signal transduction involves key membrane-related processes, such as phospholipid-based signaling and membrane trafficking. Coordination of these processes occurs in the lipid bilayer of plasma membrane (PM) and luminal/extracellular membranes. Deciphering the spatiotemporal organization of phospholipids and lipid-protein interactions provides crucial information on the mechanisms that link phospholipid-based signaling and membrane trafficking in plant immunity. In this review, we summarize recent advances in our understanding of these connections, including deployment of key enzymes and molecules in phospholipid pathways, and roles of lipid diversity in membrane trafficking. We highlight the mechanisms that mediate feedback between phospholipid-based signaling and membrane trafficking to regulate plant immunity, including their novel roles in balancing endocytosis and exocytosis.
Topics: Cell Membrane; Endocytosis; Phospholipids; Plant Immunity; Protein Transport; Signal Transduction
PubMed: 33309101
DOI: 10.1016/j.tplants.2020.11.010 -
Biochimie Dec 2023Lysophospholipid acyltransferases (LPLATs), in concert with glycerol-3-phosphate acyltransferases (GPATs) and phospholipase As, orchestrate the compositional diversity... (Review)
Review
Lysophospholipid acyltransferases (LPLATs), in concert with glycerol-3-phosphate acyltransferases (GPATs) and phospholipase As, orchestrate the compositional diversity of the fatty chains in membrane phospholipids. Fourteen LPLAT enzymes which come from two distinct families, AGPAT and MBOAT, have been identified, and in this mini-review we provide an overview of their roles in de novo and remodeling pathways of membrane phospholipid biosynthesis. Recently new nomenclature for LPLATs has been introduced (LPLATx, where x is a number 1-14), and we also give an overview of key biological functions that have been discovered for LPLAT1-14, revealed primarily through studies of LPLAT-gene-deficient mice as well as by linkages to various human diseases.
Topics: Humans; Animals; Mice; 1-Acylglycerophosphocholine O-Acyltransferase; Phospholipids; Lysophospholipids; Acyltransferases
PubMed: 37611890
DOI: 10.1016/j.biochi.2023.08.012 -
Nutrition (Burbank, Los Angeles County,... Feb 2023The role of plasma phospholipid arachidonic acid (AA) in the development of non-alcoholic fatty liver disease (NALFD), cirrhosis, and liver cancer remains unclear. This... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
The role of plasma phospholipid arachidonic acid (AA) in the development of non-alcoholic fatty liver disease (NALFD), cirrhosis, and liver cancer remains unclear. This study aimed to determine the causality of the associations of plasma phospholipid AA with NALFD, cirrhosis, and liver cancer using Mendelian randomization analysis.
METHODS
Nine independent single-nucleotide polymorphisms associated with plasma phospholipid AA at the genome-wide significance were used as instrumental variables. Summary-level data for three outcomes were obtained from 1) a genome-wide association study for NAFLD, 2) the UK Biobank study, and 3) the FinnGen study. The sensitivity analysis excluding the pleiotropic variant rs174547 in the FADS1 gene was performed. Estimates from different sources were combined using the fixed-effects meta-analysis method.
RESULTS
Per standard deviation increase in AA levels, the combined odds ratio was 1.06 (95% confidence interval, 1.02-1.11; P = 0.008) for NAFLD, 1.05 (95% confidence interval, 1.01-1.09; P = 0.009) for cirrhosis, and 0.99 (95% confidence interval, 0.94-1.05; P = 0.765) for liver cancer. The associations remained stable in the sensitivity analysis excluding rs174547.
CONCLUSIONS
This study suggests potential causal associations of high levels of plasma phospholipid AA with the risk of NAFLD and cirrhosis.
Topics: Humans; Arachidonic Acid; Genetic Predisposition to Disease; Genome-Wide Association Study; Liver Neoplasms; Mendelian Randomization Analysis; Non-alcoholic Fatty Liver Disease; Phospholipids; Polymorphism, Single Nucleotide; Risk Factors
PubMed: 36459845
DOI: 10.1016/j.nut.2022.111910 -
Emerging Topics in Life Sciences Mar 2023In mammalian cells, phospholipids are asymmetrically distributed between the outer and inner leaflets of the plasma membrane. The maintenance of asymmetric phospholipid...
In mammalian cells, phospholipids are asymmetrically distributed between the outer and inner leaflets of the plasma membrane. The maintenance of asymmetric phospholipid distribution has been demonstrated to be required for a wide range of cellular functions including cell division, cell migration, and signal transduction. However, we recently reported that asymmetric phospholipid distribution is disrupted in Drosophila cell membranes, and this unique phospholipid distribution leads to the formation of highly deformable cell membranes. In addition, it has become clear that asymmetry in the trans-bilayer distribution of phospholipids is disturbed even in living mammalian cells under certain circumstances. In this article, we introduce our recent studies while focusing on the trans-bilayer distribution of phospholipids, and discuss the cellular functions of (a)symmetric biological membranes.
Topics: Animals; Cell Membrane; Phospholipids; Cell Physiological Phenomena; Mammals
PubMed: 36562339
DOI: 10.1042/ETLS20220029 -
Nature Microbiology Oct 2019
Topics: Cell Membrane; Phospholipids
PubMed: 31541210
DOI: 10.1038/s41564-019-0570-y -
Emerging Topics in Life Sciences Mar 2023Eukaryotic pathogens with an intracellular parasitic lifestyle are shielded from extracellular threats during replication and growth. In addition to many nutrients,... (Review)
Review
Eukaryotic pathogens with an intracellular parasitic lifestyle are shielded from extracellular threats during replication and growth. In addition to many nutrients, parasites scavenge host cell lipids to establish complex membrane structures inside their host cells. To counteract the disturbance of the host cell plasma membrane they have evolved strategies to regulate phospholipid asymmetry. In this review, the function and importance of lipid asymmetry in the interactions of intracellular protozoan parasites with the target and immune cells of the host are highlighted. The malaria parasite Plasmodium infects red blood cells and extensively refurbishes these terminally differentiated cells. Cholesterol depletion and an altered intracellular calcium ion homeostasis can lead to disruption in erythrocyte membrane asymmetry and increased exposure of phosphatidylserine (PS). Binding to the PS receptor on monocytes and macrophages results in phagocytosis and destruction of infected erythrocytes. Leishmania parasites display apoptotic mimicry by actively enhancing PS exposure on their surface to trigger increased infection of macrophages. In extracellular Toxoplasma gondii a P4-type ATPase/CDC50 co-chaperone pair functions as a flippase important for exocytosis of specialised secretory organelles. Identification and functional analysis of parasite lipid-translocating proteins, i.e. flippases, floppases, and scramblases, will be central for the recognition of the molecular mechanisms of parasite/host interactions. Ultimately, a better understanding of parasitic diseases, host immunity, and immune escape by parasites require more research on the dynamics of phospholipid bilayers of parasites and the infected host cell.
Topics: Animals; Host-Parasite Interactions; Phospholipids; Parasites; Toxoplasma; Eukaryota
PubMed: 36820809
DOI: 10.1042/ETLS20220089