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Cell Reports. Medicine Jul 2023Age-related macular degeneration (AMD) is a leading cause of blindness in older adults. Investigating shared genetic components between metabolites and AMD can enhance...
Age-related macular degeneration (AMD) is a leading cause of blindness in older adults. Investigating shared genetic components between metabolites and AMD can enhance our understanding of its pathogenesis. We conduct metabolite genome-wide association studies (mGWASs) using multi-ethnic genetic and metabolomic data from up to 28,000 participants. With bidirectional Mendelian randomization analysis involving 16,144 advanced AMD cases and 17,832 controls, we identify 108 putatively causal relationships between plasma metabolites and advanced AMD. These metabolites are enriched in glycerophospholipid metabolism, lysophospholipid, triradylcglycerol, and long chain polyunsaturated fatty acid pathways. Bayesian genetic colocalization analysis and a customized metabolome-wide association approach prioritize putative causal AMD-associated metabolites. We find limited evidence linking urine metabolites to AMD risk. Our study emphasizes the contribution of plasma metabolites, particularly lipid-related pathways and genes, to AMD risk and uncovers numerous putative causal associations between metabolites and AMD risk.
Topics: Humans; Aged; Genome-Wide Association Study; Bayes Theorem; Macular Degeneration; Metabolomics; Metabolome
PubMed: 37348500
DOI: 10.1016/j.xcrm.2023.101085 -
Microbial Cell (Graz, Austria) Oct 2023Phospholipases (PLs) and Lysophospholipases (LysoPLs) are a diverse group of esterases responsible for phospholipid or lysophospholipid hydrolysis. They are involved in... (Review)
Review
Phospholipases (PLs) and Lysophospholipases (LysoPLs) are a diverse group of esterases responsible for phospholipid or lysophospholipid hydrolysis. They are involved in several biological processes, including lipid catabolism, modulation of the immune response and membrane maintenance. PLs are classified depending on their site of hydrolysis as PLA1, PLA2, PLC and PLD. In many pathogenic microorganisms, from bacteria to fungi, PLAs and LysoPLs have been described as critical virulence and/or pathogenicity factors. In protozoan parasites, a group containing major human and animal pathogens, growing literature show that PLAs and LysoPLs are also involved in the host infection. Their ubiquitous presence and role in host-pathogen interactions make them particularly interesting to study. In this review, we summarize the literature on PLAs and LysoPLs in several protozoan parasites of medical relevance, and discuss the growing interest for them as potential drug and vaccine targets.
PubMed: 37786811
DOI: 10.15698/mic2023.10.805 -
Pharmacology & Therapeutics Jun 2023Lysophosphatidic acid (LPA) is a simple phospholipid consisting of a phosphate group, glycerol moiety, and only one hydrocarbon chain. Despite its simple chemical... (Review)
Review
Lysophosphatidic acid (LPA) is a simple phospholipid consisting of a phosphate group, glycerol moiety, and only one hydrocarbon chain. Despite its simple chemical structure, LPA plays an important role as an essential bioactive signaling molecule via its specific six G protein-coupled receptors, LPA. Recent studies, especially those using genetic tools, have revealed diverse physiological and pathological roles of LPA and LPA receptors in almost every organ system. Furthermore, many studies are illuminating detailed mechanisms to orchestrate multiple LPA receptor signaling pathways and to facilitate their coordinated function. Importantly, these extensive "bench" works are now translated into the "bedside" as exemplified by approaches targeting LPA signaling to combat fibrotic diseases. In this review, we discuss the physiological and pathological roles of LPA signaling and their implications for clinical application by focusing on findings revealed by in vivo studies utilizing genetic tools targeting LPA receptors.
Topics: Humans; Receptors, Lysophosphatidic Acid; Lysophospholipids; Signal Transduction; Glycerol
PubMed: 37080433
DOI: 10.1016/j.pharmthera.2023.108421 -
International Journal of Molecular... Jan 2024One of the major global health and welfare issues is the treatment of obesity and associated metabolic disorders, such as type 2 diabetes mellitus and nonalcoholic fatty... (Review)
Review
One of the major global health and welfare issues is the treatment of obesity and associated metabolic disorders, such as type 2 diabetes mellitus and nonalcoholic fatty liver disease. Obesity, caused by the excessive accumulation of triglycerides in adipose tissues, induces adipocyte dysfunction, followed by inflammation, in adipose tissues and lipotoxicity in nonadipose tissues. Several studies have shown that obesity and glucose homeostasis are influenced by sphingolipid mediators, including ceramide and sphingosine 1-phosphate (S1P). Cellular accumulation of ceramide impairs pancreatic β-cell survival, confers insulin resistance in the liver and the skeletal muscle, and deteriorates adipose tissue inflammation via unknown molecular mechanisms. The roles of S1P are more complicated, because there are five cell-surface S1P receptors (S1PRs: S1P) which have altered functions, different cellular expression patterns, and inapparent intracellular targets. Recent findings, including those by our group, support the notable concept that the pharmacological activation of S1P or S1P improves obesity and associated metabolic disorders, whereas that of S1P has the opposite effect. In addition, the regulation of S1P production by sphingosine kinase (SphK) is an essential factor affecting glucose homeostasis. This review summarizes the current knowledge on SphK/S1P/S1PR signaling in and against obesity, insulin resistance, and associated disorders.
Topics: Humans; Diabetes Mellitus, Type 2; Insulin Resistance; Obesity; Ceramides; Inflammation; Homeostasis; Glucose; Lysophospholipids; Sphingosine
PubMed: 38256005
DOI: 10.3390/ijms25020932 -
International Journal of Molecular... Mar 2024In recent years, newly emerging therapies, such as immune checkpoint inhibitors and antibody-drug conjugates, have further improved outcomes for breast cancer patients.... (Review)
Review
In recent years, newly emerging therapies, such as immune checkpoint inhibitors and antibody-drug conjugates, have further improved outcomes for breast cancer patients. However, recurrent and metastatic breast cancer often eventually develops resistance to these drugs, and cure is still rare. As such, the development of new therapies for refractory breast cancer that differ from conventional mechanisms of action is necessary. Sphingosine-1-phosphate (S1P) is a key molecule with a variety of bioactive activities, including involvement in cancer cell proliferation, invasion, and metastasis. S1P also contributes to the formation of the cancer microenvironment by inducing surrounding vascular- and lymph-angiogenesis and regulating the immune system. In this article, we outline the basic mechanism of action of S1P, summarize previous findings on the function of S1P in cancer cells and the cancer microenvironment, and discuss the clinical significance of S1P in breast cancer and the therapeutic potential of targeting S1P signaling.
Topics: Humans; Female; Breast Neoplasms; Sphingosine; Lysophospholipids; Signal Transduction; Tumor Microenvironment
PubMed: 38542328
DOI: 10.3390/ijms25063354 -
Research Square Sep 2023Major Depressive Disorder (MDD) is an often-chronic condition with substantial molecular alterations and pathway dysregulations involved. Single metabolite, pathway and...
Major Depressive Disorder (MDD) is an often-chronic condition with substantial molecular alterations and pathway dysregulations involved. Single metabolite, pathway and targeted metabolomics platforms have indeed revealed several metabolic alterations in depression including energy metabolism, neurotransmission and lipid metabolism. More comprehensive coverage of the metabolome is needed to further specify metabolic dysregulation in depression and reveal previously untargeted mechanisms. Here we measured 820 metabolites using the metabolome-wide Metabolon platform in 2770 subjects from a large Dutch clinical cohort with extensive depression clinical phenotyping (1101 current MDD, 868 remitted MDD, 801 healthy controls) at baseline and 1805 subjects at 6-year follow up (327 current MDD, 1045 remitted MDD, 433 healthy controls). MDD diagnosis was based on DSM-IV psychiatric interviews. Depression severity was measured with the Inventory of Depressive Symptomatology self-report. Associations between metabolites and MDD status and depression severity were assessed at baseline and at the 6-year follow-up. Metabolites consistently associated with MDD status or depression severity on both occasions were examined in Mendelian randomization (MR) analysis using metabolite (N=14,000) and MDD (N=800,000) GWAS results. At baseline, 139 and 126 metabolites were associated with current MDD status and depression severity, respectively, with 79 overlapping metabolites. Six years later, 34 out of the 79 metabolite associations were subsequently replicated. Downregulated metabolites were enriched with long-chain monounsaturated (P=6.7e-07) and saturated (P=3.2e-05) fatty acids and upregulated metabolites with lysophospholipids (P=3.4e-4). Adding BMI to the models changed results only marginally. MR analyses showed that genetically-predicted higher levels of the lysophospholipid 1-linoleoyl-GPE (18:2) were associated with greater risk of depression. The identified metabolome-wide profile of depression (severity) indicated altered lipid metabolism with downregulation of long-chain fatty acids and upregulation of lysophospholipids, for which causal involvement was suggested using genetic tools. This metabolomics signature offers a window on depression pathophysiology and a potential access point for the development of novel therapeutic approaches.
PubMed: 37790319
DOI: 10.21203/rs.3.rs-3127544/v1 -
International Journal of Molecular... Aug 2023Lysophosphatidic acid (LPA) is a bioactive phospholipid that regulates physiological and pathological processes in numerous cell biological functions, including cell... (Review)
Review
Lysophosphatidic acid (LPA) is a bioactive phospholipid that regulates physiological and pathological processes in numerous cell biological functions, including cell migration, apoptosis, and proliferation. Macrophages are found in most human tissues and have multiple physiological and pathological functions. There is growing evidence that LPA signaling plays a significant role in the physiological function of macrophages and accelerates the development of diseases caused by macrophage dysfunction and inflammation, such as inflammation-related diseases, cancer, atherosclerosis, and fibrosis. In this review, we summarize the roles of LPA in macrophages, analyze numerous macrophage- and inflammation-associated diseases triggered by LPA, and discuss LPA-targeting therapeutic strategies.
Topics: Humans; Receptors, Lysophosphatidic Acid; Lysophospholipids; Macrophages; Inflammation
PubMed: 37569902
DOI: 10.3390/ijms241512524 -
The Journal of Biological Chemistry Jun 2023The vascular and lymphatic systems both comprise a series of structurally distinct vessels lined with an inner layer of endothelial cells that function to provide a... (Review)
Review
The vascular and lymphatic systems both comprise a series of structurally distinct vessels lined with an inner layer of endothelial cells that function to provide a semipermeable barrier to blood and lymph. Regulation of the endothelial barrier is critical for maintaining vascular and lymphatic barrier homeostasis. One of the regulators of endothelial barrier function and integrity is sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite secreted into the blood by erythrocytes, platelets, and endothelial cells and into the lymph by lymph endothelial cells. Binding of S1P to its G protein-coupled receptors, known as S1PR1-5, regulates its pleiotropic functions. This review outlines the structural and functional differences between vascular and lymphatic endothelium and describes current understanding of the importance of S1P/S1PR signaling in regulation of barrier functions. Most studies thus far have been primarily focused on the role of the S1P/S1PR1 axis in vasculature and have been summarized in several excellent reviews, and thus, we will only discuss new perspectives on the molecular mechanisms of action of S1P and its receptors. Much less is known about the responses of the lymphatic endothelium to S1P and the functions of S1PRs in lymph endothelial cells, and this is the major focus of this review. We also discuss current knowledge related to signaling pathways and factors regulated by the S1P/S1PR axis that control lymphatic endothelial cell junctional integrity. Gaps and limitations in current knowledge are highlighted together with the need to further understand the role of S1P receptors in the lymphatic system.
Topics: Endothelial Cells; Endothelium, Vascular; Lysophospholipids; Receptors, Lysosphingolipid; Humans; Animals; Intercellular Junctions; Signal Transduction; Lymphatic Vessels
PubMed: 37142226
DOI: 10.1016/j.jbc.2023.104775 -
Nutrients Nov 2023Multiple studies have indicated that distinct metabolites are involved in the occurrence and development of osteopenia (ON) and osteoporosis (OP); however, these... (Meta-Analysis)
Meta-Analysis Review
Multiple studies have indicated that distinct metabolites are involved in the occurrence and development of osteopenia (ON) and osteoporosis (OP); however, these metabolites in OP and ON have not yet been classified and standardized. This systematic review and meta-analysis included 21 articles aiming to investigate the distinct metabolites in patients with ON and OP. The quality of the included articles was generally high; seventeen studies had >7 stars, and the remaining four received 6 stars. This systematic review showed that three metabolites (phosphatidylcholine (PC) (lipid metabolites), galactose (carbohydrate metabolites), and succinic acid (other metabolites)) increased, four (glycylglycine (gly-gly), cystine (amino acids), sphingomyelin (SM) (lipid metabolites) and glucose (carbohydrate metabolites)) decreased, and five (glutamine, hydroxyproline, taurine (amino acids), lysophosphatidylcholine (LPC) (lipid metabolites), and lactate (other metabolites)) had conflicting directions in OP/ON. The results of the meta-analysis show that gly-gly (MD = -0.77, 95%CI -1.43 to -0.11, = 0.02) and cystine (MD = -5.52, 95%CI -7.35 to -3.68, < 0.00001) decreased in the OP group compared with the healthy control group. Moreover, LPC (MD = 1.48, 95%CI 0.11 to 2.86, = 0.03) increased in the OP group compared with the healthy control group. These results indicate that distinct metabolites were associated with ON and OP, which could be considered a predictor for OP.
Topics: Humans; Cystine; Osteoporosis; Bone Diseases, Metabolic; Amino Acids; Lysophosphatidylcholines; Carbohydrates
PubMed: 38068753
DOI: 10.3390/nu15234895