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Obafemi BA, Adedara IA, Delgado CP, Obafemi OT, Aschner M, Rocha JB. Fumonisin B1 neurotoxicity: Preclinical evidence, biochemical mechanisms and therapeutic strategies. Toxicol Rep 2025; 14:101931. [PMID: 39980663 PMCID: PMC11841125 DOI: 10.1016/j.toxrep.2025.101931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 01/22/2025] [Accepted: 01/24/2025] [Indexed: 02/22/2025] Open
Abstract
The neurotoxic effects of fungal toxins in both humans and animals have been well documented. Fumonisin B1 (FB1), a mycotoxin produced by fungi of the Fusarium species, is the most toxic fumonisin variant whose neurotoxic effect is still being elucidated. This review highlights the biochemical aspects of FB1 neurotoxicity, such as its mechanisms of action as well as therapeutic strategies. Both in vitro and in vivo studies have demonstrated that alteration in sphingolipid metabolism is a major event in FB-induced neurotoxicity. Studies have also shown that neurotoxicity due to FB1 involves dysregulation of several biochemical events in the brain, such as induction of oxidative stress and inflammation, mitochondrial dysfunction and associated programmed cell death, inhibition of acetylcholinesterase and alteration of neurotransmitter levels, decreased activity of Na+K+ ATPase, as well as disruption of blood-brain barrier. This review highlights the potential public health effects of FB1-induced neurotoxicity and the need to limit human and animal exposure to FB1in order to prevent its neurotoxic effect. Moreover, it is hoped that this review would stimulate studies aimed at filling the current research gaps such as delineating the effect of FB1 on the blood-brain barrier and appropriate therapies for neurotoxicity caused by FB1.
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Affiliation(s)
- Blessing A. Obafemi
- Department of Biochemistry and Molecular Biology, Center for Natural and Exact Sciences, Federal University of Santa Maria, Camobi, Santa Maria 97105-900, Brazil
- Department of Medical Biochemistry, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Nigeria
| | - Isaac A. Adedara
- Department of Food Science and Technology, Center of Rural Sciences, Federal University of Santa Maria, Camobi, Santa Maria, RS 97105-900, Brazil
| | - Cássia Pereira Delgado
- Department of Biochemistry and Molecular Biology, Center for Natural and Exact Sciences, Federal University of Santa Maria, Camobi, Santa Maria 97105-900, Brazil
| | - Olabisi T. Obafemi
- Department of Life and Consumer Sciences, University of South Africa, Florida 1710 Johannesburg, South Africa
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Joao B.T. Rocha
- Department of Biochemistry and Molecular Biology, Center for Natural and Exact Sciences, Federal University of Santa Maria, Camobi, Santa Maria 97105-900, Brazil
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2
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Yamada C, Akkaoui J, Morozov A, Movila A. Role of Canonical and Non-Canonical Sphingolipids and their Metabolic Enzymes in Bone Health. Curr Osteoporos Rep 2025; 23:21. [PMID: 40266422 PMCID: PMC12018623 DOI: 10.1007/s11914-025-00908-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/21/2025] [Indexed: 04/24/2025]
Abstract
PURPOSE OF REVIEW This review summarizes the recently published scientific evidence regarding the role of enzymes engaged in de novo anabolic biosynthesis, catabolic, and salvage pathways of ceramide bioactive sphingolipids in bone dynamics and skeletal health. RECENT FINDINGS Ceramides are precursors for bioactive sphingolipids, including sphingosine, sphingosine-1-phosphate, and others. Studies of bone metabolism and bone-related cells demonstrated that ceramide and sphingosine-1-phosphate control levels of bone remodeling and resorption generated by osteoblasts and osteoclasts. Multiple published studies demonstrated the critical role of enzymes in regulating the ceramide/sphingosine-1-phosphate ratio relative to bone physiology and the promotion of inflammatory osteolysis. Accordingly, emerging evidence suggests that targeting sphingolipid metabolism has the potential to alleviate inflammatory osteolysis and accelerate bone regeneration. Therefore, this study aimed to discuss current knowledge about crosstalk between sphingolipids and their metabolic enzymes within osteoclast and osteoblast coupling in bone remodeling and pathogenic osteolysis. This review highlights the complexity of de novo sphingolipid biosynthesis and knowledge gaps in bone physiology and pathology. We also discuss the importance of canonical and non-canonical mammalian and bacterial-derived sphingolipids relative to bone health.
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Affiliation(s)
- Chiaki Yamada
- Department of Biomedical Sciences and Comprehensive Care, Indiana University School of Dentistry, Indianapolis, IN, USA
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA
- Richard L. Roudebush Veterans' Administration Medical Center, Indianapolis, IN, USA
| | - Juliet Akkaoui
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA
| | - Alexandr Morozov
- Institute of Zoology, Moldova State University, Chisinau, Republic of Moldova
- Medpark International Hospital, Chisinau, Republic of Moldova
| | - Alexandru Movila
- Department of Biomedical Sciences and Comprehensive Care, Indiana University School of Dentistry, Indianapolis, IN, USA.
- Indiana Center for Musculoskeletal Health, Indiana University School of Medicine, Indianapolis, IN, USA.
- Richard L. Roudebush Veterans' Administration Medical Center, Indianapolis, IN, USA.
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3
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Zhang Y, Hao H, Li H, Duan Q, Zheng X, Feng Y, Yang K, Shen S. Cellular Metabolomics Reveals Differences in the Scope of Liver Protection Between Ammonium-Based Glycyrrhizinate and Magnesium Isoglycyrrhizinate. Metabolites 2025; 15:263. [PMID: 40278392 DOI: 10.3390/metabo15040263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 03/14/2025] [Accepted: 04/01/2025] [Indexed: 04/26/2025] Open
Abstract
Background: Despite the well-established liver-protective efficacy of monoammonium glycyrrhizinate (MONO), diammonium glycyrrhizinate (DIAM), and magnesium isoglycyrrhizinate (MAGN), which has been translated into clinical practice, their clinical differentiation remains elusive owing to their structural similarities and overlapping therapeutic effects. Methods: The present study delves into the pharmacokinetics, cellular-level liver-protective potencies, and underlying mechanisms of action of these three compounds through a comprehensive analysis. Results: The findings reveal that both DIAM and MAGN exhibit superior bioavailability and hepatoprotective profiles compared to MONO. Notably, an investigation of the metabolic pathways mediating liver protection in normal human liver cells (LO2), utilizing an ultra-performance liquid chromatography-time of flight tandem mass spectrometry (UPLC-TOF-MS/MSe) platform, demonstrated that MAGN augments antioxidant components, thereby favoring its application in drug-induced liver injury (DILI). Conversely, DIAM appears to be a more suitable candidate for addressing non-alcoholic fatty liver disease (NAFLD) and viral hepatitis. Conclusion: This study contributes novel perspectives on the mechanisms of action and potential clinical utilities of DIAM and MAGN in liver disease prevention and management.
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Affiliation(s)
- Yihua Zhang
- Key Laboratory of Analytical Science and Technology of Hebei Province, College of Chemistry and Materials Science, Hebei University, Baoding 071002, China
- NDMA Key Laboratory for Quality Control and Evaluation of Generic Drug, Hebei Institute for Drug and Medical Device Control, Shijiazhuang 050200, China
| | - Han Hao
- School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China
| | - Hui Li
- NDMA Key Laboratory for Quality Control and Evaluation of Generic Drug, Hebei Institute for Drug and Medical Device Control, Shijiazhuang 050200, China
| | - Qiong Duan
- NDMA Key Laboratory for Quality Control and Evaluation of Generic Drug, Hebei Institute for Drug and Medical Device Control, Shijiazhuang 050200, China
| | - Xiaoming Zheng
- NDMA Key Laboratory for Quality Control and Evaluation of Generic Drug, Hebei Institute for Drug and Medical Device Control, Shijiazhuang 050200, China
| | - Yan Feng
- NDMA Key Laboratory for Quality Control and Evaluation of Generic Drug, Hebei Institute for Drug and Medical Device Control, Shijiazhuang 050200, China
| | - Kun Yang
- School of Pharmacy, Hebei Medical University, Shijiazhuang 050017, China
| | - Shigang Shen
- Key Laboratory of Analytical Science and Technology of Hebei Province, College of Chemistry and Materials Science, Hebei University, Baoding 071002, China
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4
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Li N, Li G. Sphingolipid signaling in kidney diseases. Am J Physiol Renal Physiol 2025; 328:F431-F443. [PMID: 39933715 DOI: 10.1152/ajprenal.00193.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 07/22/2024] [Accepted: 02/06/2025] [Indexed: 02/13/2025] Open
Abstract
Sphingolipids are a family of bioactive lipids. The key components include ceramides, ceramide-1-phosphate, sphingosine, and sphingosine-1-phosphate. Sphingolipids were originally considered to be primarily structural elements of cell membranes but were later recognized as bioactive signaling molecules that play diverse roles in cellular behaviors such as cell differentiation, migration, proliferation, and death. Studies have demonstrated changes in key components of sphingolipids in the kidneys under different conditions and their important roles in the renal function and the pathogenesis of various kidney diseases. This review summarizes the most recent advances in the role of sphingolipid signaling in kidney diseases.
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Affiliation(s)
- Ningjun Li
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, United States
| | - Guangbi Li
- Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, Virginia, United States
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Pascoa TC, Pike ACW, Tautermann CS, Chi G, Traub M, Quigley A, Chalk R, Štefanić S, Thamm S, Pautsch A, Carpenter EP, Schnapp G, Sauer DB. Structural basis of the mechanism and inhibition of a human ceramide synthase. Nat Struct Mol Biol 2025; 32:431-440. [PMID: 39528795 PMCID: PMC11919693 DOI: 10.1038/s41594-024-01414-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 10/01/2024] [Indexed: 11/16/2024]
Abstract
Ceramides are bioactive sphingolipids crucial for regulating cellular metabolism. Ceramides and dihydroceramides are synthesized by six ceramide synthase (CerS) enzymes, each with specificity for different acyl-CoA substrates. Ceramide with a 16-carbon acyl chain (C16 ceramide) has been implicated in obesity, insulin resistance and liver disease and the C16 ceramide-synthesizing CerS6 is regarded as an attractive drug target for obesity-associated disease. Despite their importance, the molecular mechanism underlying ceramide synthesis by CerS enzymes remains poorly understood. Here we report cryo-electron microscopy structures of human CerS6, capturing covalent intermediate and product-bound states. These structures, along with biochemical characterization, reveal that CerS catalysis proceeds through a ping-pong reaction mechanism involving a covalent acyl-enzyme intermediate. Notably, the product-bound structure was obtained upon reaction with the mycotoxin fumonisin B1, yielding insights into its inhibition of CerS. These results provide a framework for understanding CerS function, selectivity and inhibition and open routes for future drug discovery.
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Affiliation(s)
- Tomas C Pascoa
- Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
| | - Ashley C W Pike
- Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | | | - Gamma Chi
- Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Michael Traub
- Boehringer Ingelheim Pharma, GmbH & Co. KG, Biberach, Germany
| | - Andrew Quigley
- Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Membrane Protein Laboratory, Research Complex at Harwell, Diamond Light Source, Ltd., Harwell Science and Innovation Campus, Didcot, UK
| | - Rod Chalk
- Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK
| | - Saša Štefanić
- Institute of Parasitology, Vetsuisse and Medical Faculty, University of Zürich, Zürich, Switzerland
- Nanobody Service Facility, University of Zürich, AgroVet-Strickhof, Lindau, Switzerland
| | - Sven Thamm
- Boehringer Ingelheim Pharma, GmbH & Co. KG, Biberach, Germany
| | | | - Elisabeth P Carpenter
- Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
| | - Gisela Schnapp
- Boehringer Ingelheim Pharma, GmbH & Co. KG, Biberach, Germany.
| | - David B Sauer
- Centre for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, UK.
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Kenney HM, Yoshida T, Berdyshev E, Calatroni A, Gill SR, Simpson EL, Lussier S, Boguniewicz M, Hata T, Chiesa Fuxench ZC, De Benedetto A, Ong PY, Ko J, Davidson W, David G, Schlievert PM, Leung DYM, Beck LA. CERS1 is a biomarker of Staphylococcus aureus abundance and atopic dermatitis severity. J Allergy Clin Immunol 2025; 155:479-490. [PMID: 39343173 PMCID: PMC11805642 DOI: 10.1016/j.jaci.2024.09.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 08/15/2024] [Accepted: 09/17/2024] [Indexed: 10/01/2024]
Abstract
BACKGROUND Atopic dermatitis (AD) is an inflammatory skin condition characterized by widely variable cutaneous Staphylococcus aureus abundance that contributes to disease severity and rapidly responds to type 2 immune blockade (ie, dupilumab). The molecular mechanisms regulating S aureus levels between AD subjects remain poorly understood. OBJECTIVE We investigated host genes that may be predictive of S aureus abundance and correspond with AD severity. METHODS We studied data derived from the National Institutes of Health/National Institute of Allergy and Infectious Diseases-funded (NCT03389893 [ADRN-09]) randomized, double-blind, placebo-controlled multicenter study of dupilumab in adults (n = 71 subjects) with moderate-to-severe AD. Bulk RNA sequencing of skin biopsy samples (n = 57 lesional, 55 nonlesional) was compared to epidermal S aureus abundance, lipidomic, and AD clinical measures. RESULTS S aureus abundance and ceramide synthase 1 (CERS1) expression positively correlated at baseline across both nonlesional (r = 0.29, P = .030) and lesional (r = 0.41, P = .0015) skin. Lesional CERS1 expression also positively correlated with AD severity (ie, SCORAD r = 0.44, P = .0006) and skin barrier dysfunction (transepidermal water loss area under the curve r = 0.31, P = .025) at baseline. CERS1 expression (forms C18:0 sphingolipids) was negatively associated with elongation of very long-chain fatty acids (ELOVL6; C16:0→C18:0) expression and corresponded with a shorter chain length sphingolipid composition. Dupilumab rapidly reduced CERS1 expression (day 7) and ablated the relationship with S aureus abundance and ELOVL6 expression by day 21. CONCLUSION CERS1 is a unique molecular biomarker of S aureus abundance and AD severity that may contribute to dysfunctional skin barrier and shorter-chain sphingolipid composition through fatty acid sequestration as a maladaptive compensatory response to reduced ELOVL6.
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Affiliation(s)
- H Mark Kenney
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY
| | - Takeshi Yoshida
- Department of Dermatology, University of Rochester Medical Center, Rochester, NY
| | - Evgeny Berdyshev
- Department of Medicine, National Jewish Health and University of Colorado School of Medicine, Denver, Colo
| | | | - Steven R Gill
- Department of Microbiology & Immunology, University of Rochester Medical Center, Rochester, NY
| | - Eric L Simpson
- Department of Dermatology, Oregon Health and Science University, Portland, Ore
| | | | - Mark Boguniewicz
- Division of Allergy-Immunology, Department of Pediatrics, National Jewish Health and University of Colorado School of Medicine, Denver, Colo
| | - Tissa Hata
- Department of Dermatology, University of California, San Diego, Calif
| | | | - Anna De Benedetto
- Department of Dermatology, University of Rochester Medical Center, Rochester, NY
| | - Peck Y Ong
- Department of Pediatrics, University of Southern California, Division of Clinical Immunology and Allergy Children's Hospital Los Angeles, Los Angeles, Calif
| | - Justin Ko
- Department of Dermatology, Stanford University, Stanford, Calif
| | - Wendy Davidson
- Division of Allergy, Immunology, and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | | | | | - Donald Y M Leung
- Division of Allergy-Immunology, Department of Pediatrics, National Jewish Health and University of Colorado School of Medicine, Denver, Colo
| | - Lisa A Beck
- Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY; Department of Dermatology, University of Rochester Medical Center, Rochester, NY.
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7
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Karmelić I, Jurilj Sajko M, Sajko T, Rotim K, Fabris D. The role of sphingolipid rheostat in the adult-type diffuse glioma pathogenesis. Front Cell Dev Biol 2024; 12:1466141. [PMID: 39723240 PMCID: PMC11668798 DOI: 10.3389/fcell.2024.1466141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 11/11/2024] [Indexed: 12/28/2024] Open
Abstract
Gliomas are highly aggressive primary brain tumors, with glioblastoma multiforme being the most severe and the most common one. Aberrations in sphingolipid metabolism are a hallmark of glioma cells. The sphingolipid rheostat represents the balance between the pro-apoptotic ceramide and pro-survival sphingosine-1-phosphate (S1P), and in gliomas it is shifted toward cell survival and proliferation, promoting gliomas' aggressiveness, cellular migration, metastasis, and invasiveness. The sphingolipid rheostat can be altered by targeting enzymes that directly or indirectly affect the ratio of ceramide to S1P, leading to increased ceramide or decreased S1P levels. Targeting the sphingolipid rheostat offers a potential therapeutic pathway for glioma treatment which can be considered through reducing S1P levels or modulating S1P receptors to reduce cell proliferation, as well as through increasing ceramide levels to induce apoptosis in glioma cells. Although the practical translation into clinical therapy is still missing, sphingolipid rheostat targeting in gliomas has been of great research interest in recent years with several interesting achievements in the glioma therapy approach, offering hope for patients suffering from these vicious malignancies.
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Affiliation(s)
- Ivana Karmelić
- Department of Medical Chemistry, Biochemistry and Clinical Chemistry, School of Medicine, University of Zagreb, Zagreb, Croatia
| | - Mia Jurilj Sajko
- Department of Neurosurgery, University Hospital Center “Sestre milosrdnice”, Zagreb, Croatia
| | - Tomislav Sajko
- Department of Neurosurgery, University Hospital Center “Sestre milosrdnice”, Zagreb, Croatia
| | - Krešimir Rotim
- Department of Neurosurgery, University Hospital Center “Sestre milosrdnice”, Zagreb, Croatia
| | - Dragana Fabris
- Department of Medical Chemistry, Biochemistry and Clinical Chemistry, School of Medicine, University of Zagreb, Zagreb, Croatia
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van Drie RWA, van de Wouw J, Zandbergen LM, Dehairs J, Swinnen JV, Mulder MT, Verhaar MC, MaassenVanDenBrink A, Duncker DJ, Sorop O, Merkus D. Vasodilator reactive oxygen species ameliorate perturbed myocardial oxygen delivery in exercising swine with multiple comorbidities. Basic Res Cardiol 2024; 119:869-887. [PMID: 38796544 PMCID: PMC11461570 DOI: 10.1007/s00395-024-01055-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 05/06/2024] [Accepted: 05/07/2024] [Indexed: 05/28/2024]
Abstract
Multiple common cardiovascular comorbidities produce coronary microvascular dysfunction. We previously observed in swine that a combination of diabetes mellitus (DM), high fat diet (HFD) and chronic kidney disease (CKD) induced systemic inflammation, increased oxidative stress and produced coronary endothelial dysfunction, altering control of coronary microvascular tone via loss of NO bioavailability, which was associated with an increase in circulating endothelin (ET). In the present study, we tested the hypotheses that (1) ROS scavenging and (2) ETA+B-receptor blockade improve myocardial oxygen delivery in the same female swine model. Healthy female swine on normal pig chow served as controls (Normal). Five months after induction of DM (streptozotocin, 3 × 50 mg kg-1 i.v.), hypercholesterolemia (HFD) and CKD (renal embolization), swine were chronically instrumented and studied at rest and during exercise. Sustained hyperglycemia, hypercholesterolemia and renal dysfunction were accompanied by systemic inflammation and oxidative stress. In vivo ROS scavenging (TEMPOL + MPG) reduced myocardial oxygen delivery in DM + HFD + CKD swine, suggestive of a vasodilator influence of endogenous ROS, while it had no effect in Normal swine. In vitro wire myography revealed a vasodilator role for hydrogen peroxide (H2O2) in isolated small coronary artery segments from DM + HFD + CKD, but not Normal swine. Increased catalase activity and ceramide production in left ventricular myocardial tissue of DM + HFD + CKD swine further suggest that increased H2O2 acts as vasodilator ROS in the coronary microvasculature. Despite elevated ET-1 plasma levels in DM + HFD + CKD swine, ETA+B blockade did not affect myocardial oxygen delivery in Normal or DM + HFD + CKD swine. In conclusion, loss of NO bioavailability due to 5 months exposure to multiple comorbidities is partially compensated by increased H2O2-mediated coronary vasodilation.
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Affiliation(s)
- R W A van Drie
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
- Laboratory of Vascular Medicine, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - J van de Wouw
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - L M Zandbergen
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
- Walter Brendel Center of Experimental Medicine (WBex), University Clinic Munich, 81377 LMU, Munich, Germany
| | - J Dehairs
- Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven-University of Leuven, Leuven, Belgium
| | - J V Swinnen
- Laboratory of Lipid Metabolism and Cancer, Department of Oncology, KU Leuven-University of Leuven, Leuven, Belgium
| | - M T Mulder
- Laboratory of Vascular Medicine, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - M C Verhaar
- Department of Nephrology and Hypertension, University Medical Center Utrecht, Utrecht, The Netherlands
| | - A MaassenVanDenBrink
- Laboratory of Vascular Medicine, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - D J Duncker
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - O Sorop
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands
| | - D Merkus
- Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus University Medical Center, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.
- Walter Brendel Center of Experimental Medicine (WBex), University Clinic Munich, 81377 LMU, Munich, Germany.
- Center for Cardiovascular Research (DZHK), Munich Heart Alliance (MHA), Partner Site Munich, 81377, Munich, Germany.
- Interfaculty Center for Endocrine and Cardiovascular Disease Network Modelling and Clinical Transfer (ICONLMU), University Clinic Munich, LMU, Munich, Germany.
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Delcheva G, Stefanova K, Stankova T. Ceramides-Emerging Biomarkers of Lipotoxicity in Obesity, Diabetes, Cardiovascular Diseases, and Inflammation. Diseases 2024; 12:195. [PMID: 39329864 PMCID: PMC11443555 DOI: 10.3390/diseases12090195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/17/2024] [Accepted: 08/23/2024] [Indexed: 09/28/2024] Open
Abstract
Abnormalities in lipid homeostasis have been associated with many human diseases, and the interrelation between lipotoxicity and cellular dysfunction has received significant attention in the past two decades. Ceramides (Cers) are bioactive lipid molecules that serve as precursors of all complex sphingolipids. Besides their function as structural components in cell and mitochondrial membranes, Cers play a significant role as key mediators in cell metabolism and are involved in numerous cellular processes, such as proliferation, differentiation, inflammation, and induction of apoptosis. The accumulation of various ceramides in tissues causes metabolic and cellular disturbances. Recent studies suggest that Cer lipotoxicity has an important role in obesity, metabolic syndrome, type 2 diabetes, atherosclerosis, and cardiovascular diseases (CVDs). In humans, elevated plasma ceramide levels are associated with insulin resistance and impaired cardiovascular and metabolic health. In this review, we summarize the role of ceramides as key mediators of lipotoxicity in obesity, diabetes, cardiovascular diseases, and inflammation and their potential as a promising diagnostic tool.
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Affiliation(s)
- Ginka Delcheva
- Department of Medical Biochemistry, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria
| | - Katya Stefanova
- Department of Medical Biochemistry, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria
| | - Teodora Stankova
- Department of Medical Biochemistry, Faculty of Pharmacy, Medical University of Plovdiv, 4002 Plovdiv, Bulgaria
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10
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Dorweiler TF, Singh A, Ganju A, Lydic TA, Glazer LC, Kolesnick RN, Busik JV. Diabetic retinopathy is a ceramidopathy reversible by anti-ceramide immunotherapy. Cell Metab 2024; 36:1521-1533.e5. [PMID: 38718792 PMCID: PMC11222062 DOI: 10.1016/j.cmet.2024.04.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 03/08/2024] [Accepted: 04/17/2024] [Indexed: 05/16/2024]
Abstract
Diabetic retinopathy is a microvascular disease that causes blindness. Using acid sphingomyelinase knockout mice, we reported that ceramide generation is critical for diabetic retinopathy development. Here, in patients with proliferative diabetic retinopathy, we identify vitreous ceramide imbalance with pathologic long-chain C16-ceramides increasing and protective very long-chain C26-ceramides decreasing. C16-ceramides generate pro-inflammatory/pro-apoptotic ceramide-rich platforms on endothelial surfaces. To geo-localize ceramide-rich platforms, we invented a three-dimensional confocal assay and showed that retinopathy-producing cytokines TNFα and IL-1β induce ceramide-rich platform formation on retinal endothelial cells within seconds, with volumes increasing 2-logs, yielding apoptotic death. Anti-ceramide antibodies abolish these events. Furthermore, intravitreal and systemic anti-ceramide antibodies protect from diabetic retinopathy in standardized rodent ischemia reperfusion and streptozotocin models. These data support (1) retinal endothelial ceramide as a diabetic retinopathy treatment target, (2) early-stage therapy of non-proliferative diabetic retinopathy to prevent progression, and (3) systemic diabetic retinopathy treatment; and they characterize diabetic retinopathy as a "ceramidopathy" reversible by anti-ceramide immunotherapy.
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Affiliation(s)
- Tim F Dorweiler
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Vascular Biology Program, Boston Children's Hospital and Department of Surgery, Harvard Medical School, Boston, MA 02113, USA
| | - Arjun Singh
- Memorial Sloan Kettering Cancer Center, Molecular Pharmacology Program, Sloan Kettering Institute New York, New York, NY 10065, USA
| | - Aditya Ganju
- Memorial Sloan Kettering Cancer Center, Molecular Pharmacology Program, Sloan Kettering Institute New York, New York, NY 10065, USA
| | - Todd A Lydic
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
| | - Louis C Glazer
- Vitreo-Retinal Associates, Grand Rapids, MI 49546, USA; Ophthalmology, Michigan State University, East Lansing, MI 48824, USA
| | - Richard N Kolesnick
- Memorial Sloan Kettering Cancer Center, Molecular Pharmacology Program, Sloan Kettering Institute New York, New York, NY 10065, USA.
| | - Julia V Busik
- Department of Physiology, Michigan State University, East Lansing, MI 48824, USA; Biochemistry and Physiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
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Lee KH, Kang DG, Kim DW, Do HK, Kim DY, Kim W. Piperlongumine regulates genes involved in the skin barrier in epidermal keratinocyte HaCaT cells. Anim Cells Syst (Seoul) 2024; 28:326-339. [PMID: 38933927 PMCID: PMC11207940 DOI: 10.1080/19768354.2024.2361144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 05/22/2024] [Indexed: 06/28/2024] Open
Abstract
Given that the skin is the largest tissue in the human body, performing external barrier functions with innate and adaptive immunity and undergoing substantial changes during aging, it is under investigation as a major target of various bioactive molecules. In the present study, we examined the biological activity of the senolytic piperlongumine by analyzing alterations in mRNA expression of notable skin genes using transformed aneuploid immortal epidermal keratinocytes, HaCaT cells. We observed that piperlongumine increased the mRNA expression of genes playing critical roles in skin barrier function. In addition, piperlongumine increased expression enzymes involved in the synthesis of ceramide, a major component of intercellular lipids. Furthermore, we measured the protein levels of various cytokines secreted by epidermal keratinocytes and found changes in the release of GRO-αβγ, CCL5, and MCP1. Additionally, we observed that piperlongumine treatment modulated the expression of keratinocyte-specific aging markers and influenced telomerase activity. Based on these findings, piperlongumine could regulate the physiological activity of epidermal keratinocytes to induce beneficial effects in human skin by regulating important skin-related genes.
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Affiliation(s)
- Kyung-Ha Lee
- Department of Molecular Biology, Pusan National University, Busan, Korea
| | - Deok Gyeong Kang
- Department of Biochemistry, Department of Convergence Medical Science, and Institute of Medical Sciences, School of Medicine, Gyeongsang National University, Jinju, Korea
| | - Dae-Wook Kim
- Department of Orthopedic Surgery, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Hwan-Kwon Do
- Department of Physical Medicine and Rehabilitation, Cancer Center, Dongnam Institute of Radiological & Medical Sciences, Busan, Korea
| | - Do-Yeon Kim
- Department of Pharmacology, School of Dentistry, Kyungpook National University, Daegu, Korea
| | - Wanil Kim
- Department of Biochemistry, Department of Convergence Medical Science, and Institute of Medical Sciences, School of Medicine, Gyeongsang National University, Jinju, Korea
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12
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Mangal N, Reebye V, Habib N, Sodergren MH. Cannabidiol's cytotoxicity in pancreatic cancer is induced via an upregulation of ceramide synthase 1 and ER stress. J Cannabis Res 2024; 6:22. [PMID: 38720356 PMCID: PMC11077855 DOI: 10.1186/s42238-024-00227-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Accepted: 03/18/2024] [Indexed: 05/12/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive malignancies with a median 5 year-survival rate of 12%. Cannabidiol (CBD) has been found to exhibit antineoplastic potential and may potentiate the anticancer effects of cytotoxic's such as gemcitabine. CBD therapy has been linked to de novo synthesis of ceramide. The sphingolipid ceramide is a potent tumour suppressor lipid with roles in apoptosis and autophagy. One of the key players involved is ceramide synthase, an enzyme with six isoforms (CerS1-CerS6), reported to have disease prognostic value. Quantitative real time PCR was used to determine mRNA expression levels of ceramide synthase isoforms, GRP78, ATF4 and CHOP. Western blotting was used to analyze protein expression of these markers and knockdown of CerS1 and GRP78 were applied via an siRNA and confirmed by the two mentioned methods. Mice with PDAC xenografts were injected via intraperitoneal method with drugs and tumours were analysed with flow cytometry and processed using H&E and IHC staining. siRNA knockdown of ceramide synthase 1 (CerS1) and analysis point to evidence of a putative CerS1 dependent pathway driven by CBD in activating endoplasmic reticulum (ER) stress target; GRP78. Upon CBD treatment, CerS1 was upregulated and downstream this led to the GRP78/ATF4/CHOP arm of the unfolded protein response (UPR) pathway being activated. In an in vivo model of PDAC in which CerS1 was not upregulated on IHC, there was no observed improvement in survival of animals, however a reduction in tumour growth was observed in combination chemotherapy and CBD group, indicating further investigations in vivo. These findings provide evidence of a potential ceramide induced cytotoxic mechanism of action of CBD in pancreatic ductal adenocarcinoma.
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Affiliation(s)
- Nagina Mangal
- Medical Cannabis Research Group, Department of Surgery and Cancer, Imperial College London, London, W12 0NN, UK.
- Systems and Precision Cancer Medicine Team, Division of Molecular Pathology, Institute of Cancer Research, Sutton, SM2 5NG, UK.
| | - Vikash Reebye
- Medical Cannabis Research Group, Department of Surgery and Cancer, Imperial College London, London, W12 0NN, UK
| | - Nagy Habib
- Medical Cannabis Research Group, Department of Surgery and Cancer, Imperial College London, London, W12 0NN, UK
| | - Mikael H Sodergren
- Medical Cannabis Research Group, Department of Surgery and Cancer, Imperial College London, London, W12 0NN, UK
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13
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Jacobs J, Iranpour R, Behrooz AB, da Silva Rosa SC, Ghavami S. The role of BCL2L13 in glioblastoma: turning a need into a target. Biochem Cell Biol 2024; 102:127-134. [PMID: 37988705 DOI: 10.1139/bcb-2023-0221] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2023] Open
Abstract
Glioblastoma (GBM) is the most common aggressive central nervous system cancer. GBM has a high mortality rate, with a median survival time of 12-15 months after diagnosis. A poor prognosis and a shorter life expectancy may result from resistance to standard treatments such as radiation and chemotherapy. Temozolomide has been the mainstay treatment for GBM, but unfortunately, there are high rates of resistance with GBM bypassing apoptosis. A proposed mechanism for bypassing apoptosis is decreased ceramide levels, and previous research has shown that within GBM cells, B cell lymphoma 2-like 13 (BCL2L13) can inhibit ceramide synthase. This review aims to discuss the causes of resistance in GBM cells, followed by a brief description of BCL2L13 and an explanation of its mechanism of action. Further, lipids, specifically ceramide, will be discussed concerning cancer and GBM cells, focusing on ceramide synthase and its role in developing GBM. By gathering all current information on BCL2L13 and ceramide synthase, this review seeks to enable an understanding of these pieces of GBM in the hope of finding an effective treatment for this disease.
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Affiliation(s)
- Joadi Jacobs
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - Rosa Iranpour
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - Amir Barzegar Behrooz
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
- Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Simone C da Silva Rosa
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada
- Research Institute of Hematology and Oncology, Cancer Care Manitoba, Winnipeg, MB R3E 0V9, Canada
- Faculty of Medicine in Zabrze, University of Technology in Katowice, Academia of Silesia, 41-800 Zabrze, Poland
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14
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Wang J, Zheng G, Wang L, Meng L, Ren J, Shang L, Li D, Bao Y. Dysregulation of sphingolipid metabolism in pain. Front Pharmacol 2024; 15:1337150. [PMID: 38523645 PMCID: PMC10957601 DOI: 10.3389/fphar.2024.1337150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2023] [Accepted: 02/27/2024] [Indexed: 03/26/2024] Open
Abstract
Pain is a clinical condition that is currently of great concern and is often caused by tissue or nerve damage or occurs as a concomitant symptom of a variety of diseases such as cancer. Severe pain seriously affects the functional status of the body. However, existing pain management programs are not fully satisfactory. Therefore, there is a need to delve deeper into the pathological mechanisms underlying pain generation and to find new targets for drug therapy. Sphingolipids (SLs), as a major component of the bilayer structure of eukaryotic cell membranes, also have powerful signal transduction functions. Sphingolipids are abundant, and their intracellular metabolism constitutes a huge network. Sphingolipids and their various metabolites play significant roles in cell proliferation, differentiation, apoptosis, etc., and have powerful biological activities. The molecules related to sphingolipid metabolism, mainly the core molecule ceramide and the downstream metabolism molecule sphingosine-1-phosphate (S1P), are involved in the specific mechanisms of neurological disorders as well as the onset and progression of various types of pain, and are closely related to a variety of pain-related diseases. Therefore, sphingolipid metabolism can be the focus of research on pain regulation and provide new drug targets and ideas for pain.
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Affiliation(s)
- Jianfeng Wang
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Guangda Zheng
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Linfeng Wang
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Linghan Meng
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Juanxia Ren
- Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning Province, China
| | - Lu Shang
- Liaoning University of Traditional Chinese Medicine, Shenyang, Liaoning Province, China
| | - Dongtao Li
- Department of Oncology, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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15
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Bae JC, Wander PL, Lemaitre RN, Fretts AM, Sitlani CM, Bui HH, Thomas MK, Leonetti D, Fujimoto WY, Boyko EJ, Utzschneider KM. Associations of plasma sphingolipids with measures of insulin sensitivity, β-cell function, and incident diabetes in Japanese Americans. Nutr Metab Cardiovasc Dis 2024; 34:633-641. [PMID: 38161124 PMCID: PMC10922320 DOI: 10.1016/j.numecd.2023.10.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 10/18/2023] [Accepted: 10/23/2023] [Indexed: 01/03/2024]
Abstract
BACKGROUND AND AIMS To prospectively investigate associations of plasma sphingolipids with insulin sensitivity, β-cell function, and incident diabetes in the Japanese American Community Diabetes Study. METHODS AND RESULTS Baseline plasma samples from adults without diabetes (n = 349; mean age 56.7 years, 51 % men) were assayed for circulating ceramide and sphingomyelin species. Adjusted regression models examined cross-sectional and longitudinal associations with insulin sensitivity (HOMA2-%S), β-cell function (oral disposition index: DIo) and with incident diabetes over 5 years follow-up. Concentrations of four species (Ceramide C16:0, C18:0, C20:0, and C22:0) were inversely associated with HOMA2-%S at baseline (all P values < 0.05, Q values < 0.05) and change in HOMA2-%S over 5 years (all P values < 0.05, Q values < 0.05). No sphingolipids were associated with baseline or change in DIo. Of the four species associated with HOMA2-%S, only Ceramide C18:0 was significantly and positively associated with incident diabetes (RR/1SD 1.44, 95 % CI 1.10-1.80, P = 0.006, Q = 0.024). The association of plasma Ceramide C18:0 with the risk of diabetes was partially mediated by change in HOMA2-%S between baseline and 5 years (mediation proportion: 61.5 %, 95 % CI 21.1%-212.5 %). CONCLUSION Plasma Ceramide C18:0 was associated with higher risk of incident diabetes which was partially mediated through a decrease in insulin sensitivity between baseline and five years. Circulating Ceramide C18:0 could be a potential biomarker for identifying those at risk of developing diabetes.
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Affiliation(s)
- Ji Cheol Bae
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, South Korea
| | - Pandora L Wander
- Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States
| | - Rozenn N Lemaitre
- Department of Medicine, University of Washington, Seattle, WA, United States
| | - Amanda M Fretts
- Department of Epidemiology, University of Washington, Seattle, WA, United States
| | - Colleen M Sitlani
- Department of Medicine, University of Washington, Seattle, WA, United States
| | - Hai H Bui
- Eli Lilly and Company, Indianapolis, IN, United States
| | | | - Donna Leonetti
- Department of Anthropology, University of Washington, Seattle, WA, United States
| | - Wilfred Y Fujimoto
- Department of Medicine, University of Washington, Seattle, WA, United States
| | - Edward J Boyko
- Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States; Department of Medicine, University of Washington, Seattle, WA, United States
| | - Kristina M Utzschneider
- Veterans Affairs Puget Sound Health Care System, Seattle, WA, United States; Department of Medicine, University of Washington, Seattle, WA, United States.
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16
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Xie T, Fang Q, Zhang Z, Wang Y, Dong F, Gong X. Structure and mechanism of a eukaryotic ceramide synthase complex. EMBO J 2023; 42:e114889. [PMID: 37953642 PMCID: PMC10711658 DOI: 10.15252/embj.2023114889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2023] [Revised: 10/20/2023] [Accepted: 10/24/2023] [Indexed: 11/14/2023] Open
Abstract
Ceramide synthases (CerS) catalyze ceramide formation via N-acylation of a sphingoid base with a fatty acyl-CoA and are attractive drug targets for treating numerous metabolic diseases and cancers. Here, we present the cryo-EM structure of a yeast CerS complex, consisting of a catalytic Lac1 subunit and a regulatory Lip1 subunit, in complex with C26-CoA substrate. The CerS holoenzyme exists as a dimer of Lac1-Lip1 heterodimers. Lac1 contains a hydrophilic reaction chamber and a hydrophobic tunnel for binding the CoA moiety and C26-acyl chain of C26-CoA, respectively. Lip1 interacts with both the transmembrane region and the last luminal loop of Lac1 to maintain the proper acyl chain binding tunnel. A lateral opening on Lac1 serves as a potential entrance for the sphingoid base substrate. Our findings provide a template for understanding the working mechanism of eukaryotic ceramide synthases and may facilitate the development of therapeutic CerS modulators.
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Affiliation(s)
- Tian Xie
- Department of Chemical Biology, School of Life SciencesSouthern University of Science and TechnologyShenzhenChina
| | - Qi Fang
- Department of Chemical Biology, School of Life SciencesSouthern University of Science and TechnologyShenzhenChina
| | - Zike Zhang
- Department of Chemical Biology, School of Life SciencesSouthern University of Science and TechnologyShenzhenChina
| | - Yanfei Wang
- Department of Chemical Biology, School of Life SciencesSouthern University of Science and TechnologyShenzhenChina
| | - Feitong Dong
- Department of Chemical Biology, School of Life SciencesSouthern University of Science and TechnologyShenzhenChina
| | - Xin Gong
- Department of Chemical Biology, School of Life SciencesSouthern University of Science and TechnologyShenzhenChina
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17
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Koutsogiannis Z, Mina JG, Albus CA, Kol MA, Holthuis JM, Pohl E, Denny PW. Toxoplasma ceramide synthases: Gene duplication, functional divergence, and roles in parasite fitness. FASEB J 2023; 37:e23229. [PMID: 37795915 PMCID: PMC10946778 DOI: 10.1096/fj.202201603rrr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Revised: 08/16/2023] [Accepted: 09/18/2023] [Indexed: 10/06/2023]
Abstract
Toxoplasma gondii is an obligate, intracellular apicomplexan protozoan parasite of both humans and animals that can cause fetal damage and abortion and severe disease in the immunosuppressed. Sphingolipids have indispensable functions as signaling molecules and are essential and ubiquitous components of eukaryotic membranes that are both synthesized and scavenged by the Apicomplexa. Ceramide is the precursor for all sphingolipids, and here we report the identification, localization and analyses of the Toxoplasma ceramide synthases TgCerS1 and TgCerS2. Interestingly, we observed that while TgCerS1 was a fully functional orthologue of the yeast ceramide synthase (Lag1p) capable of catalyzing the conversion of sphinganine to ceramide, in contrast TgCerS2 was catalytically inactive. Furthermore, genomic deletion of TgCerS1 using CRISPR/Cas-9 led to viable but slow-growing parasites indicating its importance but not indispensability. In contrast, genomic knock out of TgCerS2 was only accessible utilizing the rapamycin-inducible Cre recombinase system. Surprisingly, the results demonstrated that this "pseudo" ceramide synthase, TgCerS2, has a considerably greater role in parasite fitness than its catalytically active orthologue (TgCerS1). Phylogenetic analyses indicated that, as in humans and plants, the ceramide synthase isoforms found in Toxoplasma and other Apicomplexa may have arisen through gene duplication. However, in the Apicomplexa the duplicated copy is hypothesized to have subsequently evolved into a non-functional "pseudo" ceramide synthase. This arrangement is unique to the Apicomplexa and further illustrates the unusual biology that characterize these protozoan parasites.
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Affiliation(s)
| | - John G. Mina
- Department of BiosciencesDurham UniversityDurhamUK
| | | | - Matthijs A. Kol
- Molecular Cell Biology Division, Department of Biology/ChemistryUniversity of OsnabrückOsnabrückGermany
| | - Joost C. M. Holthuis
- Molecular Cell Biology Division, Department of Biology/ChemistryUniversity of OsnabrückOsnabrückGermany
| | - Ehmke Pohl
- Department of BiosciencesDurham UniversityDurhamUK
- Department of ChemistryDurham UniversityDurhamUK
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18
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Yu B, Hu M, Jiang W, Ma Y, Ye J, Wu Q, Guo W, Sun Y, Zhou M, Xu Y, Wu Z, Wang Y, Lam SM, Shui G, Gu J, Li JZ, Fu Z, Gong Y, Zhou H. Ceramide d18:1/24:1 as a potential biomarker to differentiate obesity subtypes with unfavorable health outcomes. Lipids Health Dis 2023; 22:166. [PMID: 37794463 PMCID: PMC10548646 DOI: 10.1186/s12944-023-01921-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Accepted: 09/11/2023] [Indexed: 10/06/2023] Open
Abstract
BACKGROUND The criteria for metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO) remain controversial. This research aimed to identify a potential biomarker to differentiate the subtypes of obesity. METHODS The study conducted a lipidomic evaluation of ceramide in the serum of 77 Chinese adults who had undergone hyperinsulinemic-euglycemic clamps. These adults were divided into three groups according to the clinical data: normal weight control group (N = 21), MHO (N = 20), and MUO (N = 36). RESULTS The serum Cer d18:1/24:1 level in the MHO group was lower than that in the MUO group. As the Cer d18:1/24:1 level increased, insulin sensitivity decreased, and the unfavorable parameters increased in parallel. Multivariate logistic regression analysis revealed that serum Cer d18:1/24:1 levels were independently correlated with MUO in obesity. Individuals with higher levels of Cer d18:1/24:1 also had an elevated risk of cardiovascular disease. Most ceramide subtype levels increased in obesity compared to normal-weight individuals, but the levels of serum Cer d18:0/18:0 and Cer d18:1/16:0 decreased in obesity. CONCLUSIONS The relationships between ceramide subtypes and metabolic profiles might be heterogeneous in populations with different body weights. Cer d18:1/24:1 could be a biomarker that can be used to differentiate MUO from MHO, and to better predict who will develop unfavorable health outcomes among obese individuals. TRIAL REGISTRATION The First Affiliated Hospital of Nanjing Medical University's Institutional Review Board authorized this study protocol, and all participants provided written informed consent (2014-SR-003) prior to study entry.
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Affiliation(s)
- Baowen Yu
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Moran Hu
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wanzi Jiang
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yizhe Ma
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Jingya Ye
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Qinyi Wu
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Wen Guo
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yan Sun
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Min Zhou
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yiwen Xu
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhoulu Wu
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Yiwen Wang
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Sin Man Lam
- Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Guanghou Shui
- Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China
| | - Jingyu Gu
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - John Zhong Li
- Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
| | - Zhenzhen Fu
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Yingyun Gong
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
| | - Hongwen Zhou
- Department of Endocrinology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
- Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China.
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19
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Lidgard B, Bansal N, Zelnick LR, Hoofnagle AN, Fretts AM, Longstreth WT, Shlipak MG, Siscovick DS, Umans JG, Lemaitre RN. Evaluation of plasma sphingolipids as mediators of the relationship between kidney disease and cardiovascular events. EBioMedicine 2023; 95:104765. [PMID: 37634384 PMCID: PMC10474367 DOI: 10.1016/j.ebiom.2023.104765] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 08/04/2023] [Accepted: 08/06/2023] [Indexed: 08/29/2023] Open
Abstract
BACKGROUND Sphingolipids are a family of circulating lipids with regulatory and signaling roles that are strongly associated with both eGFR and cardiovascular disease. Patients with chronic kidney disease (CKD) are at high risk for cardiovascular events, and have different plasma concentrations of certain plasma sphingolipids compared to patients with normal kidney function. We hypothesize that circulating sphingolipids partially mediate the associations between eGFR and cardiovascular events. METHODS We measured the circulating concentrations of 8 sphingolipids, including 4 ceramides and 4 sphingomyelins with the fatty acids 16:0, 20:0, 22:0, and 24:0, in plasma from 3,463 participants in a population-based cohort (Cardiovascular Health Study) without prevalent cardiovascular disease. We tested the adjusted mediation effects by these sphingolipids of the associations between eGFR and incident cardiovascular disease via quasi-Bayesian Monte Carlo method with 2,000 simulations, using a Bonferroni correction for significance. FINDINGS The mean (±SD) eGFR was 70 (±16) mL/min/1.73 m2; 62% of participants were women. Lower eGFR was associated with higher plasma ceramide-16:0 and sphingomyelin-16:0, and lower ceramides and sphingomyelins-20:0 and -22:0. Lower eGFR was associated with risk of incident heart failure and ischemic stroke, but not myocardial infarction. Five of eight sphingolipids partially mediated the association between eGFR and heart failure. The sphingolipids associated with the greatest proportion mediated were ceramide-16:0 (proportion mediated 13%, 95% CI 8-22%) and sphingomyelin-16:0 (proportion mediated 10%, 95% CI 5-17%). No sphingolipids mediated the association between eGFR and ischemic stroke. INTERPRETATION Plasma sphingolipids partially mediated the association between lower eGFR and incident heart failure. Altered sphingolipids metabolism may be a novel mechanism for heart failure in patients with CKD. FUNDING This study was supported by T32 DK007467 and a KidneyCure Ben J. Lipps Research Fellowship (Dr. Lidgard). Sphingolipid measurements were supported by R01 HL128575 (Dr. Lemaitre) and R01 HL111375 (Dr. Hoofnagle) from the National Heart, Lung, and Blood Institute (NHLBI).
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Affiliation(s)
- Benjamin Lidgard
- Department of Medicine, University of Washington, United States.
| | - Nisha Bansal
- Department of Medicine, University of Washington, United States
| | - Leila R Zelnick
- Department of Medicine, University of Washington, United States
| | | | - Amanda M Fretts
- Department of Medicine, University of Washington, United States
| | | | - Michael G Shlipak
- Kidney Health Research Collaborative, San Francisco Veterans Affairs Healthcare System and University of California San Francisco, United States
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20
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Rigamonti AE, Dei Cas M, Caroli D, Bondesan A, Cella SG, Paroni R, Sartorio A. Ceramide Risk Score in the Evaluation of Metabolic Syndrome: An Additional or Substitutive Biochemical Marker in the Clinical Practice? Int J Mol Sci 2023; 24:12452. [PMID: 37569827 PMCID: PMC10420317 DOI: 10.3390/ijms241512452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Revised: 08/01/2023] [Accepted: 08/02/2023] [Indexed: 08/13/2023] Open
Abstract
Ceramide risk score (CERT1, ceramide test 1), based on specific ceramides (Cers) and their corresponding ratios in the plasma, has been reported as a promising biochemical marker for primary and secondary prediction of cardiovascular disease (CVD) risk in different populations of patients. Thus far, limited attention has been paid to metabolic syndrome, a condition considered at high CVD risk. The aim of the present study was to evaluate CERT1 in a group of obese subjects without (OB-MetS-) and with (OB-MetS+) metabolic syndrome (according to the International Diabetes Federation (IDF) diagnostic criteria), compared to an age- and sex-matched normal-weight (NW) group. In all participants, plasma levels of Cer 16:0, Cer 18:0, Cer 24:1, and Cer 24:0 were measured, and the corresponding ratios Cer 16:0/24:0, Cer 18:0/24:0, and Cer 24:1/24:0 were calculated together with CERT1. Subjects with obesity showed higher CERT1 values than the NW group (p < 0.05), with no difference between OB-MetS- and OB-MetS+ groups. Waist circumference (WC), homeostatic model assessment of insulin-resistance (HOMA-IR) (surrogates of IDF diagnostic criteria for metabolic syndrome), and C reactive protein (CRP) (a marker of inflammation) were predictors of CERT1 (p < 0.05), with the contribution of the other IDF criteria such as arterial hypertension and dyslipidemia being negligible. Adjustment for WC resulted in a loss of the difference in CERT1 between OB-MetS- and NW subjects, with the combination of WC and HOMA-IR or CRP as covariates being necessary to yield the same effect for the difference in CERT1 between OB-MetS+ and NW subjects. Importantly, an association was found between CERT1 and vascular age (VA) (p < 0.05). Proportions of NW, OB-MetS- and OB-MetS+ subjects appeared to be distributed according to the CERT1-based risk groups (i.e., low, moderate, increased, and high risk; p < 0.05), with some OB-MetS- subjects included in the increased/high-risk group and some OB-MetS+ in the low/moderate-risk one. In conclusion, the clinical diagnosis of metabolic syndrome seems to be inaccurate to assess CVD risk in the obese population; however, further studies are needed before considering CERT1 as an additional or substitutive biochemical marker in clinical practice.
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Affiliation(s)
- Antonello E. Rigamonti
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20129 Milan, Italy;
| | - Michele Dei Cas
- Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy; (M.D.C.); (R.P.)
| | - Diana Caroli
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy; (D.C.); (A.B.); (A.S.)
| | - Adele Bondesan
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy; (D.C.); (A.B.); (A.S.)
| | - Silvano G. Cella
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20129 Milan, Italy;
| | - Rita Paroni
- Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy; (M.D.C.); (R.P.)
| | - Alessandro Sartorio
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy; (D.C.); (A.B.); (A.S.)
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 20145 Milan, Italy
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21
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Xiao N, Zhang T, Han M, Tian D, Liu J, Li S, Yang L, Pan G. Chlorogenic Acid Inhibits Ceramide Accumulation to Restrain Hepatic Glucagon Response. Nutrients 2023; 15:3173. [PMID: 37513589 PMCID: PMC10384019 DOI: 10.3390/nu15143173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/05/2023] [Accepted: 07/13/2023] [Indexed: 07/30/2023] Open
Abstract
Chlorogenic acid (CGA), a dietary natural phenolic acid, has been widely reported to regulate glucose and lipid metabolism. However, the protective effects and the underlying mechanisms of CGA on glucagon-induced hepatic glucose production remain largely uncharacterized. Herein, we investigated the efficacy of CGA on hepatic gluconeogenesis both in vivo and in vitro. The elevated levels of endogenous glucose production induced by infusion of glucagon or pyruvate were lowered in mice administered with CGA. Furthermore, chronic CGA treatment ameliorated the accumulation of glucose and ceramide in high-fat diet (HFD)-fed mice. CGA also attenuated HFD-fed-induced inflammation response. The protective effect of CGA on glucose production was further confirmed in primary mouse hepatocytes by inhibiting accumulation of ceramide and expression of p38 MAPK. Moreover, CGA administration in HFD-fed mice preserved the decreased phosphorylation of Akt in the liver, resulting in the inhibition of FoxO1 activation and, ultimately, hepatic gluconeogenesis. However, these protective effects were significantly attenuated by the addition of C2 ceramide. These results suggest that CGA inhibits ceramide accumulation to restrain hepatic glucagon response.
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Affiliation(s)
- Na Xiao
- College of Agronomy, Shandong Agriculture University, Tai'an 271018, China
| | - Tengfei Zhang
- College of Agronomy, Shandong Agriculture University, Tai'an 271018, China
| | - Mingli Han
- College of Agronomy, Shandong Agriculture University, Tai'an 271018, China
| | - Dan Tian
- College of Agronomy, Shandong Agriculture University, Tai'an 271018, China
| | - Jiawei Liu
- College of Agronomy, Shandong Agriculture University, Tai'an 271018, China
| | - Shan Li
- College of Agronomy, Shandong Agriculture University, Tai'an 271018, China
| | - Lele Yang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China
| | - Guojun Pan
- College of Life Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an 271000, China
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22
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Ren L, Li F, Tan X, Fan Y, Ke B, Zhang Y, Jiang H, Jia L, Wang Y, Du J. Abnormal plasma ceramides refine high-risk patients with worsening heart failure. Front Cardiovasc Med 2023; 10:1185595. [PMID: 37456812 PMCID: PMC10339027 DOI: 10.3389/fcvm.2023.1185595] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 06/13/2023] [Indexed: 07/18/2023] Open
Abstract
Background Worsening heart failure (WHF) is a heterogeneous clinical syndrome with poor prognosis. More effective risk stratification tools are required to identify high-risk patients. Evidence suggest that aberrant ceramide accumulation can be affected by heart failure risk factors and as a driver of tissue damage. We hypothesized that specific ceramide lengths and ratios serve as biomarkers for risk stratification in WHF patients by reflecting pathological changes of distinct organ dysfunctions. Medthods We measured seven plasma ceramides using liquid chromatography-mass spectrometry (LC-MS) in 1,558 patients, including 1,262 participants in retrospective discovery set and 296 WHF patients in prospective validation set in BIOMS-HF study (Registry Study of Biomarkers in Heart Failure). Univariable and multivariable logistic regression models were constructed to identify associations of ceramides with organ dysfunctions. Results We constructed three ceramide-based scores linked independently to heart, liver, and kidney dysfunction, with ceramides and ratios included in each score specifying systemic inflammation, chronic metabolic disorder, and water-sodium retention. The combined ceramide heart failure score (CHFS) was independently associated with adverse outcomes [Hazard Ratio, 2.80 (95% CI: 1.78-4.40; P < 0.001); 2.68 995% CI: 1.12-6.46; P = 0.028)] and improved the predictive value of Acute Decompensated Heart Failure National Registry score and BNP [net reclassification index, 0.34 (95% confidence interval, CI: 0.19-0.50); 0.42 (95% CI: 0.13-0.70)] in the discovery and validation set, respectively. Lower BNP levels, but higher CHFS had the highest hazard of future adverse events in WHF patients. Conclusion Abnormal plasma ceramides, associated with heart and peripheral organ dysfunctions, provide incremental prognostic information over the ADHERE score and brain natriuretic peptide concentration for risk stratification in WHF patients. This may facilitate the reclassification of high-risk patients in need of aggressive therapeutic interventions.
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Affiliation(s)
- Lu Ren
- Beijing Collaborative Innovation Centre for Cardiovascular Disorders, The Key Laboratory of Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- Beijing lnstitute of Heart, Lung, and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Fengjuan Li
- Beijing Collaborative Innovation Centre for Cardiovascular Disorders, The Key Laboratory of Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- Beijing lnstitute of Heart, Lung, and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Xin Tan
- Beijing Collaborative Innovation Centre for Cardiovascular Disorders, The Key Laboratory of Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- Beijing lnstitute of Heart, Lung, and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Yangkai Fan
- Beijing Collaborative Innovation Centre for Cardiovascular Disorders, The Key Laboratory of Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- Beijing lnstitute of Heart, Lung, and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Bingbing Ke
- Department of Cardiology, Cardiovascular Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Yixin Zhang
- Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universitat Munchen (LMU), Munich, Germany
| | - Hongfeng Jiang
- Beijing Collaborative Innovation Centre for Cardiovascular Disorders, The Key Laboratory of Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- Beijing lnstitute of Heart, Lung, and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Lixin Jia
- Beijing Collaborative Innovation Centre for Cardiovascular Disorders, The Key Laboratory of Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- Beijing lnstitute of Heart, Lung, and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Yuan Wang
- Beijing Collaborative Innovation Centre for Cardiovascular Disorders, The Key Laboratory of Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- Beijing lnstitute of Heart, Lung, and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
| | - Jie Du
- Beijing Collaborative Innovation Centre for Cardiovascular Disorders, The Key Laboratory of Remodeling-Related Cardiovascular Disease, Ministry of Education, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
- Beijing lnstitute of Heart, Lung, and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital Medical University, Beijing, China
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SenthilKumar G, Katunaric B, Zirgibel Z, Lindemer B, Jaramillo-Torres MJ, Bordas-Murphy H, Schulz ME, Pearson PJ, Freed JK. Necessary Role of Acute Ceramide Formation in The Human Microvascular Endothelium During Health and Disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.06.02.543341. [PMID: 37333082 PMCID: PMC10274701 DOI: 10.1101/2023.06.02.543341] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/20/2023]
Abstract
Background Elevated plasma ceramides independently predict adverse cardiac events and we have previously shown that exposure to exogenous ceramide induces microvascular endothelial dysfunction in arterioles from otherwise healthy adults (0-1 risk factors for heart disease). However, evidence also suggests that activation of the shear-sensitive, ceramide forming enzyme neutral sphingomyelinase (NSmase) enhances vasoprotective nitric oxide (NO) production. Here we explore a novel hypothesis that acute ceramide formation through NSmase is necessary for maintaining NO signaling within the human microvascular endothelium. We further define the mechanism through which ceramide exerts beneficial effects and discern key mechanistic differences between arterioles from otherwise healthy adults and patients with coronary artery disease (CAD). Methods Human arterioles were dissected from otherwise discarded surgical adipose tissue (n=123), and vascular reactivity to flow and C2-ceramide was assessed. Shear-induced NO production was measured in arterioles using fluorescence microscopy. Hydrogen peroxide (H2O2) fluorescence was assessed in isolated human umbilical vein endothelial cells. Results Inhibition of NSmase in arterioles from otherwise healthy adults induced a switch from NO to H2O2-mediated flow-induced dilation within 30 minutes. In endothelial cells, NSmase inhibition acutely increased H2O2 production. Endothelial dysfunction in both models was prevented by treatment with C2-ceramide, S1P, and an agonist of S1P-receptor 1 (S1PR1), while the inhibition of S1P/S1PR1 signaling axis induced endothelial dysfunction. Ceramide increased NO production in arterioles from healthy adults, an effect that was diminished with inhibition of S1P/S1PR1/S1PR3 signaling. In arterioles from patients with CAD, inhibition of NSmase impaired dilation to flow. This effect was not restored with exogenous S1P. Although, inhibition of S1P/S1PR3 signaling impaired normal dilation to flow. Acute ceramide administration to arterioles from patients with CAD also promoted H2O2 as opposed to NO production, an effect dependent on S1PR3 signaling. Conclusion These data suggest that despite key differences in downstream signaling between health and disease, acute NSmase-mediated ceramide formation and its subsequent conversion to S1P is necessary for proper functioning of the human microvascular endothelium. As such, therapeutic strategies that aim to significantly lower ceramide formation may prove detrimental to the microvasculature.
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Affiliation(s)
- Gopika SenthilKumar
- Department of Physiology, Medical College of Wisconsin
- Cardiovasular Center, Medical College of Wisconsin
- Department of Anesthesiology, Medical College of Wisconsin
| | | | - Zachary Zirgibel
- Cardiovasular Center, Medical College of Wisconsin
- Department of Anesthesiology, Medical College of Wisconsin
| | - Brian Lindemer
- Cardiovasular Center, Medical College of Wisconsin
- Department of Anesthesiology, Medical College of Wisconsin
| | - Maria J. Jaramillo-Torres
- Cardiovasular Center, Medical College of Wisconsin
- Department of Anesthesiology, Medical College of Wisconsin
| | - Henry Bordas-Murphy
- Cardiovasular Center, Medical College of Wisconsin
- Department of Anesthesiology, Medical College of Wisconsin
| | - Mary E. Schulz
- Cardiovasular Center, Medical College of Wisconsin
- Department of Anesthesiology, Medical College of Wisconsin
| | - Paul J. Pearson
- Department of Surgery, Division of Cardiothoracic Surgery, Medical College of Wisconsin
| | - Julie K. Freed
- Department of Physiology, Medical College of Wisconsin
- Cardiovasular Center, Medical College of Wisconsin
- Department of Anesthesiology, Medical College of Wisconsin
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24
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Gautam J, Kumari D, Aggarwal H, Gupta SK, Kasarla SS, Sarkar S, Priya MRK, Kamboj P, Kumar Y, Dikshit M. Characterization of lipid signatures in the plasma and insulin-sensitive tissues of the C57BL/6J mice fed on obesogenic diets. Biochim Biophys Acta Mol Cell Biol Lipids 2023:159348. [PMID: 37285928 DOI: 10.1016/j.bbalip.2023.159348] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 05/23/2023] [Accepted: 05/29/2023] [Indexed: 06/09/2023]
Abstract
Diet-induced obesity mouse models are widely utilized to investigate the underlying mechanisms of dyslipidemia, glucose intolerance, insulin resistance, hepatic steatosis, and type 2 diabetes mellitus (T2DM), as well as for screening potential drug compounds. However, there is limited knowledge regarding specific signature lipids that accurately reflect dietary disorders. In this study, we aimed to identify key lipid signatures using LC/MS-based untargeted lipidomics in the plasma, liver, adipose tissue (AT), and skeletal muscle tissues (SKM) of male C57BL/6J mice that were fed chow, LFD, or obesogenic diets (HFD, HFHF, and HFCD) for a duration of 20 weeks. Furthermore, we conducted a comprehensive lipid analysis to assess similarities and differences with human lipid profiles. The mice fed obesogenic diets exhibited weight gain, glucose intolerance, elevated BMI, glucose and insulin levels, and a fatty liver, resembling characteristics of T2DM and obesity in humans. In total, we identified approximately 368 lipids in plasma, 433 in the liver, 493 in AT, and 624 in SKM. Glycerolipids displayed distinct patterns across the tissues, differing from human findings. However, changes in sphingolipids, phospholipids, and the expression of inflammatory and fibrotic genes showed similarities to reported human findings. Significantly modulated pathways in the obesogenic diet-fed groups included ceramide de novo synthesis, sphingolipid remodeling, and the carboxylesterase pathway, while lipoprotein-mediated pathways were minimally affected.
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Affiliation(s)
- Jyoti Gautam
- Non-communicable Disease Centre, Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, Haryana, India
| | - Deepika Kumari
- Non-communicable Disease Centre, Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, Haryana, India
| | - Hobby Aggarwal
- Non-communicable Disease Centre, Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, Haryana, India
| | - Sonu Kumar Gupta
- Non-communicable Disease Centre, Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, Haryana, India
| | - Siva Swapna Kasarla
- Non-communicable Disease Centre, Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, Haryana, India
| | - Soumalya Sarkar
- Non-communicable Disease Centre, Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, Haryana, India
| | - M R Kamla Priya
- Non-communicable Disease Centre, Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, Haryana, India
| | - Parul Kamboj
- Non-communicable Disease Centre, Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, Haryana, India
| | - Yashwant Kumar
- Non-communicable Disease Centre, Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, Haryana, India.
| | - Madhu Dikshit
- Non-communicable Disease Centre, Translational Health Science and Technology Institute (THSTI), NCR Biotech Science Cluster, 3rd Milestone, Faridabad 121001, Haryana, India.
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25
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Hurley LD, Lee H, Wade G, Simcox J, Engin F. Ormdl3 regulation of specific ceramides is dispensable for mouse β-cell function and glucose homeostasis under obesogenic conditions. Front Endocrinol (Lausanne) 2023; 14:1170461. [PMID: 37124760 PMCID: PMC10140491 DOI: 10.3389/fendo.2023.1170461] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 03/31/2023] [Indexed: 05/02/2023] Open
Abstract
Chronic elevation of sphingolipids contributes to β-cell failure. ORMDL3 has been identified as a key regulator of sphingolipid homeostasis, however, its function in pancreatic β-cell pathophysiology remains unclear. Here, we generated a mouse model lacking Ormdl3 within pancreatic β-cells (Ormdl3 β-/-). We show that loss of β-cell Ormdl3 does not alter glucose tolerance, insulin sensitivity, insulin secretion, islet morphology, or cellular ceramide levels on standard chow diet. When challenged with a high fat diet, while Ormdl3 β-/- mice did not exhibit any alteration in metabolic parameters or islet architecture, lipidomics analysis revealed significantly higher levels of very long chain ceramides in their islets. Taken together, our results reveal that loss of Ormdl3 alone is not sufficient to impinge upon β-cell function or whole-body glucose and insulin homeostasis, however, β-cell-specific loss of Ormdl3 does significantly alter levels of specific sphingolipid species in islets upon high fat feeding.
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Affiliation(s)
- Liam D. Hurley
- Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
| | - Hugo Lee
- Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
| | - Gina Wade
- Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, WI, United States
| | - Judith Simcox
- Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, WI, United States
| | - Feyza Engin
- Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
- Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, United States
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26
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Rahimi S, Angaji SA, Majd A, Hatami B, Baghaei K. Evaluating the effect of basic fibroblast growth factor on the progression of NASH disease by inhibiting ceramide synthesis and ER stress-related pathways. Eur J Pharmacol 2023; 942:175536. [PMID: 36693552 DOI: 10.1016/j.ejphar.2023.175536] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 01/05/2023] [Accepted: 01/20/2023] [Indexed: 01/22/2023]
Abstract
Non-alcoholic steatohepatitis (NASH) is associated with intrahepatic lipid accumulation, inflammation, and hepatocyte death. Several studies have indicated that high-fat diets increase ceramide synthases-6 (CerS-6) expression and a concomitant elevation of C16-ceramides, which can modulate endoplasmic reticulum (ER) stress and further contribute to the progression of NASH. Ceramide levels have reportedly been impacted by basic fibroblast growth factor (bFGF) in various diseases. This study looked into the role of bFGF on CerS6/C16-ceramide and ER stress-related pathways in a mouse model of NASH. Male C57BL/6J mice were fed a western diet (WD) combined with carbon tetrachloride (CCl4) for eight weeks. Next, bFGF was injected into the NASH mice for seven days of continuous treatment. The effects of bFGF on NASH endpoints (including steatosis, inflammation, ballooning, and fibrosis), ceramide levels and ER-stress-induced inflammation, reactive oxygen species (ROS) production, and apoptosis were evaluated. Treatment with bFGF significantly reduced CerS-6/C16-ceramide. Further, the inflammatory condition was alleviated with reduction of nuclear factor-kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), and interleukin 6 (IL-6) gene expression. ROS level was also reduced. ER stress-related cell death diminished by reducing C/EBP homologous protein (CHOP) mRNA expression and caspase 3 activity. Furthermore, activation of the hepatic stellate cells was inhibited in the bFGF-treated mice by lowering the amount of alpha-smooth muscle actin (α-SMA) at the mRNA and protein level. According to our findings, CerS-6/C16-ceramide alteration impacts ER stress-mediated inflammation, oxidative stress, and apoptosis. The bFGF treatment effectively attenuated the development of NASH by downregulating CerS-6/C16-ceramide and subsequent ER stress-related pathways.
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Affiliation(s)
- Shahrzad Rahimi
- Department of Genetic, North Tehran Branch, Islamic Azad University, Tehran, 1651153311, Iran
| | - Seyyed Abdolhamid Angaji
- Department of Genetic, North Tehran Branch, Islamic Azad University, Tehran, 1651153311, Iran; Department of Cell and Molecular Biology, Faculty of Biological Science, Kharazmi University, Tehran, 1571914911, Iran
| | - Ahmad Majd
- Department of Biology, North Tehran Branch, Islamic Azad University, Tehran, 1651153311, Iran
| | - Behzad Hatami
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, 1985717413, Iran
| | - Kaveh Baghaei
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, 1985717413, Iran; Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, 1985717413, Iran.
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27
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Hurley LD, Lee H, Wade G, Simcox J, Engin F. Ormdl3 regulation of specific ceramides is dispensable for β-cell function and glucose homeostasis under obesogenic conditions. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.02.11.528130. [PMID: 36798417 PMCID: PMC9934654 DOI: 10.1101/2023.02.11.528130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/14/2023]
Abstract
Chronic elevation of sphingolipids contributes to β-cell failure. ORMDL3 has been identified as a key regulator of sphingolipid homeostasis, however, its function in pancreatic β-cell pathophysiology remains unclear. Here, we generated a mouse model lacking Ormdl3 within pancreatic β-cells ( Ormdl3 β-/- ). We show that loss of β-cell Ormdl3 does not alter glucose tolerance, insulin sensitivity, insulin secretion, islet morphology, or cellular ceramide levels on standard chow diet. When challenged with a high fat diet, while Ormdl3 β-/- mice did not exhibit any alteration in metabolic parameters or islet architecture, lipidomics analysis revealed significantly higher levels of very long chain ceramides in their islets. Taken together, our results reveal that loss of Ormdl3 alone is not sufficient to impinge upon β-cell function or whole-body glucose and insulin homeostasis, but loss of Ormdl3 does alter specific sphingolipid levels.
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Affiliation(s)
- Liam D Hurley
- Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53706, USA
| | - Hugo Lee
- Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53706, USA
| | - Gina Wade
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Judith Simcox
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Feyza Engin
- Department of Biomolecular Chemistry, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53706, USA
- Department of Medicine, Division of Endocrinology, Diabetes & Metabolism, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, WI 53705, USA
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI, USA
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28
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Zhang R, Zhang Z, Wu W, Shi J, Berk E, Li W, Deng Y, Wang Z, Hou J, Long H, Lei M, Wu W. Multi-omics profiling of PC-3 cells reveals bufadienolides-induced lipid metabolic remodeling by regulating long-chain lipids synthesis and hydrolysis. Metabolomics 2023; 19:6. [PMID: 36645548 DOI: 10.1007/s11306-022-01968-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 12/13/2022] [Indexed: 01/17/2023]
Abstract
INTRODUCTION Lipid metabolism participates in various biological processes such as proliferation, apoptosis, migration, invasion, and maintenance of membrane homeostasis of prostate tumor cells. Bufadienolides, the active ingredients of Chansu, show a robust anti-proliferative effect against prostate cancer cells in vitro, but whether bufadienolides could regulate the lipid metabolism in prostate cancer has not been evaluated. OBJECTIVES Our study explored the regulatory effects of bufadienolides on lipid metabolism in human prostate carcinoma cells (PC-3). METHODS Untargeted lipidomics and transcriptomics were combined to study the effect of different bufadienolides interventions on lipid and gene changes of PC-3 cells. The key genes related to lipid metabolism and prostate cancer development were verified by qPCR and western blotting. RESULTS Lipidomic analysis showed that the active bufadienolides significantly downregulated the content of long-chain lipids of PC-3 cells. Based on transcriptomic and qPCR analyses, many genes related to lipid metabolism were significantly regulated by active bufadienolides, such as ELOVL6, CYP2E1, GAL3ST1, CERS1, PLA2G10, PLD1, SPTLC3, and GPX2. Bioinformatics analysis of the Cancer Genome Atlas database and literature retrieval showed that elongation of very long-chain fatty acids protein 6 (ELOVL6) and phospholipase D1 (PLD1) might be important regulatory genes. Western blot analysis revealed that active bufadienolides could downregulate PLD1 protein levels which might promote anti-prostate cancer effect. CONCLUSIONS All these findings support that bufadienolides might induce lipid metabolic remodeling by regulating long-chain lipids synthesis and phospholipid hydrolysis to achieve an anti-prostate cancer effect, and PLD1 would probably be the key protein.
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Affiliation(s)
- Rong Zhang
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Center for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China
| | - Zijia Zhang
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Center for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China
| | - Wenyong Wu
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Center for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210029, China
| | - Jingying Shi
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Center for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China
| | - Entezar Berk
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Center for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China
- Beijing Key Lab of TCM Collateral Disease Theory Research, School of Traditional Chinese Medicine, Capital Medical University, Beijing, 100069, China
| | - Wei Li
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Center for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China
| | - Yanping Deng
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Center for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China
| | - Zhaojun Wang
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Center for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China
| | - Jinjun Hou
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Center for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China
| | - Huali Long
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Center for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China
- University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China
| | - Min Lei
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Center for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China.
- University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China.
| | - Wanying Wu
- Shanghai Research Center for Modernization of Traditional Chinese Medicine, National Engineering Center for TCM Standardization Technology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, People's Republic of China.
- University of Chinese Academy of Sciences, Beijing, 100049, People's Republic of China.
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Zhu C, Huai Q, Zhang X, Dai H, Li X, Wang H. Insights into the roles and pathomechanisms of ceramide and sphigosine-1-phosphate in nonalcoholic fatty liver disease. Int J Biol Sci 2023; 19:311-330. [PMID: 36594091 PMCID: PMC9760443 DOI: 10.7150/ijbs.78525] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/12/2022] [Indexed: 11/24/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), as one of the main causes of chronic liver disease worldwide, encompasses a spectrum of liver conditions that are not caused by other etiology, such as overt alcohol consumption, from simple steatosis to more aggressive non-alcoholic steatohepatitis (NASH) that involves liver inflammation and fibrosis, and to the lethal cirrhosis that may result in liver cancer and liver failure. The molecular mechanisms governing the transition from steatosis to NASH remain not fully understood, but the hepatic lipidome is extensively altered in the setting of steatosis and steatohepatitis, which also correlate with disease progression. With the tremendous advancement in the field of lipidomics in last two decades, a better understanding of the specific role of sphingolipids in fatty liver disease has taken shape. Among the numerous lipid subtypes that accumulate, ceramides are particularly impactful. On the one hand, excessive ceramides deposition in the liver cause hepatic steatosis. On the other hand, ceramides as lipotoxic lipid have significant effects on hepatic inflammation, apoptosis and insulin resistance that contribute to NAFLD. In this review, we summarize and evaluate current understanding of the multiple roles of ceramides in the onset of fatty liver disease and the pathogenic mechanisms underlying their effects, and we also discuss recent advances and challenges in pharmacological interventions targeting ceramide metabolism for the treatment of NAFLD.
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Affiliation(s)
- Cheng Zhu
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Qian Huai
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Xu Zhang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Hanren Dai
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Xiaolei Li
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Hua Wang
- Department of Oncology, the First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
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Guzman G, Creek C, Farley S, Tafesse FG. Genetic Tools for Studying the Roles of Sphingolipids in Viral Infections. Methods Mol Biol 2022; 2610:1-16. [PMID: 36534277 DOI: 10.1007/978-1-0716-2895-9_1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Sphingolipids are a critical family of membrane lipids with diverse functions in eukaryotic cells, and a growing body of literature supports that these lipids play essential roles during the lifecycles of viruses. While small molecule inhibitors of sphingolipid synthesis and metabolism are widely used, the advent of CRISPR-based genomic editing techniques allows for nuanced exploration into the manners in which sphingolipids influence various stages of viral infections. Here we describe some of these critical considerations needed in designing studies utilizing genomic editing techniques for manipulating the sphingolipid metabolic pathway, as well as the current body of literature regarding how viruses depend on the products of this pathway. Here, we highlight the ways in which sphingolipids affect viruses as these pathogens interact with and influence their host cell and describe some of the many open questions remaining in the field.
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Affiliation(s)
- Gaelen Guzman
- Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR, USA
| | - Cameron Creek
- Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR, USA
| | - Scotland Farley
- Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR, USA
| | - Fikadu G Tafesse
- Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, OR, USA.
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31
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Zhu M, Jia Z, Yan X, Liu L, Fang C, Feng M, Dai Y, Zhang Y, Wu H, Huang B, Li Y, Liu J, Xiao H. Danhe granule ameliorates nonalcoholic steatohepatitis and fibrosis in rats by inhibiting ceramide de novo synthesis related to CerS6 and CerK. JOURNAL OF ETHNOPHARMACOLOGY 2022; 295:115427. [PMID: 35654350 DOI: 10.1016/j.jep.2022.115427] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/18/2022] [Accepted: 05/26/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Danhe granule (DHG) is used by Chinese doctors to treat blood stasis, phlegm and dampness. Its lipid-lowering ability has been investigated in our previous research. However, the anti-liver inflammatory and fibrotic effects and mechanism of action of DHG in non-alcoholic steatohepatitis (NASH) have not been explored. AIM OF THE STUDY To evaluate the ameliorative effects of DHG on liver inflammation and fibrosis in a methionine/choline-deficient (MCD) diet-induced NASH rat model, and its underlying mechanism. MATERIALS AND METHODS Sprague-Dawley rats were fed an MCD diet for two weeks and then treated with or without DHG by oral gavage for eight weeks. Their body weight and liver index were measured. The serum alanine aminotransferase (ALT) and aspartate transaminase (AST) activities as well as the liver triglyceride (TG) and free fatty acid (FFA) levels were tested using reagent kits. Inflammatory cytokines, including Tnf-α, Il-β and Il-6, and fibrosis genes, including Acta2, Col1a1, Col1a2 and Tgf-β were examined by real-time quantitative PCR (RT-qPCR). Hematoxylin-eosin (H&E), Oil Red O, Masson's and Sirius Red staining were used to observe liver changes. The plasma and liver ceramide levels were analyzed using HPLC-QQQ-MS/MS. The expression of serine palmitoyl-CoA transferase (Spt), ceramide synthase 6 (Cers6), dihydroceramide desaturase 1 (Des1), glucosylceramide synthase (Gcs), and ceramide kinase (Cerk) mRNA was assayed by RT-qPCR, while the protein expression of CerS6, DES1, GCS, CerK, and casein kinase 2α (CK2α) was tested by western blotting (WB). CerS6 degradation was evaluated using a cycloheximide (CHX) assay in vitro. RESULTS The liver index decreased by 20% in DHG groups and the serum ALT and AST decreased by approximately 50% and 30%, respectively in the DHG-H group. The liver Oil Red O staining, TG, and FFA changes showed that DHG reduced hepatic lipid accumulation by approximately 30% in NASH rats. H&E, Masson's and Sirius Red staining and the mRNA levels of Tnf-α, Il-β, Il-6, Acta2, Col1a1, Col1a2 and Tgf-β revealed that DHG alleviated liver inflammation and fibrosis in NASH rats. The ceramide (Cer 16:0), and hexosylceramide (HexCer 16:0, HexCer 18:0, HexCer 22:0, HexCer 24:0 and HexCer 24:1) levels decreased by approximately 17-56% in the plasma of the DHG-M and H rats. The Cer 16:0 content in the liver decreased by 20%, 50%, and 70% with the DHG-L, M, and H treatments; additionally, the dhCer 16:0, Cer 18:0, HexCer 18:0, HexCer 20:0 Cer 22:0-1P, Cer 24:0-1p, Cer 24:1-1p, and Cer 26:1-1p levels decreased in the DHG groups. The mRNA and protein expression levels of DES1, GCS, Cerk, CerS6, and CHX assay indicated that DHG decreased the mRNA and protein expression levels of CerK and reduced CerS6 protein expression by promoting its degradation. Additionally, DHG attenuated the protein expression of CK2α which could increase CerS6 enzymatic activity by phosphorylating its C-terminal region. CONCLUSION DHG ameliorated the levels of liver FFA and TG and inflammation and fibrosis in MCD-induced rats, which were associated with decreasing ceramide species in the plasma and liver by reducing the expression levels of CerS6 and CerK.
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Affiliation(s)
- Meixia Zhu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China; Research Center of Chinese Medicine Analysis and Transformation, Beijing University of Chinese Medicine, Beijing, China
| | - Zhixin Jia
- Research Center of Chinese Medicine Analysis and Transformation, Beijing University of Chinese Medicine, Beijing, China; Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Xiaoning Yan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China; Research Center of Chinese Medicine Analysis and Transformation, Beijing University of Chinese Medicine, Beijing, China
| | - Lirong Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China; Research Center of Chinese Medicine Analysis and Transformation, Beijing University of Chinese Medicine, Beijing, China
| | - Cong Fang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China; Research Center of Chinese Medicine Analysis and Transformation, Beijing University of Chinese Medicine, Beijing, China
| | - Menghan Feng
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China; Research Center of Chinese Medicine Analysis and Transformation, Beijing University of Chinese Medicine, Beijing, China
| | - Yihang Dai
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China; Research Center of Chinese Medicine Analysis and Transformation, Beijing University of Chinese Medicine, Beijing, China
| | - Yinhuan Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China; Research Center of Chinese Medicine Analysis and Transformation, Beijing University of Chinese Medicine, Beijing, China
| | - Hao Wu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China; Research Center of Chinese Medicine Analysis and Transformation, Beijing University of Chinese Medicine, Beijing, China
| | - Beibei Huang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China; Research Center of Chinese Medicine Analysis and Transformation, Beijing University of Chinese Medicine, Beijing, China
| | - Yueting Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China; Research Center of Chinese Medicine Analysis and Transformation, Beijing University of Chinese Medicine, Beijing, China
| | - Jie Liu
- Research Center of Chinese Medicine Analysis and Transformation, Beijing University of Chinese Medicine, Beijing, China; Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Hongbin Xiao
- Research Center of Chinese Medicine Analysis and Transformation, Beijing University of Chinese Medicine, Beijing, China; Beijing Research Institute of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
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Yu XD, Wang JW. Ceramide de novo synthesis in non-alcoholic fatty liver disease: Pathogenic mechanisms and therapeutic perspectives. Biochem Pharmacol 2022; 202:115157. [PMID: 35777449 DOI: 10.1016/j.bcp.2022.115157] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 06/23/2022] [Accepted: 06/24/2022] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, and its advanced form non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma. Ceramides have been shown to exacerbate NAFLD development through enhancing insulin resistance, reactive oxygen species production, liver steatosis, lipotoxicity and hepatocyte apoptosis, and eventually causing hepatic inflammation and fibrosis. Emerging evidence indicates that ceramide production in NAFLD is predominantly attributed to activation of the de novo synthesis pathway of ceramides in hepatocytes. More importantly, pharmacological modulation of ceramide de novo synthesis in preclinical studies seems efficacious for the treatment of NAFLD. In this review, we provide an overview of the pathogenic mechanisms of ceramides in NAFLD, discuss recent advances and challenges in pharmacological interventions targeting ceramide de novo synthesis, and propose some research directions in the field.
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Affiliation(s)
- Xiao-Dong Yu
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Nanomedicine Translational Research Programme, Centre for NanoMedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Jiong-Wei Wang
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Nanomedicine Translational Research Programme, Centre for NanoMedicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore; Cardiovascular Research Institute (CVRI), National University Heart Centre Singapore (NUHCS), Singapore, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
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Contribution of specific ceramides to obesity-associated metabolic diseases. Cell Mol Life Sci 2022; 79:395. [PMID: 35789435 PMCID: PMC9252958 DOI: 10.1007/s00018-022-04401-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Revised: 05/20/2022] [Accepted: 05/26/2022] [Indexed: 12/04/2022]
Abstract
Ceramides are a heterogeneous group of bioactive membrane sphingolipids that play specialized regulatory roles in cellular metabolism depending on their characteristic fatty acyl chain lengths and subcellular distribution. As obesity progresses, certain ceramide molecular species accumulate in metabolic tissues and cause cell-type-specific lipotoxic reactions that disrupt metabolic homeostasis and lead to the development of cardiometabolic diseases. Several mechanisms for ceramide action have been inferred from studies in vitro, but only recently have we begun to better understand the acyl chain length specificity of ceramide-mediated signaling in the context of physiology and disease in vivo. New discoveries show that specific ceramides affect various metabolic pathways and that global or tissue-specific reduction in selected ceramide pools in obese rodents is sufficient to improve metabolic health. Here, we review the tissue-specific regulation and functions of ceramides in obesity, thus highlighting the emerging concept of selectively inhibiting production or action of ceramides with specific acyl chain lengths as novel therapeutic strategies to ameliorate obesity-associated diseases.
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Yang Y, Wang Y, Lv Y, Ding H. Dissecting the Roles of Lipids in Preeclampsia. Metabolites 2022; 12:metabo12070590. [PMID: 35888713 PMCID: PMC9323219 DOI: 10.3390/metabo12070590] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Revised: 06/17/2022] [Accepted: 06/22/2022] [Indexed: 02/04/2023] Open
Abstract
Preeclampsia is a multisystem pregnancy disorder that is characterized by different degrees of placental malperfusion, with release of antiangiogenic factors into the circulation, leading to maternal vascular endothelial injury and high blood pressure. As a major cause of maternal and perinatal mortality and morbidity worldwide, once preeclampsia has been diagnosed, there are no curative treatments except for delivery. Lipids serve as ubiquitous and multifunctional metabolites that are integral and essential to many diverse functions on both a cellular and organismal level. Lipid metabolic abnormalities have emerged as potential risk factors for the development and progression of preeclampsia. This review comprehensively examines decades of discovery to illuminate the roles of lipids and dysregulation in the levels of various lipid classes in preeclampsia. In addition, the roles of lipids are summarized to further understand the pathogenic mechanisms of preeclampsia. Overall, the review highlights the promising potential of pathophysiology and lipid-targeting therapeutic strategies in preeclampsia.
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Affiliation(s)
| | | | - Yan Lv
- Correspondence: (Y.L.); (H.D.)
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35
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Xia QS, Wu F, Wu WB, Dong H, Huang ZY, Xu L, Lu FE, Gong J. Berberine reduces hepatic ceramide levels to improve insulin resistance in HFD-fed mice by inhibiting HIF-2α. Biomed Pharmacother 2022; 150:112955. [PMID: 35429745 DOI: 10.1016/j.biopha.2022.112955] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Revised: 04/05/2022] [Accepted: 04/08/2022] [Indexed: 11/24/2022] Open
Abstract
Several studies have documented the effects of hypoxia and ceramides on lipid and glucose metabolism, resulting in insulin resistance. However, the roles of ceramide in hepatic hypoxia and hepatic insulin resistance remain to be clarified. This study aimed to explore the relationship between hypoxia, ceramide synthesis, and hepatic insulin resistance in high-fat diet (HFD)-fed mice. Given the interaction of hypoxia-inducible factors 2α(HIF-2α) and berberine determined using molecular docking, this study also assessed the pharmacological effects of berberine on the HIF-2α-ceramide-insulin resistance pathway. In the preliminary phase of the study, gradually aggravated hepatic hypoxia and varying levels of ceramides were observed with the development of type 2 diabetes mellitus (T2DM) due to increasing HIF-2α accumulation. Lipidomic analyses of animal and cell models revealed that berberine reduced hypoxia-induced ceramide production and attenuated ceramide-induced insulin resistance. This research provides timely and necessary evidence for the role of ceramide in hypoxia and insulin resistance in the liver. It also contributes to a better understanding of the pharmacological effects of berberine on ameliorating hypoxia and insulin resistance in T2DM therapy.
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Affiliation(s)
- Qing-Song Xia
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Fan Wu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Wen-Bin Wu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Hui Dong
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Zhao-Yi Huang
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Lijun Xu
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China
| | - Fu-Er Lu
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
| | - Jing Gong
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, Hubei Province, China.
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Passaro AP, Marzuillo P, Guarino S, Scaglione F, Miraglia del Giudice E, Di Sessa A. Omics era in type 2 diabetes: From childhood to adulthood. World J Diabetes 2021; 12:2027-2035. [PMID: 35047117 PMCID: PMC8696648 DOI: 10.4239/wjd.v12.i12.2027] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 04/01/2021] [Accepted: 11/03/2021] [Indexed: 02/06/2023] Open
Abstract
Parallel to the dramatic rise of pediatric obesity, estimates reported an increased prevalence of type 2 diabetes (T2D) already in childhood. The close relationship between obesity and T2D in children is mainly sustained by insulin resistance (IR). In addition, the cardiometabolic burden of T2D including nonalcoholic fatty liver disease, cardiovascular disease and metabolic syndrome is also strictly related to IR. Although T2D pathophysiology has been largely studied in an attempt to improve therapeutic options, molecular mechanisms are still not fully elucidated. In this perspective, omics approaches (including lipidomics, metabolomics, proteomics and metagenomics) are providing the most attractive therapeutic options for T2D. In particular, distinct both lipids and metabolites are emerging as potential therapeutic tools. Of note, among lipid classes, the pathogenic role of ceramides in T2D context has been supported by several data. Thus, selective changes of ceramides expression might represent innovative therapeutic strategies for T2D treatment. More, distinct metabolomics pathways have been also found to be associated with higher T2D risk, by providing novel potential T2D biomarkers. Taken together, omics data are responsible for the expanding knowledge of T2D pathophysiology, by providing novel insights to improve therapeutic strategies for this tangled disease. We aimed to summarize the most recent evidence in the intriguing field of the omics approaches in T2D both in adults and children.
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Affiliation(s)
- Antonio Paride Passaro
- Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania “Luigi Vanvitelli”, Napoli 80138, Italy
| | - Pierluigi Marzuillo
- Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania “Luigi Vanvitelli”, Napoli 80138, Italy
| | - Stefano Guarino
- Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania “Luigi Vanvitelli”, Napoli 80138, Italy
| | - Federica Scaglione
- Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania “Luigi Vanvitelli”, Napoli 80138, Italy
| | - Emanuele Miraglia del Giudice
- Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania “Luigi Vanvitelli”, Napoli 80138, Italy
| | - Anna Di Sessa
- Department of Woman, Child and of General and Specialized Surgery, Università degli Studi della Campania “Luigi Vanvitelli”, Napoli 80138, Italy
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Tanase DM, Gosav EM, Petrov D, Jucan AE, Lacatusu CM, Floria M, Tarniceriu CC, Costea CF, Ciocoiu M, Rezus C. Involvement of Ceramides in Non-Alcoholic Fatty Liver Disease (NAFLD) Atherosclerosis (ATS) Development: Mechanisms and Therapeutic Targets. Diagnostics (Basel) 2021; 11:2053. [PMID: 34829402 PMCID: PMC8621166 DOI: 10.3390/diagnostics11112053] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/01/2021] [Accepted: 11/02/2021] [Indexed: 12/26/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and atherosclerosis (ATS) are worldwide known diseases with increased incidence and prevalence. These two are driven and are interconnected by multiple oxidative and metabolic functions such as lipotoxicity. A gamut of evidence suggests that sphingolipids (SL), such as ceramides, account for much of the tissue damage. Although in humans they are proving to be accurate biomarkers of adverse cardiovascular disease outcomes and NAFLD progression, in rodents, pharmacological inhibition or depletion of enzymes driving de novo ceramide synthesis prevents the development of metabolic driven diseases such as diabetes, ATS, and hepatic steatosis. In this narrative review, we discuss the pathways which generate the ceramide synthesis, the potential use of circulating ceramides as novel biomarkers in the development and progression of ATS and related diseases, and their potential use as therapeutic targets in NAFDL-ATS development which can further provide new clues in this field.
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Affiliation(s)
- Daniela Maria Tanase
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (D.M.T.); (E.M.G.); (C.R.)
- Internal Medicine Clinic, “Sf. Spiridon” County Clinical Emergency Hospital Iasi, 700111 Iasi, Romania
| | - Evelina Maria Gosav
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (D.M.T.); (E.M.G.); (C.R.)
- Internal Medicine Clinic, “Sf. Spiridon” County Clinical Emergency Hospital Iasi, 700111 Iasi, Romania
| | - Daniela Petrov
- Department of Rheumatology and Physiotherapy, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- I Rheumatology Clinic, Clinical Rehabilitation Hospital, 700661 Iasi, Romania
| | - Alina Ecaterina Jucan
- Department of Gastroenterology, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Institute of Gastroenterology and Hepatology, “Sf. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Cristina Mihaela Lacatusu
- Unit of Diabetes, Nutrition and Metabolic Diseases, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Clinical Center of Diabetes, Nutrition and Metabolic Diseases, “Sf. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Mariana Floria
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (D.M.T.); (E.M.G.); (C.R.)
- Internal Medicine Clinic, Emergency Military Clinical Hospital Iasi, 700483 Iasi, Romania
| | - Claudia Cristina Tarniceriu
- Department of Morpho-Functional Sciences I, Discipline of Anatomy, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Hematology Clinic, “Sf. Spiridon” County Clinical Emergency Hospital, 700111 Iasi, Romania
| | - Claudia Florida Costea
- Department of Ophthalmology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
- 2nd Ophthalmology Clinic, “Prof. Dr. Nicolae Oblu” Emergency Clinical Hospital, 700309 Iasi, Romania
| | - Manuela Ciocoiu
- Department of Pathophysiology, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania;
| | - Ciprian Rezus
- Department of Internal Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, 700115 Iasi, Romania; (D.M.T.); (E.M.G.); (C.R.)
- Internal Medicine Clinic, “Sf. Spiridon” County Clinical Emergency Hospital Iasi, 700111 Iasi, Romania
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Gaggini M, Pingitore A, Vassalle C. Plasma Ceramides Pathophysiology, Measurements, Challenges, and Opportunities. Metabolites 2021; 11:metabo11110719. [PMID: 34822377 PMCID: PMC8622894 DOI: 10.3390/metabo11110719] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 10/15/2021] [Accepted: 10/19/2021] [Indexed: 01/22/2023] Open
Abstract
Ceramides are a family of lipid molecules, composed of sphingosine and a fatty acid, and transported by lipoproteins (primarily by low-density lipoproteins) in the bloodstream. They are not only structural lipids, but multifunctional and bioactive molecules with key roles in many important cellular pathways, such as inflammatory processes and apoptosis, representing potential biomarkers of cardiometabolic diseases as well as pharmacological targets. Recent data reported ceramide modulation by diet and aerobic exercise, suggesting nutrients and exercise-targeting sphingolipid pathways as a countermeasure, also in combination with other therapies, for risk and progression of chronic disease prevention and health maintenance. In this review, we focus on the available data regarding remarks on ceramide structure and metabolism, their pathophysiologic roles, and the effect of dietary habit and aerobic exercise on ceramide levels. Moreover, advancements and limitations of lipidomic techniques and simplification attempts to overcome difficulties of interpretation and to facilitate practical applications, such as the proposal of scores, are also discussed.
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Affiliation(s)
- Melania Gaggini
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (M.G.); (A.P.)
| | - Alessandro Pingitore
- Institute of Clinical Physiology, National Research Council, 56124 Pisa, Italy; (M.G.); (A.P.)
| | - Cristina Vassalle
- Fondazione CNR-Regione Toscana G. Monasterio, Via Moruzzi, 1, 56124 Pisa, Italy
- Correspondence: ; Tel.: +39-050-3153525
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Zelnik ID, Kim JL, Futerman AH. The Complex Tail of Circulating Sphingolipids in Atherosclerosis and Cardiovascular Disease. J Lipid Atheroscler 2021; 10:268-281. [PMID: 34621698 PMCID: PMC8473959 DOI: 10.12997/jla.2021.10.3.268] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 04/07/2021] [Accepted: 04/19/2021] [Indexed: 12/22/2022] Open
Abstract
Sphingolipids (SLs) are critical players in a number of cellular processes and have recently been implicated in a large number of human diseases, including atherosclerosis and cardiovascular disease (CVD). SLs are generated intracellularly in a stepwise manner, starting with the generation of the sphingoid long chain base (LCB), followed by N-acylation of the LCB to form ceramide, which can be subsequently metabolized to sphingomyelin and glycosphingolipids. Fatty acids, which are taken up by cells prior to their activation to fatty acyl-CoAs, are used in 2 of these enzymatic steps, including by ceramide synthases, which use fatty acyl-CoAs of different chain lengths to generate ceramides with different N-acyl chain lengths. Recently, alterations in plasma ceramides with specific N-acyl chain lengths and degrees of saturation have emerged as novel biomarkers for the prediction of atherosclerosis and overall cardiovascular risk in the general population. We briefly review the sources of plasma SLs in atherosclerosis, the roles of SLs in CVD, and the possible use of the "ceramide score" as a prognostic marker for CVD.
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Affiliation(s)
- Iris D Zelnik
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Jiyoon L Kim
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
| | - Anthony H Futerman
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel
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40
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Choi RH, Tatum SM, Symons JD, Summers SA, Holland WL. Ceramides and other sphingolipids as drivers of cardiovascular disease. Nat Rev Cardiol 2021; 18:701-711. [PMID: 33772258 PMCID: PMC8978615 DOI: 10.1038/s41569-021-00536-1] [Citation(s) in RCA: 218] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/22/2021] [Indexed: 02/03/2023]
Abstract
Increases in calorie consumption and sedentary lifestyles are fuelling a global pandemic of cardiometabolic diseases, including coronary artery disease, diabetes mellitus, cardiomyopathy and heart failure. These lifestyle factors, when combined with genetic predispositions, increase the levels of circulating lipids, which can accumulate in non-adipose tissues, including blood vessel walls and the heart. The metabolism of these lipids produces bioactive intermediates that disrupt cellular function and survival. A compelling body of evidence suggests that sphingolipids, such as ceramides, account for much of the tissue damage in these cardiometabolic diseases. In humans, serum ceramide levels are proving to be accurate biomarkers of adverse cardiovascular disease outcomes. In mice and rats, pharmacological inhibition or depletion of enzymes driving de novo ceramide synthesis prevents the development of diabetes, atherosclerosis, hypertension and heart failure. In cultured cells and isolated tissues, ceramides perturb mitochondrial function, block fuel usage, disrupt vasodilatation and promote apoptosis. In this Review, we discuss the body of literature suggesting that ceramides are drivers - and not merely passengers - on the road to cardiovascular disease. Moreover, we explore the feasibility of therapeutic strategies to lower ceramide levels to improve cardiovascular health.
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Affiliation(s)
- Ran Hee Choi
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA
| | - Sean M Tatum
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA
| | - J David Symons
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA
| | - Scott A Summers
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA.
| | - William L Holland
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT, USA
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41
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Schmidt S, Gallego SF, Zelnik ID, Kovalchuk S, Albæk N, Sprenger RR, Øverup C, Pewzner-Jung Y, Futerman AH, Lindholm MW, Jensen ON, Ejsing CS. Silencing of ceramide synthase 2 in hepatocytes modulates plasma ceramide biomarkers predictive of cardiovascular death. Mol Ther 2021; 30:1661-1674. [PMID: 34400330 PMCID: PMC9077316 DOI: 10.1016/j.ymthe.2021.08.021] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 07/26/2021] [Accepted: 08/08/2021] [Indexed: 12/15/2022] Open
Abstract
Emerging clinical data show that three ceramide molecules, Cer d18:1/16:0, Cer d18:1/24:1, and Cer d18:1/24:0, are biomarkers of a fatal outcome in patients with cardiovascular disease. This finding raises basic questions about their metabolic origin, their contribution to disease pathogenesis, and the utility of targeting the underlying enzymatic machinery for treatment of cardiometabolic disorders. Here, we outline the development of a potent N-acetylgalactosamine-conjugated antisense oligonucleotide engineered to silence ceramide synthase 2 specifically in hepatocytes in vivo. We demonstrate that this compound reduces the ceramide synthase 2 mRNA level and that this translates into efficient lowering of protein expression and activity as well as Cer d18:1/24:1 and Cer d18:1/24:0 levels in liver. Intriguingly, we discover that the hepatocyte-specific antisense oligonucleotide also triggers a parallel modulation of blood plasma ceramides, revealing that the biomarkers predictive of cardiovascular death are governed by ceramide biosynthesis in hepatocytes. Our work showcases a generic therapeutic framework for targeting components of the ceramide enzymatic machinery to disentangle their roles in disease causality and to explore their utility for treatment of cardiometabolic disorders.
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Affiliation(s)
- Steffen Schmidt
- Roche Pharma Research and Early Development, Roche Innovation Center Copenhagen, 2970 Hørsholm, Denmark
| | - Sandra F Gallego
- Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark
| | - Iris Daphne Zelnik
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Sergey Kovalchuk
- Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark
| | - Nanna Albæk
- Roche Pharma Research and Early Development, Roche Innovation Center Copenhagen, 2970 Hørsholm, Denmark
| | - Richard R Sprenger
- Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark
| | - Charlotte Øverup
- Roche Pharma Research and Early Development, Roche Innovation Center Copenhagen, 2970 Hørsholm, Denmark
| | - Yael Pewzner-Jung
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Anthony H Futerman
- Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel
| | - Marie W Lindholm
- Roche Pharma Research and Early Development, Roche Innovation Center Copenhagen, 2970 Hørsholm, Denmark
| | - Ole N Jensen
- Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark
| | - Christer S Ejsing
- Department of Biochemistry and Molecular Biology, VILLUM Center for Bioanalytical Sciences, University of Southern Denmark, 5230 Odense, Denmark; Cell Biology and Biophysics Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
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42
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Magaye RR, Savira F, Xiong X, Huynh K, Meikle PJ, Reid C, Flynn BL, Kaye D, Liew D, Wang BH. Dihydrosphingosine driven enrichment of sphingolipids attenuates TGFβ induced collagen synthesis in cardiac fibroblasts. IJC HEART & VASCULATURE 2021; 35:100837. [PMID: 34277924 PMCID: PMC8264607 DOI: 10.1016/j.ijcha.2021.100837] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 06/24/2021] [Accepted: 06/27/2021] [Indexed: 01/22/2023]
Abstract
The sphingolipid de novo synthesis pathway, encompassing the sphingolipids, the enzymes and the cell membrane receptors, are being investigated for their role in diseases and as potential therapeutic targets. The intermediate sphingolipids such as dihydrosphingosine (dhSph) and sphingosine (Sph) have not been investigated due to them being thought of as precursors to other more active lipids such as ceramide (Cer) and sphingosine 1 phosphate (S1P). Here we investigated their effects in terms of collagen synthesis in primary rat neonatal cardiac fibroblasts (NCFs). Our results in NCFs showed that both dhSph and Sph did not induce collagen synthesis, whilst dhSph reduced collagen synthesis induced by transforming growth factor β (TGFβ). The mechanisms of these inhibitory effects were associated with the increased activation of the de novo synthesis pathway that led to increased dihydrosphingosine 1 phosphate (dhS1P). Subsequently, through a negative feedback mechanism that may involve substrate-enzyme receptor interactions, S1P receptor 1 expression (S1PR1) was reduced.
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Key Words
- Akt, protein kinase B
- CTGF, connective tissue growth factor
- Cardiac fibroblasts
- Cer, ceramide
- Cer1P, ceramide 1 phosphate
- Coll1a1, collagen 1a1
- Collagen synthesis
- Degs1, dihydroceramide desaturase 1 gene
- Des-1, dihydroceramide desaturase 1 enzyme
- Dihydrosphingosine
- ECM, extracellular matrix inhibitor of nuclear kappa B (NFKβ) kinase alpha and beta (IKKα/β)
- MA3PK, mitogen activated protein kinase kinase kinase
- MAPK, mitogren activated protein kinase
- MI, myocardial infarct
- MMP2, matrix metalloproteinase 2
- NCF, neonatal cardiac fibroblasts
- RPS6, ribosomal protein S6
- S1P, sphingosine-1 Phosphate
- S1PR1, sphingosine -1-phosphate receptor 1
- S1PRs, sphingosine 1 phosphate receptor 1-5
- SK1, sphingosine kinase 1
- Sph, sphingosine
- Sphingolipid
- TAK1, transforming growth factor β activating kinase 1
- TGFβ
- TGFβ, transforming growth factor β
- TIMP1, tissue inhibitor of metalloproteinase 1
- d7dhSph, deuterated dihydrosphingosine
- dhCer, dihydroceramide
- dhS1P, dihydrosphingosine 1 phosphate
- mTOR, mammalian target for rapamycin
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Affiliation(s)
- Ruth R. Magaye
- Biomarker Discovery Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
- Monash Centre of Cardiovascular Research and Education in Therapeutics, Melbourne, Australia
| | - Feby Savira
- Biomarker Discovery Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
- Monash Centre of Cardiovascular Research and Education in Therapeutics, Melbourne, Australia
| | - Xin Xiong
- Biomarker Discovery Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
- Monash Centre of Cardiovascular Research and Education in Therapeutics, Melbourne, Australia
- Shanghai Institute of Heart Failure, Research Centre for Translational Medicine, Shanghai East Hospital, Tongji University, School of Medicine, Shanghai 200120, PR China
| | - Kevin Huynh
- Metabolomics Research Group, Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Peter J. Meikle
- Metabolomics Research Group, Baker Heart and Diabetes Institute, Melbourne, Australia
- School of Public Health School, Curtin University, Perth, Australia
| | - Christopher Reid
- Monash Centre of Cardiovascular Research and Education in Therapeutics, Melbourne, Australia
- School of Public Health School, Curtin University, Perth, Australia
| | - Bernard L. Flynn
- Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, Australia
| | - David Kaye
- Heart Failure Research Group, Baker Heart and Diabetes Institute, Melbourne, Australia
| | - Danny Liew
- Monash Centre of Cardiovascular Research and Education in Therapeutics, Melbourne, Australia
| | - Bing H. Wang
- Biomarker Discovery Laboratory, Baker Heart and Diabetes Institute, Melbourne, Australia
- Monash Centre of Cardiovascular Research and Education in Therapeutics, Melbourne, Australia
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Di Sessa A, Riccio S, Pirozzi E, Verde M, Passaro AP, Umano GR, Guarino S, Miraglia del Giudice E, Marzuillo P. Advances in paediatric nonalcoholic fatty liver disease: Role of lipidomics. World J Gastroenterol 2021; 27:3815-3824. [PMID: 34321846 PMCID: PMC8291022 DOI: 10.3748/wjg.v27.i25.3815] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/06/2021] [Accepted: 06/04/2021] [Indexed: 02/06/2023] Open
Abstract
Due its close relationship with obesity, nonalcoholic fatty liver disease (NAFLD) has become a major worldwide health issue even in childhood. The most accepted pathophysiological hypothesis is represented by the “multiple hits” theory, in which both hepatic intracellular lipid accumulation and insulin resistance mainly contribute to liver injury through several factors. Among these, lipotoxicity has gained particular attention. In this view, the pathogenic role of different lipid classes in NAFLD (e.g., sphingolipids, fatty acids, ceramides, etc.) has been highlighted in recent lipidomics studies. Although there is some contrast between plasma and liver findings, lipidomic profile in the NAFLD context provides novel insights by expanding knowledge in the intricate field of NAFLD pathophysiology as well as by suggesting innovative therapeutic approaches in order to improve both NAFLD prevention and treatment strategies. Selective changes of distinct lipid species might be an attractive therapeutic target for treating NAFLD. Herein the most recent evidence in this attractive field has been summarized to provide a comprehensive overview of the lipidomic scenario in paediatric NAFLD.
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Affiliation(s)
- Anna Di Sessa
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Simona Riccio
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Emilia Pirozzi
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Martina Verde
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Antonio Paride Passaro
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Giuseppina Rosaria Umano
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Stefano Guarino
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Emanuele Miraglia del Giudice
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
| | - Pierluigi Marzuillo
- Department of Woman, Child, and General and Specialized Surgery, University of Campania Luigi Vanvitelli, Naples 80138, Italy
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44
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Ren R, Pang B, Han Y, Li Y. A Glimpse of the Structural Biology of the Metabolism of Sphingosine-1-Phosphate. CONTACT (THOUSAND OAKS (VENTURA COUNTY, CALIF.)) 2021; 4:2515256421995601. [PMID: 37366379 PMCID: PMC10243590 DOI: 10.1177/2515256421995601] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 01/28/2021] [Accepted: 01/28/2021] [Indexed: 06/28/2023]
Abstract
As a key sphingolipid metabolite, sphingosine-1-phosphate (S1P) plays crucial roles in vascular and immune systems. It regulates angiogenesis, vascular integrity and homeostasis, allergic responses, and lymphocyte trafficking. S1P is interconverted with sphingosine, which is also derived from the deacylation of ceramide. S1P levels and the ratio to ceramide in cells are tightly regulated by its metabolic pathways. Abnormal S1P production causes the occurrence and progression of numerous severe diseases, such as metabolic syndrome, cancers, autoimmune disorders such as multiple sclerosis, and kidney and cardiovascular diseases. In recent years, huge advances on the structure of S1P metabolic pathways have been accomplished. In this review, we have got a glimpse of S1P metabolism through structural and biochemical studies of: sphingosine kinases, S1P transporters and S1P receptors, and the development of therapeutics targeting S1P signaling. The progress we summarize here could provide fresh perspectives to further the exploration of S1P functions and facilitate the development of therapeutic molecules targeting S1P signaling with improved specificity and therapeutic effects.
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Affiliation(s)
- Ruobing Ren
- Kobilka Institute of Innovative Drug
Discovery, School of Life and Health Sciences, the Chinese University
of Hong Kong, Shenzhen, China
| | - Bin Pang
- Kobilka Institute of Innovative Drug
Discovery, School of Life and Health Sciences, the Chinese University
of Hong Kong, Shenzhen, China
| | - Yufei Han
- Kobilka Institute of Innovative Drug
Discovery, School of Life and Health Sciences, the Chinese University
of Hong Kong, Shenzhen, China
| | - Yihao Li
- Kobilka Institute of Innovative Drug
Discovery, School of Life and Health Sciences, the Chinese University
of Hong Kong, Shenzhen, China
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