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Denimal D, Ponnaiah M, Phan F, Jeannin AC, Redheuil A, Salem JE, Boussouar S, Paulstephenraj P, Laroche S, Amouyal C, Hartemann A, Foufelle F, Bourron O. Metabolic dysfunction-associated steatotic liver disease (MASLD) biomarkers and progression of lower limb arterial calcification in patients with type 2 diabetes: a prospective cohort study. Cardiovasc Diabetol 2025; 24:176. [PMID: 40269920 PMCID: PMC12020187 DOI: 10.1186/s12933-025-02705-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Accepted: 03/24/2025] [Indexed: 04/25/2025] Open
Abstract
BACKGROUND Studies have demonstrated that both lower limb arterial calcification and metabolic dysfunction-associated steatotic liver disease (MASLD) are linked to the development of peripheral artery disease. However, the potential relationship between MASLD biomarkers and progression of lower limb arterial calcification in individuals with type 2 diabetes (T2D) remains unclear. This study aimed to investigate whether the biomarkers of MASLD included in the FibroMax® panels are associated with the progression of lower limb arterial calcification in patients with T2D. METHODS The lower limb arterial calcification score (LLACS) was evaluated through computed tomography at baseline and after an average follow-up of 31.2 ± 3.7 months in a cohort of 150 patients with T2D. We also measured the serum biomarkers included in the FibroMax® panels (SteatoTest®, FibroTest®, NashTest®, ActiTest®). The predictive ability of these biomarkers of MASLD on LLACS progression was assessed through univariate and multivariate linear regression models, principal component regression analysis, as well as machine learning algorithms. RESULTS During the follow-up period, LLACS increased in 127 (85%) of the 150 patients with T2D. In univariate analysis, the annualized change in LLACS was positively and mainly correlated with baseline LLACS (r = 0.860, p < 0.0001), the FibroTest® score (r = 0.304, p = 0.0002), and age (r = 0.275, p = 0.0006), and negatively correlated with glomerular filtration rate (r = - 0.242, p = 0.003). In multivariate analysis, the FibroTest® score remained independently associated with the annualized change in LLACS, after adjusting for baseline LLACS and risk factors for lower extremity artery disease (β coefficient [95% confidence interval]: 988 [284-1692], p = 0.006). This association persisted even after adjustment for variables selected by principal component analysis (β = 1029 [289-1768], p = 0.007). Two advanced machine learning models identified the FibroTest® score as the second most important predictor of annualized change in LLACS, following baseline LLACS. CONCLUSIONS This study represents the first demonstration of an independent relationship between a non-invasive liver fibrosis test and the progression of lower limb arterial calcification in patients with T2D. Beyond its utility in assessing liver fibrosis, the FibroTest® could be a valuable and easy-to-use biomarker for predicting the risk of worsening lower limb arterial calcification. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT02431234.
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Affiliation(s)
- Damien Denimal
- INSERM U1231, Center for Translational and Molecular Medicine, Dijon, France.
- Department of Clinical Biochemistry, CHU Dijon-Bourgogne, Dijon Bourgogne University Hospital, 2 rue Ducoudray, 21000, Dijon, France.
| | | | - Franck Phan
- Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
- Sorbonne Université, Paris, France
- Department of Diabetology, Assistance Publique‑Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, 47‑83 Boulevard de l'Hôpital, Paris, France
- INSERM UMR_S 1166, Sorbonne University, Team Metabolic Diseases, Diabetes and Co-Morbidities, Paris, France
| | - Anne-Caroline Jeannin
- Sorbonne Université, Paris, France
- Department of Diabetology, Assistance Publique‑Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, 47‑83 Boulevard de l'Hôpital, Paris, France
| | - Alban Redheuil
- Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
- Laboratoire d'Imagerie Biomédicale INSERM_1146, CNRS_7371, Paris, France
- ICT Cardiovascular and Thoracic Imaging Unit, AP-HP, Pitié Salpêtrière University Hospital, Paris, France
| | - Joe-Elie Salem
- Department of Pharmacology, INSERM, AP-HP, CIC-1901, Pitié-Salpêtrière Hospital, Sorbonne Université, Paris, France
| | - Samia Boussouar
- Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
- Laboratoire d'Imagerie Biomédicale INSERM_1146, CNRS_7371, Paris, France
- ICT Cardiovascular and Thoracic Imaging Unit, AP-HP, Pitié Salpêtrière University Hospital, Paris, France
| | | | - Suzanne Laroche
- Sorbonne Université, Paris, France
- Department of Diabetology, Assistance Publique‑Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, 47‑83 Boulevard de l'Hôpital, Paris, France
| | - Chloé Amouyal
- Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
- Sorbonne Université, Paris, France
- Department of Diabetology, Assistance Publique‑Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, 47‑83 Boulevard de l'Hôpital, Paris, France
- INSERM UMR_S 1166, Sorbonne University, Team Metabolic Diseases, Diabetes and Co-Morbidities, Paris, France
| | - Agnès Hartemann
- Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
- Sorbonne Université, Paris, France
- Department of Diabetology, Assistance Publique‑Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, 47‑83 Boulevard de l'Hôpital, Paris, France
- INSERM UMR_S 1166, Sorbonne University, Team Metabolic Diseases, Diabetes and Co-Morbidities, Paris, France
| | - Fabienne Foufelle
- Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
- INSERM UMR_S 1166, Sorbonne University, Team Metabolic Diseases, Diabetes and Co-Morbidities, Paris, France
| | - Olivier Bourron
- Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
- Sorbonne Université, Paris, France
- Department of Diabetology, Assistance Publique‑Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, 47‑83 Boulevard de l'Hôpital, Paris, France
- INSERM UMR_S 1166, Sorbonne University, Team Metabolic Diseases, Diabetes and Co-Morbidities, Paris, France
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Khereldin RM, Abouelela YS, Yasin NAE, Youssef FS, Abdelhameed MI, Tohamy AF, Rizk H, Daghash SM. Comparing the therapeutic influence of bone marrow Mesenchymal stem cells versus its derived exosomes against diabetic hepatopathy in rats. Exp Cell Res 2025; 447:114436. [PMID: 40057260 DOI: 10.1016/j.yexcr.2025.114436] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/24/2025] [Accepted: 02/07/2025] [Indexed: 03/15/2025]
Abstract
Diabetes mellitus (DM) is a chronic widespread metabolic disorder, involving a high blood glucose level which causes multiple serious complications including liver, kidney, brain and peripheral nerves damage. Due to the undesirable side effects of the anti-diabetic drugs, the current studies directed to use stem cells and exosomes to overcome the limitations of traditional therapy. We aimed to compare the antidiabetic effect of Bone marrow mesenchymal stem cells (BMMSCs) and its derived exosomes against diabetic hepatopathy induced by streptozotocin (STZ) in albino rats. Our study was conducted on 28 male albino rats divided into 4 groups {control negative non diabetic group, control positive diabetic group, exosomes treated group received (5 × 109 particle/rat) through tail vein twice per week for one month} and Stem cell treated group received (107) BMMSCs through tail vein twice per week for one month. Hepatic structure together with blood glucose level, liver function enzymes were assayed in addition to a lipid profile tests, oxidative stress, and gene expression. Both treated groups by exosomes and stem cells expressed significantly low levels of fasting blood glucose, liver function parameters (ALT, AST, ALP), lipid profile tests (cholesterol and triglycerides), lipid peroxidation index (MDA), with substantial reduction in IL-1β expression compared to diabetic group. Significantly downregulating the VEGF and elevation of eNOS genes and GSH which suggest the effective role provided by BMMSCs and its derived exosomes for treatment of diabetic hepatopathy. Although, the results of both groups showed near average outcomes, the exosome treated group significantly enhanced liver function enzymes and triglyceride, cholesterol level compared to stem cells treated group. These findings were reinforced by the histopathological and immunohistochemistry examination. The latter showed slight but non-significant improvements in VEGF, eNOS, and IL-1β expression. These minor differences together with practical advantages of exosomes make it preferable over BMMSCs in treatment of diabetic hepatopathy.
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Affiliation(s)
- Rehab Mahmoud Khereldin
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Cairo University, Giza square, 12211, Giza, Egypt.
| | - Yara Sayed Abouelela
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Cairo University, Giza square, 12211, Giza, Egypt.
| | - Noha Ali Elsayed Yasin
- Department of Cytology and Histology, Faculty of Veterinary Medicine, Cairo University, Giza square, 12211, Giza, Egypt.
| | - Fady Sayed Youssef
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza square, 12211, Giza, Egypt.
| | - Marwa Ibrahim Abdelhameed
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Cairo University, Giza square, 12211, Giza, Egypt.
| | - Adel Fathy Tohamy
- Department of Toxicology and Forensic Medicine, Faculty of Veterinary Medicine, Cairo University, Giza square, 12211, Giza, Egypt.
| | - Hamdy Rizk
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Cairo University, Giza square, 12211, Giza, Egypt.
| | - Samer Mohamed Daghash
- Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Cairo University, Giza square, 12211, Giza, Egypt.
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Le Goff W, Bourron O, Materne C, Galier S, Phan F, Tan-Chen S, Guillas I, Hartemann A, Salem JE, Redheuil A, Foufelle F, Le Stunff H, Hajduch E, Guerin M. Inverse relationship between circulating sphingosine-1-phosphate and precursor species and coronary artery calcification score in type 2 diabetes. Cardiovasc Diabetol 2025; 24:85. [PMID: 39984928 PMCID: PMC11846453 DOI: 10.1186/s12933-025-02624-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 01/31/2025] [Indexed: 02/23/2025] Open
Abstract
BACKGROUND Sphingosine 1-phosphate (S1P) is a key mediator of lipid signaling with strong immunomodulatory and anti-inflammatory effects. Circulating S1P levels including S1P in high-density lipoproteins (HDL) were demonstrated to be inversely associated with cardiovascular diseases (CVD). However, no studies are available regarding a potential implication of S1P on the risk of CVD in type 2 diabetes (T2D). The objective of this study is to determine if the increased CVD risk in T2D may involve an alteration of circulating S1P species as well as their precursors. METHODS A total of 168 and 31 patients with T2D (154 men and 45 women) with available Coronary artery calcification (CAC) score from the DIACART and CERABIAB cohorts, respectively, were included in the study. Quantification of S1P species and their precursors was carried out by LC-MS/MS in plasma and isolated HDL. CAC score was modeled as a binary variable (0/1 below or equal/above 100) using CAC < 100 for reference. S1P species or precursors were modeled as binary variables dichotomized at the median (0/1: below or equal/above the median). The relationships between S1P species and CAC score modeled as a binary variable (below or equal/above 100) was evaluated by linear regression analyses. In vitro experiments were conducted to evaluate the contribution of HDL-S1P content on anti-inflammatory properties of HDL particles. RESULTS Multivariate analysis revealed that plasma S1P levels, especially d18:1-S1P, and sphingosine in HDL were inversely associated with the high risk of CVD (CAC > 100) in patients with T2D. Clustering of HDL according to their concentration in S1P species and their precursors revealed that S1P-impoverished HDL is a major feature of patients with a CAC > 100. In vitro analysis of monocyte adhesion and inflammation in human umbilical vein endothelial cells as well as inflammatory phenotype of human macrophages demonstrated that low HDL-S1P exhibited impaired anti-inflammatory properties in comparison to high HDL-S1P. CONCLUSION This study unraveled that circulating S1P and their precursors are biomarkers of coronary atherosclerosis in T2D, which may underlie the lower abundance of S1P and anti-inflammatory activities of HDL. Trial registration ClinicalTrials.gov number, NCT02431234.
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Affiliation(s)
- Wilfried Le Goff
- INSERM, Foundation for Innovation in Cardiometabolism and Nutrition (ICAN), UMR_S1166, Sorbonne Université, 75013, Paris, France
| | - Olivier Bourron
- INSERM, Foundation for Innovation in Cardiometabolism and Nutrition (ICAN), UMR_S1166, Sorbonne Université, 75013, Paris, France
- Diabetology Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Paris, France
| | - Clément Materne
- INSERM, Foundation for Innovation in Cardiometabolism and Nutrition (ICAN), UMR_S1166, Sorbonne Université, 75013, Paris, France
| | - Sophie Galier
- INSERM, Foundation for Innovation in Cardiometabolism and Nutrition (ICAN), UMR_S1166, Sorbonne Université, 75013, Paris, France
| | - Franck Phan
- INSERM, Foundation for Innovation in Cardiometabolism and Nutrition (ICAN), UMR_S1166, Sorbonne Université, 75013, Paris, France
- Diabetology Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Paris, France
| | - Sophie Tan-Chen
- Centre de Recherche Des Cordeliers, INSERM, Sorbonne Université, Paris, France
| | - Isabelle Guillas
- INSERM, Foundation for Innovation in Cardiometabolism and Nutrition (ICAN), UMR_S1166, Sorbonne Université, 75013, Paris, France
| | - Agnès Hartemann
- Diabetology Department, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Paris, France
| | - Joe-Elie Salem
- AP-HP, INSERM, CIC-1901, Hôpital Pitié-Salpêtrière, Sorbonne Université, Paris, France
| | - Alban Redheuil
- Laboratoire d'Imagerie Biomédicale INSERM_1146, CNRS_7371, ICT Cardiovascular and Thoracic Imaging Unit, Assistance Publique‑Hôpitaux de Paris (AP-HP), Hôpital Pitié-Salpêtrière, Paris, France
| | - Fabienne Foufelle
- INSERM, Foundation for Innovation in Cardiometabolism and Nutrition (ICAN), UMR_S1166, Sorbonne Université, 75013, Paris, France
| | - Hervé Le Stunff
- CNRS UMR 9197, Institut des Neurosciences Paris-Saclay, Université Paris-Saclay, Saclay, France.
| | - Eric Hajduch
- INSERM, Foundation for Innovation in Cardiometabolism and Nutrition (ICAN), UMR_S1166, Sorbonne Université, 75013, Paris, France.
| | - Maryse Guerin
- INSERM, Foundation for Innovation in Cardiometabolism and Nutrition (ICAN), UMR_S1166, Sorbonne Université, 75013, Paris, France.
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Mocciaro G, George AL, Allison M, Frontini M, Huang‐Doran I, Reiman F, Gribble F, Griffin JL, Vidal‐Puig A, Azzu V, Kay R, Vacca M. Oxidised Apolipoprotein Peptidome Characterises Metabolic Dysfunction-Associated Steatotic Liver Disease. Liver Int 2025; 45:e16200. [PMID: 39822152 PMCID: PMC11740006 DOI: 10.1111/liv.16200] [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: 09/18/2024] [Revised: 11/07/2024] [Accepted: 11/25/2024] [Indexed: 01/19/2025]
Abstract
BACKGROUND Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) encompasses a spectrum of histological conditions ranging from simple steatosis to fibrosing steatohepatitis, and is a risk factor for cardiovascular diseases (CVD). While oxidised apolipoproteins A and B have been linked to obesity and CVD, the association between other oxidised apolipoproteins and MASLD is yet to be established. To fill this gap, we characterised the circulating serum peptidome of patients with MASLD. METHODS We studied the serum of 87 biopsy-confirmed MASLD patients and 20 age- and sex-matched control (CTRL) subjects. We first employed an untargeted LC-MS/MS peptidomics approach (9 CTRL, 32 MASLD) to identify key hits differentially modulated, and subsequently validated the most relevant findings through targeted peptidomics in an enlarged study population (87 MASLD and 20 CTRL). RESULTS Untargeted serum peptidomics identified several oxidised apolipoprotein peptide fragments, including ApoE and ApoC-III, significantly upregulated in MASLD compared to CTRL. Specifically focusing on the oxidative status of intact ApoC-III, studied through its major glycoforms (ApoC-III0, ApoC-IIIi and ApoC-IIIii), we observed a marked reduction in non-oxidised forms of these circulating peptides alongside substantially increased levels of their oxidised proteoforms in MASLD versus controls (but not within the disease stages). Oxidised ApoE and ApoC-III peptide fragments were also significantly correlated with obesity, insulin resistance, dyslipidaemia and transaminases, suggesting a potential link between circulating apolipoprotein oxidation and systemic/hepatic metabolic dysfunction. CONCLUSION Our data reveals a previously unreported oxidised apolipoprotein profile associated with MASLD. The functional and clinical implications of these findings warrant further mechanistic investigation.
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Grants
- Wellcome Trust
- MR/S010483/1 Medical Research Council
- This research was supported by NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) funding to V.A., M.A., and M.V.The initial establishment of the cohorts was supported by the Evelyn Trust (funding to M.A. and A.V.P.), Mason Medical Research Trust (funding to V.A.), and the Academy of Medical Sciences (funding to V.A.). V.A. was supported by the University of Cambridge. M.A. is supported by Cambridge University Hospitals NHS Foundation Trust. M.V. is supported by the University of Bari (Horizon Europe Seed cod. id. S06-miRNASH), the Foundation for Liver Research (Intramural Funding), Associazione Italiana Ricerca sul Cancro (IG2022 Grant n. 27521) and Ministry of University and Research on Next Generation EU Funds [COD: P202222FCC, CUP: H53D23009960001, D.D. MUR 1366 (01-09-2023), Title: "System Biology" approaches in HCV Patients with Residual Hepatic Steatosis after Viral Eradication; Cod PE00000003, CUP: H93C22000630001, DD MUR 1550, Title: "ON Foods - Research and innovation network on food and nutrition Sustainability, Safety and Security - Working ON Foods"; Cod: CN00000041, CUP: H93C22000430007, Title PNRR "National Center for Gene Therapy and Drugs based on RNA Technology", M4C2-Investment 1.4; Code: CN00000013, CUP: H93C22000450007, Title PNNR: "National Centre for HPC, Big Data and Quantum Computing").A.V.P. is funded by MRC MDU, MRC Metabolic Diseases Unit (MC_UU_00014/5): Disease Model Core, Biochemistry Assay Lab, Histology Core and British Heart Foundation. M.F. is supported by the British Heart Foundation (FS/18/53/33863) and the British Heart Foundation Cambridge Centre for Research Excellence (RE/18/1/34212). This study was supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre. We would like to thank all participants in this study and the NIHR National BioResource. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. JLG is funded by the Medical Research Council (MR/S010483/1; MR/P011705/1; MR/P01836X/1; MR/X012700/1). F.G., F.R., R.K. and A.L.G. were funded by the Wellcome Trust (grants 106262/Z/14/Z, 106263/Z/14/Z), the MRC Metabolic Diseases Unit (grants MRC MC UU 12012/3, MRC MC UU12012/5) and by the NIHR Cambridge Biomedical Research Centre. The mass spectrometers were obtained using the Medical Research Council "Enhancing UK Clinical Research" grant (MR/M009041/1). The views expressed are those of the author(s) and not necessarily those of the relevant funding or supporting institutions. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript
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Affiliation(s)
- Gabriele Mocciaro
- Roger Williams Institute of Liver StudiesFoundation for Liver ResearchLondonUK
| | - Amy L. George
- Institute of Metabolic Science Metabolic Research LaboratoriesAddenbrooke's HospitalCambridgeUK
| | - Michael Allison
- Liver Unit, Cambridge NIHR Biomedical Research CentreCambridge University Hospitals NHS Foundation TrustCambridgeUK
| | - Mattia Frontini
- Faculty of Health and Life Sciences, Clinical and Biomedical SciencesUniversity of Exeter Medical SchoolExeterUK
| | - Isabel Huang‐Doran
- Institute of Metabolic Science Metabolic Research LaboratoriesAddenbrooke's HospitalCambridgeUK
| | - Frank Reiman
- Institute of Metabolic Science Metabolic Research LaboratoriesAddenbrooke's HospitalCambridgeUK
| | - Fiona Gribble
- Institute of Metabolic Science Metabolic Research LaboratoriesAddenbrooke's HospitalCambridgeUK
| | - Julian L. Griffin
- The Rowett Institute, Foresterhill CampusUniversity of AberdeenAberdeenUK
| | - Antonio Vidal‐Puig
- Institute of Metabolic Science Metabolic Research LaboratoriesAddenbrooke's HospitalCambridgeUK
| | - Vian Azzu
- Institute of Metabolic Science Metabolic Research LaboratoriesAddenbrooke's HospitalCambridgeUK
- Liver Unit, Cambridge NIHR Biomedical Research CentreCambridge University Hospitals NHS Foundation TrustCambridgeUK
| | - Richard Kay
- Institute of Metabolic Science Metabolic Research LaboratoriesAddenbrooke's HospitalCambridgeUK
| | - Michele Vacca
- Roger Williams Institute of Liver StudiesFoundation for Liver ResearchLondonUK
- University of Bari "Aldo Moro"Department of Interdisciplinary Medicine, Clinica Medica "C. Frugoni"BariItaly
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Meng L, Jin H, Yulug B, Altay O, Li X, Hanoglu L, Cankaya S, Coskun E, Idil E, Nogaylar R, Ozsimsek A, Shoaie S, Turkez H, Nielsen J, Zhang C, Borén J, Uhlén M, Mardinoglu A. Multi-omics analysis reveals the key factors involved in the severity of the Alzheimer's disease. Alzheimers Res Ther 2024; 16:213. [PMID: 39358810 PMCID: PMC11448018 DOI: 10.1186/s13195-024-01578-6] [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: 02/26/2024] [Accepted: 09/22/2024] [Indexed: 10/04/2024]
Abstract
Alzheimer's disease (AD) is a debilitating neurodegenerative disorder with a global impact, yet its pathogenesis remains poorly understood. While age, metabolic abnormalities, and accumulation of neurotoxic substances are potential risk factors for AD, their effects are confounded by other factors. To address this challenge, we first utilized multi-omics data from 87 well phenotyped AD patients and generated plasma proteomics and metabolomics data, as well as gut and saliva metagenomics data to investigate the molecular-level alterations accounting the host-microbiome interactions. Second, we analyzed individual omics data and identified the key parameters involved in the severity of the dementia in AD patients. Next, we employed Artificial Intelligence (AI) based models to predict AD severity based on the significantly altered features identified in each omics analysis. Based on our integrative analysis, we found the clinical relevance of plasma proteins, including SKAP1 and NEFL, plasma metabolites including homovanillate and glutamate, and Paraprevotella clara in gut microbiome in predicting the AD severity. Finally, we validated the predictive power of our AI based models by generating additional multi-omics data from the same group of AD patients by following up for 3 months. Hence, we observed that these results may have important implications for the development of potential diagnostic and therapeutic approaches for AD patients.
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Affiliation(s)
- Lingqi Meng
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Han Jin
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Burak Yulug
- Department of Neurology and Neuroscience, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya, Turkey
| | - Ozlem Altay
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Xiangyu Li
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Lutfu Hanoglu
- Department of Neurology, Faculty of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | - Seyda Cankaya
- Department of Neurology and Neuroscience, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya, Turkey
| | - Ebru Coskun
- Department of Neurology, Faculty of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | - Ezgi Idil
- Department of Neurology and Neuroscience, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya, Turkey
| | - Rahim Nogaylar
- Department of Neurology and Neuroscience, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya, Turkey
| | - Ahmet Ozsimsek
- Department of Neurology and Neuroscience, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya, Turkey
| | - Saeed Shoaie
- Centre for Host-Microbiome Interaction's, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK
| | - Hasan Turkez
- Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum, Turkey
| | - Jens Nielsen
- Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
| | - Cheng Zhang
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Jan Borén
- Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Mathias Uhlén
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.
- Centre for Host-Microbiome Interaction's, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK.
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Varela YR, Iriondo MN, Goñi FM, Alonso A, Montes LR. Ceramide regulation of autophagy: A biophysical approach. Biochim Biophys Acta Mol Cell Biol Lipids 2024; 1869:159444. [PMID: 38056762 DOI: 10.1016/j.bbalip.2023.159444] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 11/29/2023] [Accepted: 11/30/2023] [Indexed: 12/08/2023]
Abstract
Specific membrane lipids play unique roles in (macro)autophagy. Those include phosphatidylethanolamine, to which LC3/GABARAP autophagy proteins become covalently bound in the process, or cardiolipin, an important effector in mitochondrial autophagy (or mitophagy). Ceramide (Cer), or N-acyl sphingosine, is one of the simplest sphingolipids, known as a stress signal in the apoptotic pathway. Moreover, Cer is increasingly being recognized as an autophagy activator, although its mechanism of action is unclear. In the present review, the proposed Cer roles in autophagy are summarized, together with some biophysical properties of Cer in membranes. Possible pathways for Cer activation of autophagy are discussed, including specific protein binding of the lipid, and Cer-dependent perturbation of bilayer properties. Cer generation of lateral inhomogeneities (domain formation) is given special attention. Recent biophysical results, including fluorescence and atomic force microscopy data, show Cer-promoted enhanced binding of LC3/GABARAP to lipid bilayers. These observations could be interpreted in terms of the putative formation of Cer-rich nanodomains.
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Affiliation(s)
- Yaiza R Varela
- Instituto Biofisika (UPV/EHU, CSIC) and Departamento de Bioquímica, Universidad del País Vasco, 48940 Leioa, Spain
| | - Marina N Iriondo
- Instituto Biofisika (UPV/EHU, CSIC) and Departamento de Bioquímica, Universidad del País Vasco, 48940 Leioa, Spain
| | - Félix M Goñi
- Instituto Biofisika (UPV/EHU, CSIC) and Departamento de Bioquímica, Universidad del País Vasco, 48940 Leioa, Spain
| | - Alicia Alonso
- Instituto Biofisika (UPV/EHU, CSIC) and Departamento de Bioquímica, Universidad del País Vasco, 48940 Leioa, Spain.
| | - L Ruth Montes
- Instituto Biofisika (UPV/EHU, CSIC) and Departamento de Bioquímica, Universidad del País Vasco, 48940 Leioa, Spain
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Denimal D, Béland-Bonenfant S, Pais-de-Barros JP, Rouland A, Bouillet B, Duvillard L, Vergès B, Petit JM. Plasma ceramides are associated with MRI-based liver fat content but not with noninvasive scores of liver fibrosis in patients with type 2 diabetes. Cardiovasc Diabetol 2023; 22:310. [PMID: 37940926 PMCID: PMC10634084 DOI: 10.1186/s12933-023-02049-2] [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: 08/28/2023] [Accepted: 11/01/2023] [Indexed: 11/10/2023] Open
Abstract
BACKGROUND There is growing evidence that ceramides play a significant role in the onset and progression of non-alcoholic fatty liver disease (NAFLD), a highly prevalent condition in patients with type 2 diabetes associated with hepatic and cardiovascular events. However, the relationship between plasma ceramide levels and NAFLD severity in type 2 diabetes remains unclear. The main purpose of the present study was to investigate whether circulating levels of ceramides in patients with type 2 diabetes are associated with liver steatosis assessed by the highly accurate magnetic resonance imaging proton density fat fraction (MRI-PDFF). The secondary objective was to assess the relationship between plasma ceramides and noninvasive scores of liver fibrosis. METHODS In this cross-sectional single-center study, plasma concentrations of 7 ceramides were measured by liquid chromatography-mass spectrometry in 255 patients with type 2 diabetes (GEPSAD cohort). Liver fat content was assessed by MRI-PDFF, and noninvasive scores of liver fibrosis (i.e. Fibrosis-4 index, NAFLD Fibrosis Score, FibroTest® and Fibrotic NASH Index) were calculated. A validation cohort of 80 patients with type 2 diabetes was also studied (LIRA-NAFLD cohort). RESULTS Liver steatosis, defined as a liver fat content > 5.56%, was found in 62.4 and 82.5% of individuals with type 2 diabetes in the GEPSAD and LIRA-NAFLD cohorts, respectively. In GEPSAD, MRI-PDFF-measured liver fat content was positively associated with plasma levels of total ceramides (r = 0.232, p = 0.0002), and 18:0, 20:0, 22:0 and 24:0 ceramides in univariate analysis (p ≤ 0.0003 for all). In multivariate analysis, liver fat content remained significantly associated with total ceramides (p = 0.001), 18:0 (p = 0.006), 22:0 (p = 0.0009) and 24:0 ceramides (p = 0.0001) in GEPSAD, independently of age, diabetes duration, body mass index and dyslipidemia. Overall, similar relationship between plasma ceramides and liver fat content was observed in the LIRA-NAFLD validation cohort. No significant association was found between plasma ceramides and noninvasive scores of fibrosis after adjustment for age in both cohorts. CONCLUSIONS Plasma ceramide levels are associated with liver steatosis in patients with type 2 diabetes, independently of traditional risk factors for NAFLD. The independent association between plasma ceramides and liver steatosis adds new insights regarding the relationship between ceramides and NAFLD in type 2 diabetes.
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Affiliation(s)
- Damien Denimal
- University of Burgundy, INSERM LNC UMR1231, Dijon, F-21000, France.
- Department of Biochemistry, CHU Dijon Bourgogne, Dijon, F-21079, France.
| | - Sarah Béland-Bonenfant
- University of Burgundy, INSERM LNC UMR1231, Dijon, F-21000, France
- Department of Endocrinology and Diabetology, CHU Dijon Bourgogne, Dijon, F-21000, France
| | | | - Alexia Rouland
- University of Burgundy, INSERM LNC UMR1231, Dijon, F-21000, France
- Department of Endocrinology and Diabetology, CHU Dijon Bourgogne, Dijon, F-21000, France
| | - Benjamin Bouillet
- University of Burgundy, INSERM LNC UMR1231, Dijon, F-21000, France
- Department of Endocrinology and Diabetology, CHU Dijon Bourgogne, Dijon, F-21000, France
| | - Laurence Duvillard
- University of Burgundy, INSERM LNC UMR1231, Dijon, F-21000, France
- Department of Biochemistry, CHU Dijon Bourgogne, Dijon, F-21079, France
| | - Bruno Vergès
- University of Burgundy, INSERM LNC UMR1231, Dijon, F-21000, France
- Department of Endocrinology and Diabetology, CHU Dijon Bourgogne, Dijon, F-21000, France
| | - Jean-Michel Petit
- University of Burgundy, INSERM LNC UMR1231, Dijon, F-21000, France
- Department of Endocrinology and Diabetology, CHU Dijon Bourgogne, Dijon, F-21000, France
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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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Ali-Berrada S, Guitton J, Tan-Chen S, Gyulkhandanyan A, Hajduch E, Le Stunff H. Circulating Sphingolipids and Glucose Homeostasis: An Update. Int J Mol Sci 2023; 24:12720. [PMID: 37628901 PMCID: PMC10454113 DOI: 10.3390/ijms241612720] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/07/2023] [Accepted: 08/08/2023] [Indexed: 08/27/2023] Open
Abstract
Sphingolipids are a family of lipid molecules produced through different pathways in mammals. Sphingolipids are structural components of membranes, but in response to obesity, they are implicated in the regulation of various cellular processes, including inflammation, apoptosis, cell proliferation, autophagy, and insulin resistance which favors dysregulation of glucose metabolism. Of all sphingolipids, two species, ceramides and sphingosine-1-phosphate (S1P), are also found abundantly secreted into the bloodstream and associated with lipoproteins or extracellular vesicles. Plasma concentrations of these sphingolipids can be altered upon metabolic disorders and could serve as predictive biomarkers of these diseases. Recent important advances suggest that circulating sphingolipids not only serve as biomarkers but could also serve as mediators in the dysregulation of glucose homeostasis. In this review, advances of molecular mechanisms involved in the regulation of ceramides and S1P association to lipoproteins or extracellular vesicles and how they could alter glucose metabolism are discussed.
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Affiliation(s)
- Sarah Ali-Berrada
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, F-75006 Paris, France; (S.A.-B.); (S.T.-C.); (A.G.)
- Institut Hospitalo-Universitaire ICAN, 75013 Paris, France
| | - Jeanne Guitton
- Institut des Neurosciences Paris-Saclay, Université Paris-Saclay, CNRS UMR 9197, 91400 Saclay, France;
| | - Sophie Tan-Chen
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, F-75006 Paris, France; (S.A.-B.); (S.T.-C.); (A.G.)
- Institut Hospitalo-Universitaire ICAN, 75013 Paris, France
| | - Anna Gyulkhandanyan
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, F-75006 Paris, France; (S.A.-B.); (S.T.-C.); (A.G.)
- Institut Hospitalo-Universitaire ICAN, 75013 Paris, France
| | - Eric Hajduch
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, F-75006 Paris, France; (S.A.-B.); (S.T.-C.); (A.G.)
- Institut Hospitalo-Universitaire ICAN, 75013 Paris, France
| | - Hervé Le Stunff
- Institut des Neurosciences Paris-Saclay, Université Paris-Saclay, CNRS UMR 9197, 91400 Saclay, France;
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10
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Yang L, Jian Y, Zhang ZY, Qi BW, Li YB, Long P, Yang Y, Wang X, Huang S, Huang J, Zhou LF, Ma J, Jiang CQ, Hu YH, Xiao WJ. Network-pharmacology-based research on protective effects and underlying mechanism of Shuxin decoction against myocardial ischemia/reperfusion injury with diabetes. World J Diabetes 2023; 14:1057-1076. [PMID: 37547579 PMCID: PMC10401449 DOI: 10.4239/wjd.v14.i7.1057] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 04/14/2023] [Accepted: 05/05/2023] [Indexed: 07/12/2023] Open
Abstract
BACKGROUND Patients with diabetes mellitus are at higher risk of myocardial ischemia/ reperfusion injury (MI/RI). Shuxin decoction (SXT) is a proven recipe modi-fication from the classic herbal formula "Wu-tou-chi-shi-zhi-wan" according to the traditional Chinese medicine theory. It has been successfully used to alleviate secondary MI/RI in patients with diabetes mellitus in the clinical setting. However, the underlying mechanism is still unclear.
AIM To further determine the mechanism of SXT in attenuating MI/RI associated with diabetes.
METHODS This paper presents an ensemble model combining network pharmacology and biology. The Traditional Chinese Medicine System Pharmacology Database was accessed to select key components and potential targets of the SXT. In parallel, therapeutic targets associated with MI/RI in patients with diabetes were screened from various databases including Gene Expression Omnibus, DisGeNet, Genecards, Drugbank, OMIM, and PharmGKB. The potential targets of SXT and the therapeutic targets related to MI/RI in patients with diabetes were intersected and subjected to bioinformatics analysis using the Database for Annotation, Visualization and Integrated Discovery. The major results of bioinformatics analysis were subsequently validated by animal experiments.
RESULTS According to the hypothesis derived from bioinformatics analysis, SXT could possibly ameliorate lipid metabolism disorders and exert anti-apoptotic effects in MI/RI associated with diabetes by reducing oxidized low density lipoprotein (LDL) and inhibiting the advanced glycation end products (AGE)-receptor for AGE (RAGE) signaling pathway. Subsequent animal experiments confirmed the hypothesis. The treatment with a dose of SXT (2.8 g/kg/d) resulted in a reduction in oxidized LDL, AGEs, and RAGE, and regulated the level of blood lipids. Besides, the expression of apoptosis-related proteins such as Bax and cleaved caspase 3 was down-regulated, whereas Bcl-2 expression was up-regulated. The findings indicated that SXT could inhibit myocardial apoptosis and improve cardiac function in MI/RI in diabetic rats.
CONCLUSION This study indicated the active components and underlying molecular therapeutic mechanisms of SXT in MI/RI with diabetes. Moreover, animal experiments verified that SXT could regulate the level of blood lipids, alleviate cardiomyocyte apoptosis, and improve cardiac function through the AGE-RAGE signaling pathway.
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Affiliation(s)
- Ling Yang
- School of Clinical Medicine, Chengdu University of TCM, Chengdu 610072, Sichuan Province, China
| | - Yang Jian
- Department of Clinical Pharmacy, The General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China
| | - Zai-Yuan Zhang
- College of Medicine, Southwest Jiaotong University, Chengdu 610031, Sichuan Province, China
| | - Bao-Wen Qi
- South China Hospital of Shenzhen University, Shenzhen 518116, Guangdong Province, China
| | - Yu-Bo Li
- School of Clinical Medicine, Chengdu University of TCM, Chengdu 610072, Sichuan Province, China
| | - Pan Long
- Department of Ophthalmology, The General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China
| | - Yao Yang
- Department of Pharmacy, The General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China
| | - Xue Wang
- School of Clinical Medicine, Chengdu University of TCM, Chengdu 610072, Sichuan Province, China
| | - Shuo Huang
- School of Clinical Medicine, Chengdu University of TCM, Chengdu 610072, Sichuan Province, China
| | - Jing Huang
- College of Medicine, Southwest Jiaotong University, Chengdu 610031, Sichuan Province, China
| | - Long-Fu Zhou
- Department of Biomedical Engineering, The General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China
| | - Jie Ma
- Department of Pharmacy, The General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China
| | - Chang-Qing Jiang
- Department of Pharmacy, The General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China
| | - Yong-He Hu
- School of Clinical Medicine, Chengdu University of TCM, Chengdu 610072, Sichuan Province, China
- College of Medicine, Southwest Jiaotong University, Chengdu 610031, Sichuan Province, China
| | - Wen-Jing Xiao
- Department of Pharmacy, The General Hospital of Western Theater Command, Chengdu 610083, Sichuan Province, China
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11
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Planas-Serra L, Launay N, Goicoechea L, Heron B, Jou C, Juliá-Palacios N, Ruiz M, Fourcade S, Casasnovas C, De La Torre C, Gelot A, Marsal M, Loza-Alvarez P, García-Cazorla À, Fatemi A, Ferrer I, Portero-Otin M, Area-Gómez E, Pujol A. Sphingolipid desaturase DEGS1 is essential for mitochondria-associated membrane integrity. J Clin Invest 2023; 133:e162957. [PMID: 36951944 PMCID: PMC10178845 DOI: 10.1172/jci162957] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 03/22/2023] [Indexed: 03/24/2023] Open
Abstract
Sphingolipids function as membrane constituents and signaling molecules, with crucial roles in human diseases, from neurodevelopmental disorders to cancer, best exemplified in the inborn errors of sphingolipid metabolism in lysosomes. The dihydroceramide desaturase Δ4-dihydroceramide desaturase 1 (DEGS1) acts in the last step of a sector of the sphingolipid pathway, de novo ceramide biosynthesis. Defects in DEGS1 cause the recently described hypomyelinating leukodystrophy-18 (HLD18) (OMIM #618404). Here, we reveal that DEGS1 is a mitochondria-associated endoplasmic reticulum membrane-resident (MAM-resident) enzyme, refining previous reports locating DEGS1 at the endoplasmic reticulum only. Using patient fibroblasts, multiomics, and enzymatic assays, we show that DEGS1 deficiency disrupts the main core functions of the MAM: (a) mitochondrial dynamics, with a hyperfused mitochondrial network associated with decreased activation of dynamin-related protein 1; (b) cholesterol metabolism, with impaired sterol O-acyltransferase activity and decreased cholesteryl esters; (c) phospholipid metabolism, with increased phosphatidic acid and phosphatidylserine and decreased phosphatidylethanolamine; and (d) biogenesis of lipid droplets, with increased size and numbers. Moreover, we detected increased mitochondrial superoxide species production in fibroblasts and mitochondrial respiration impairment in patient muscle biopsy tissues. Our findings shed light on the pathophysiology of HLD18 and broaden our understanding of the role of sphingolipid metabolism in MAM function.
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Affiliation(s)
- Laura Planas-Serra
- Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Catalonia, Spain
- Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Nathalie Launay
- Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Catalonia, Spain
- Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Leire Goicoechea
- Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Catalonia, Spain
- Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Bénédicte Heron
- Department of Paediatric Neurology, Reference Centre for Neurogenetic Diseases, Armand Trousseau–La Roche Guyon University Hospital, and I2-D2 Federation, Sorbonne-Université, Paris, France
| | - Cristina Jou
- Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
- Neurometabolic Unit and Synaptic Metabolism Lab, Neurology and Pathology Department, Institut Pediàtric de Recerca, Hospital Sant Joan de Déu, and MetabERN, Barcelona, Catalonia, Spain
| | - Natalia Juliá-Palacios
- Neurometabolic Unit and Synaptic Metabolism Lab, Neurology and Pathology Department, Institut Pediàtric de Recerca, Hospital Sant Joan de Déu, and MetabERN, Barcelona, Catalonia, Spain
| | - Montserrat Ruiz
- Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Catalonia, Spain
- Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Stéphane Fourcade
- Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Catalonia, Spain
- Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
| | - Carlos Casasnovas
- Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Catalonia, Spain
- Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
- Neuromuscular Unit, Neurology Department, Hospital Universitari de Bellvitge, Universitat de Barcelona, L’Hospitalet de Llobregat, Barcelona, Catalonia, Spain
| | | | - Antoinette Gelot
- Armand Trousseau–La Roche Guyon University Hospital, Sorbonne-Université, Paris, France
| | - Maria Marsal
- ICFO–Institut de Ciències Fotòniques, The Barcelona Institute of Science and Technology, Castelldefels, Barcelona, Catalonia, Spain
| | - Pablo Loza-Alvarez
- ICFO–Institut de Ciències Fotòniques, The Barcelona Institute of Science and Technology, Castelldefels, Barcelona, Catalonia, Spain
| | - Àngels García-Cazorla
- Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
- Neurometabolic Unit and Synaptic Metabolism Lab, Neurology and Pathology Department, Institut Pediàtric de Recerca, Hospital Sant Joan de Déu, and MetabERN, Barcelona, Catalonia, Spain
| | - Ali Fatemi
- Departments of Neurology and Pediatrics, The Kennedy Krieger Institute, and Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Isidre Ferrer
- Department of Pathology and Experimental Therapeutics, University of Barcelona, L’Hospitalet de Llobregat, Barcelona, Catalonia, Spain
- Network Centre of Biomedical Research of Neurodegenerative Diseases (CIBERNED), Institute of Health Carlos III, L’Hospitalet de Llobregat, Barcelona, Catalonia, Spain
| | - Manel Portero-Otin
- Departament de Medicina Experimental, Universitat de Lleida–Institut de Recerca Biomedica de Lleida, Lleida, Catalonia, Spain
| | - Estela Area-Gómez
- Department of Neurology, Columbia University Medical Center, New York, New York, USA
- Centro de Investigaciones Biológicas “Margarita Salas,” Madrid, Spain
| | - Aurora Pujol
- Neurometabolic Diseases Laboratory, Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Catalonia, Spain
- Centre for Biomedical Research on Rare Diseases (CIBERER), Instituto de Salud Carlos III, Madrid, Spain
- Catalan Institution of Research and Advanced Studies (ICREA), Barcelona, Catalonia, Spain
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12
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Denimal D, Bergas V, Pais-de-Barros JP, Simoneau I, Demizieux L, Passilly-Degrace P, Bouillet B, Petit JM, Rouland A, Bataille A, Duvillard L, Vergès B. Liraglutide reduces plasma dihydroceramide levels in patients with type 2 diabetes. Cardiovasc Diabetol 2023; 22:104. [PMID: 37143040 PMCID: PMC10158384 DOI: 10.1186/s12933-023-01845-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 04/29/2023] [Indexed: 05/06/2023] Open
Abstract
BACKGROUND Emerging evidence supports that dihydroceramides (DhCer) and ceramides (Cer) contribute to the pathophysiology of insulin resistance and liver steatosis, and that their circulating concentrations are independently associated with cardiovascular outcomes. Circulating DhCer levels are increased in patients with type 2 diabetes (T2D). On the other hand, the GLP-1 receptor agonist liraglutide reduces major adverse cardiac events, insulin resistance and liver steatosis in T2D patients. The main purpose of the present study was therefore to investigate whether liraglutide decreases circulating levels of DhCer and Cer in T2D patients, which could be a mechanism involved in its cardiometabolic benefits. The secondary purpose was to assess the relationship between liraglutide-induced changes in DhCer/Cer levels and insulin resistance and liver steatosis. METHODS Plasma concentrations of 11 DhCer and 15 Cer species were measured by a highly-sensitive mass spectrometry system in 35 controls and 86 T2D patients before and after 6 months of liraglutide (1.2 mg/day). Insulin resistance was estimated by the triglyceride-glucose (TyG) index. Liver fat content (LFC) was assessed in 53 patients by proton magnetic resonance spectroscopy. RESULTS Plasma levels of total DhCer, 7 DhCer and 7 Cer species were increased in T2D patients compared to controls. Liraglutide decreased total DhCer by 15.1% (p = 0.005), affecting 16:0 (p = 0.037), 18:0 (p < 0.0001), 18:1 (p = 0.0005), 20:0 (p = 0.0003), 23:0 (p = 0.005) and 24:1 (p = 0.04) species. Total plasma Cer did not significantly change after liraglutide (p = 0.18), but 5 Cer species decreased significantly, i.e. 18:0 and 18:1 (both p < 0.0001), 19:0 and 24:1 (both p < 0.01) and 26:1 (p = 0.04). In multivariate analysis, the reduction in DhCer after liraglutide was independently associated with the reduction in LFC (p = 0.0005) and in TyG index (p = 0.05). CONCLUSIONS Liraglutide reduces plasma levels of numerous DhCer and Cer species in T2D patients, which may contribute to the cardiovascular benefit observed in the LEADER trial. The independent association between the decrease in plasma DhCer level with the reduction in LFC and TyG index adds new insights regarding the relationship between DhCer, liver steatosis and insulin resistance. Trial registration ClinicalTrials.gov identifier: NCT02721888.
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Affiliation(s)
- Damien Denimal
- University of Burgundy, INSERM LNC UMR1231, 21000, Dijon, France.
- Department of Biochemistry, CHU Dijon Bourgogne, 21079, Dijon, France.
| | - Victoria Bergas
- University of Burgundy, INSERM LNC UMR1231, 21000, Dijon, France
- Lipidomic Analytical Platform, University of Burgundy, 21000, Dijon, France
| | - Jean-Paul Pais-de-Barros
- University of Burgundy, INSERM LNC UMR1231, 21000, Dijon, France
- Lipidomic Analytical Platform, University of Burgundy, 21000, Dijon, France
| | - Isabelle Simoneau
- University of Burgundy, INSERM LNC UMR1231, 21000, Dijon, France
- Department of Endocrinology and Diabetology, CHU Dijon Bourgogne, 21000, Dijon, France
| | | | | | - Benjamin Bouillet
- University of Burgundy, INSERM LNC UMR1231, 21000, Dijon, France
- Department of Endocrinology and Diabetology, CHU Dijon Bourgogne, 21000, Dijon, France
| | - Jean-Michel Petit
- University of Burgundy, INSERM LNC UMR1231, 21000, Dijon, France
- Department of Endocrinology and Diabetology, CHU Dijon Bourgogne, 21000, Dijon, France
| | - Alexia Rouland
- University of Burgundy, INSERM LNC UMR1231, 21000, Dijon, France
- Department of Endocrinology and Diabetology, CHU Dijon Bourgogne, 21000, Dijon, France
| | | | - Laurence Duvillard
- University of Burgundy, INSERM LNC UMR1231, 21000, Dijon, France
- Department of Biochemistry, CHU Dijon Bourgogne, 21079, Dijon, France
| | - Bruno Vergès
- University of Burgundy, INSERM LNC UMR1231, 21000, Dijon, France
- Department of Endocrinology and Diabetology, CHU Dijon Bourgogne, 21000, Dijon, France
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Lytle KA, Chung JO, Bush NC, Triay JM, Jensen MD. Ceramide concentrations in liver, plasma, and very low-density lipoproteins of humans with severe obesity. Lipids 2023; 58:107-115. [PMID: 36849669 DOI: 10.1002/lipd.12367] [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: 10/06/2022] [Revised: 01/31/2023] [Accepted: 02/05/2023] [Indexed: 03/01/2023]
Abstract
We investigated the relationships between ceramide species concentrations in liver, plasma and very low-density lipoproteins (VLDL) particles of humans with obesity as well as the relationships between hepatic fat content and hepatic ceramide concentrations and proportional distribution. Twenty-five obese (body mass index >35 kg/m2 ) adults participated in this study. Plasma, VLDL and hepatocellular ceramide concentrations were measured by liquid chromatography/tandem mass spectrometry. The proportionate distribution of measured ceramide species differed between liver, whole plasma and the VLDL fraction. We found significant, positive correlations between the proportion of C14:0, C18:0, C20:0 and C24:1 ceramide in the liver and whole plasma (γ = 0.491, p = 0.013; γ = 0.573, p = 0.003; γ = 0.479, p = 0.015; γ = 0.716, p = 0.00006; respectively). In contrast, only the proportional contribution of C24:1 ceramide correlated positively between VLDL and liver (γ = 0.425, p = 0.013). The percent hepatic fat correlated positively with the proportion of C18:1, C18:0 and C20:0 hepatic ceramides (γ = 0.415, p = 0.039; γ = 0.426, p = 0.034; γ = 0.612, p = 0.001; respectively), but not with total hepatic ceramide concentration. The proportions of whole plasma ceramide subspecies, especially C14:0, C18:0, C20:0 and C24:1chain length, are reflective of those of hepatic ceramide subspecies in obese humans; these appear to be markers of hepatic ceramide species composition.
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Affiliation(s)
- Kelli A Lytle
- Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota, USA.,Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Jin Ook Chung
- Chonnam National University Medical School, Gwangju, Republic of Korea
| | - Nikki C Bush
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | | | - Michael D Jensen
- Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota, USA.,Division of Endocrinology and Metabolism, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
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14
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Jain V, Harper SL, Versace AM, Fingerman D, Brown GS, Bhardwaj M, Crissey MAS, Goldman AR, Ruthel G, Liu Q, Zivkovic A, Stark H, Herlyn M, Gimotty PA, Speicher DW, Amaravadi RK. Targeting UGCG Overcomes Resistance to Lysosomal Autophagy Inhibition. Cancer Discov 2023; 13:454-473. [PMID: 36331284 PMCID: PMC9905280 DOI: 10.1158/2159-8290.cd-22-0535] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2022] [Revised: 08/10/2022] [Accepted: 11/01/2022] [Indexed: 11/06/2022]
Abstract
Lysosomal autophagy inhibition (LAI) with hydroxychloroquine or DC661 can enhance cancer therapy, but tumor regrowth is common. To elucidate LAI resistance, proteomics and immunoblotting demonstrated that LAI induced lipid metabolism enzymes in multiple cancer cell lines. Lipidomics showed that LAI increased cholesterol, sphingolipids, and glycosphingolipids. These changes were associated with striking levels of GM1+ membrane microdomains (GMM) in plasma membranes and lysosomes. Inhibition of cholesterol/sphingolipid metabolism proteins enhanced LAI cytotoxicity. Targeting UDP-glucose ceramide glucosyltransferase (UGCG) synergistically augmented LAI cytotoxicity. Although UGCG inhibition decreased LAI-induced GMM and augmented cell death, UGCG overexpression led to LAI resistance. Melanoma patients with high UGCG expression had significantly shorter disease-specific survival. The FDA-approved UGCG inhibitor eliglustat combined with LAI significantly inhibited tumor growth and improved survival in syngeneic tumors and a therapy-resistant patient-derived xenograft. These findings nominate UGCG as a new cancer target, and clinical trials testing UGCG inhibition in combination with LAI are warranted. SIGNIFICANCE We discovered UGCG-dependent lipid remodeling drives resistance to LAI. Targeting UGCG with a drug approved for a lysosomal storage disorder enhanced LAI antitumor activity without toxicity. LAI and UGCG inhibition could be tested clinically in multiple cancers. This article is highlighted in the In This Issue feature, p. 247.
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Affiliation(s)
- Vaibhav Jain
- Abramson Cancer Center and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | | | - Amanda M. Versace
- Abramson Cancer Center and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | | | | | - Monika Bhardwaj
- Abramson Cancer Center and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Mary Ann S. Crissey
- Abramson Cancer Center and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | | | - Gordon Ruthel
- Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA
| | - Qin Liu
- The Wistar Institute, Philadelphia, PA 19104, USA
| | - Aleksandra Zivkovic
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetsstr. 1, 40225, Düsseldorf, Germany
| | - Holgar Stark
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetsstr. 1, 40225, Düsseldorf, Germany
| | | | - Phyllis A. Gimotty
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - David W. Speicher
- The Wistar Institute, Philadelphia, PA 19104, USA
- Corresponding authors: Ravi K. Amaravadi, MD, University of Pennsylvania, 852 BRB 2/3, 421 Curie Blvd, Philadelphia, PA 19104, Tel: 215-796-5159, ; David W. Speicher, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, Tel: 215-898-3972,
| | - Ravi K. Amaravadi
- Abramson Cancer Center and Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Corresponding authors: Ravi K. Amaravadi, MD, University of Pennsylvania, 852 BRB 2/3, 421 Curie Blvd, Philadelphia, PA 19104, Tel: 215-796-5159, ; David W. Speicher, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, Tel: 215-898-3972,
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15
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Huang JK, Lee HC. Emerging Evidence of Pathological Roles of Very-Low-Density Lipoprotein (VLDL). Int J Mol Sci 2022; 23:4300. [PMID: 35457118 PMCID: PMC9031540 DOI: 10.3390/ijms23084300] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Revised: 04/10/2022] [Accepted: 04/11/2022] [Indexed: 12/18/2022] Open
Abstract
Embraced with apolipoproteins (Apo) B and Apo E, triglyceride-enriched very-low-density lipoprotein (VLDL) is secreted by the liver into circulation, mainly during post-meal hours. Here, we present a brief review of the physiological role of VLDL and a systemic review of the emerging evidence supporting its pathological roles. VLDL promotes atherosclerosis in metabolic syndrome (MetS). VLDL isolated from subjects with MetS exhibits cytotoxicity to atrial myocytes, induces atrial myopathy, and promotes vulnerability to atrial fibrillation. VLDL levels are affected by a number of endocrinological disorders and can be increased by therapeutic supplementation with cortisol, growth hormone, progesterone, and estrogen. VLDL promotes aldosterone secretion, which contributes to hypertension. VLDL induces neuroinflammation, leading to cognitive dysfunction. VLDL levels are also correlated with chronic kidney disease, autoimmune disorders, and some dermatological diseases. The extra-hepatic secretion of VLDL derived from intestinal dysbiosis is suggested to be harmful. Emerging evidence suggests disturbed VLDL metabolism in sleep disorders and in cancer development and progression. In addition to VLDL, the VLDL receptor (VLDLR) may affect both VLDL metabolism and carcinogenesis. Overall, emerging evidence supports the pathological roles of VLDL in multi-organ diseases. To better understand the fundamental mechanisms of how VLDL promotes disease development, elucidation of the quality control of VLDL and of the regulation and signaling of VLDLR should be indispensable. With this, successful VLDL-targeted therapies can be discovered in the future.
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Affiliation(s)
- Jih-Kai Huang
- Department of General Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Hsiang-Chun Lee
- Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Internal Medicine, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Lipid Science and Aging Research Center, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Institute of Medical Science and Technology, National Sun Yat-sen University, Kaohsiung 80708, Taiwan
- Graduate Institute of Animal Vaccine Technology, National Pingtung University of Science and Technology, Pingtung 91201, Taiwan
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16
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El-Sawah SG, Rashwan HM, Althobaiti F, Aldhahrani A, Fayad E, Shabana ES, El-Hallous EI, Amen RM. AD-MSCs and BM-MSCs Ameliorating Effects on The Metabolic and Hepato-renal Abnormalities in Type 1 Diabetic Rats. Saudi J Biol Sci 2022; 29:1053-1060. [PMID: 35197774 PMCID: PMC8847940 DOI: 10.1016/j.sjbs.2021.09.067] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 09/14/2021] [Accepted: 09/25/2021] [Indexed: 01/31/2023] Open
Abstract
Diabetes mellitus (DM) is one of the most serious threats in the 21th century throughout the human population that needs to be addressed cautiously. Nowadays, stem cell injection is considered among the most promising protocols for DM therapy; owing to its marked tissues and organs repair capability. Therefore, our 4 weeks study was undertaken to elucidate the probable beneficial effects of two types of adult mesenchymal stem cells (MSCs) on metabolism disturbance and some tissue function defects in diabetic rats. Animals were classified into 4 groups; the control group, the diabetic group, the diabetic group received a single dose of adipose tissue-derived MSCs and the diabetic group received a single dose of bone marrow-derived MSCs. Herein, both MSCs treated groups markedly reduced hyperglycemia resulting from diabetes induction via lowering serum glucose and rising insulin and C-peptide levels, compared to the diabetic group. Moreover, the increased lipid fractions levels were reverted back to near normal values as a consequence to MSCs injection compared to the diabetic untreated rats. Furthermore, both MSCs types were found to have hepato-renal protective effects indicated through the decreased serum levels of both liver and kidney functions markers in the treated diabetic rats. Taken together, our results highlighted the therapeutic benefits of both MSCs types in alleviating metabolic anomalies and hepato-renal diabetic complications.
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Key Words
- AD-MSCs, Adipose-derived mesenchymal stem cells
- AGEs, Advanced glycation end products
- ALP, Alkaline phosphatase
- ALT, Alanine aminotransferase
- AST, Aspartate aminotransferase
- BM-MSCs, Bone marrow-derived mesenchymal stem cells
- BUN, Blood urea nitrogen
- CD, Cluster of differentiation
- D, Diabetic
- DM, Diabetes mellitus
- DMEM, Dulbecco's modified Eagle's medium
- DN, Diabetic nephropathy
- Diabetes
- Diabetic nephropathy
- FBG, Fasting blood glucose
- FBS, Fetal bovine serum
- HDL-C, High-density lipoprotein cholesterol
- HO-1, Heme-oxygenase 1
- HbA1c, Glycosylated hemoglobin
- Hyperlipidemia
- IPCs, Insulin producing cells
- ISCT, International Society for Cellular Therapy
- LDL-C, Low-density lipoprotein cholesterol
- LPO, Lipid peroxidation
- MSCs
- MSCs, Mesenchymal stem cells
- PBS, Phosphate-buffered saline
- ROS, Reactive oxygen species
- SEM, Standard error of mean
- SPSS, Statistical Package for Social Scientists
- STZ, Streptozotocin
- T1DM, Type 1 diabetes mellitus
- TC, Total cholesterol
- TG, Triglycerides
- TL, Total lipids
- γ-GT, gamma glutamyl transferase
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Affiliation(s)
- Shady G. El-Sawah
- Zoology Department, Faculty of Science, Arish University, North Sinai, Egypt
| | - Hanan M. Rashwan
- Zoology Department, Faculty of Science, Arish University, North Sinai, Egypt
| | - Fayez Althobaiti
- Biotechnology Department, Faculty of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - Adil Aldhahrani
- Clinical Laboratory Science Department, Turabah University College, Taif University, Taif 21995, Saudi Arabia
| | - Eman Fayad
- Biotechnology Department, Faculty of Science, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia
| | - El-Shaimaa Shabana
- Fellow of Biochemistry, Genetic Unit, Children Hospital, Faculty of Medicine, Mansoura University, Egypt
| | | | - Rehab M. Amen
- Biology Department, College of Science, University of Bisha, Bisha 61922, P.O. Box 344, Saudi Arabia
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17
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Ismaiel A, Spinu M, Socaciu C, Budisan L, Leucuta DC, Popa SL, Chis BA, Berindan-Neagoe I, Olinic DM, Dumitrascu DL. Metabolic biomarkers related to cardiac dysfunction in metabolic-dysfunction-associated fatty liver disease: a cross-sectional analysis. Nutr Diabetes 2022; 12:4. [PMID: 35042855 PMCID: PMC8764324 DOI: 10.1038/s41387-022-00182-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Revised: 11/17/2021] [Accepted: 12/07/2021] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION Hepatic steatosis is associated with cardiac systolic and diastolic dysfunction. Therefore, we evaluated metabolites and their potential cardiovascular effects in metabolic-dysfunction-associated fatty liver disease (MAFLD). MATERIALS AND METHODS We conducted a cross-sectional study involving 75 participants (38 MAFLD and 37 controls). Hepatic steatosis was confirmed by hepatic ultrasonography and SteatoTestTM. Cardiac function was assessed using echocardiography. Metabolomic analysis was conducted using ultra-high-performance liquid chromatography-mass spectrometry. RESULTS The median age for participants' age was 45 (IQR 30-56.5), with gender distribution of 35 males and 40 females. MAFLD patients had lower levels of glycyl tyrosine (p-value < 0.001), lysophosphatidylcholine (LPC) (18:2/0:0) (p-value < 0.001), LPC (22:6) (p-value < 0.001), and ceramide (Cer) (d18:0/23:0) (p-value 0.003) compared to controls. MAFLD patients presented lower left ventricular ejection fraction (LVEF), E/A ratio, E/e' ratio, and average global longitudinal strain (GLS) values, with a p-value of 0.047, <0.001, 0.008, and <0.001, respectively. Decreased glycyl tyrosine levels were significantly correlated with reduced LVEF, even after performing multiple linear regression with 95% CI (1.34-3.394, p-value < 0.001). Moreover, decreased LPC (18:2/0:0) levels remained significantly associated with E/A ratio, even after adjusting for confounding factors with 95% CI (0.008-0.258, p-value = 0.042). CONCLUSION MAFLD patients are at risk for developing cardiac systolic and subclinical systolic dysfunctions, as well as diastolic dysfunction. Decreased glycyl tyrosine levels correlate with reduced LVEF and LPC (18:2/0:0) levels with diastolic dysfunction, even after adjusting for confounding factors, suggesting their potential to be used as metabolic biomarkers in detecting cardiovascular risk.
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Affiliation(s)
- Abdulrahman Ismaiel
- 2nd Department of Internal Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, 400006, Cluj-Napoca, Romania
| | - Mihail Spinu
- Medical Clinic No. 1, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, 400006, Romania
| | - Carmen Socaciu
- Department of Biochemistry, University of Agricultural Sciences and Veterinary Medicine & BIODIATECH - Research Center on Applied Biotechnology in Diagnosis and Molecular Therapy, Cluj-Napoca, Romania
| | - Livia Budisan
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400337, Cluj-Napoca, Romania
| | - Daniel-Corneliu Leucuta
- Department of Medical Informatics and Biostatistics, "Iuliu Hatieganu" University of Medicine and Pharmacy, 400349, Cluj-Napoca, Romania
| | - Stefan-Lucian Popa
- 2nd Department of Internal Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, 400006, Cluj-Napoca, Romania.
| | - Bogdan Augustin Chis
- 2nd Department of Internal Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, 400006, Cluj-Napoca, Romania
| | - Ioana Berindan-Neagoe
- Research Center for Functional Genomics, Biomedicine and Translational Medicine, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400337, Cluj-Napoca, Romania
- Research Center for Advanced Medicine-Medfuture, Iuliu Hatieganu University of Medicine and Pharmacy, 23 Marinescu Street, 400337, Cluj-Napoca, Romania
- Department of Functional Genomics and Experimental Pathology, The Oncology Institute "Prof. Dr. Ion Chiricuta", 400015, Cluj-Napoca, Romania
| | - Dan Mircea Olinic
- Medical Clinic No. 1, "Iuliu Hatieganu" University of Medicine and Pharmacy, Cluj-Napoca, 400006, Romania
- Interventional Cardiology Department, Emergency Clinical Hospital, Cluj-Napoca, 400006, Romania
| | - Dan L Dumitrascu
- 2nd Department of Internal Medicine, "Iuliu Hatieganu" University of Medicine and Pharmacy, 400006, Cluj-Napoca, Romania
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18
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Fouqueray P, Bolze S, Dubourg J, Hallakou-Bozec S, Theurey P, Grouin JM, Chevalier C, Gluais-Dagorn P, Moller DE, Cusi K. Pharmacodynamic effects of direct AMP kinase activation in humans with insulin resistance and non-alcoholic fatty liver disease: A phase 1b study. Cell Rep Med 2021; 2:100474. [PMID: 35028615 PMCID: PMC8714938 DOI: 10.1016/j.xcrm.2021.100474] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 10/14/2021] [Accepted: 11/19/2021] [Indexed: 12/17/2022]
Abstract
AMPK is an energy sensor modulating metabolism, inflammation, and a target for metabolic disorders. Metabolic dysfunction results in lower AMPK activity. PXL770 is a direct AMPK activator, inhibiting de novo lipogenesis (DNL) and producing efficacy in preclinical models. We aimed to assess pharmacokinetics, safety, and pharmacodynamics of PXL770 in humans with metabolic syndrome-associated fatty liver disease. In a randomized, double-blind four-week trial, 12 overweight/obese patients with non-alcoholic fatty liver disease (NAFLD) and insulin resistance received PXL770 500 mg QD; 4 subjects received matching placebo. Endpoints included pharmacokinetics, hepatic fractional DNL, oral glucose tolerance testing, additional pharmacodynamic parameters, and safety. PK parameters show adequate plasma exposure in NAFLD patients for daily oral dosing. PXL770 decreases DNL—both peak and AUC are reduced versus baseline—and improves glycemic parameters and indices of insulin sensitivity versus baseline. Assessment of specific lipids reveals decrease in diacyglycerols/triacylglycerols. Safety/tolerability are similar to placebo. These results unveil initial human translation of AMPK activation and support this therapeutic strategy for metabolic disorders.
AMPK is impaired in metabolic diseases—PXL770 is a direct AMPK activator In humans with NAFLD, PXL770 inhibits hepatic de novo lipogenesis (target engagement) PXL770 also improves glucose tolerance and insulin sensitivity PXL770 reduces plasma levels of di- and triglycerides
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA
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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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Kotlyarov S, Bulgakov A. Lipid Metabolism Disorders in the Comorbid Course of Nonalcoholic Fatty Liver Disease and Chronic Obstructive Pulmonary Disease. Cells 2021; 10:2978. [PMID: 34831201 PMCID: PMC8616072 DOI: 10.3390/cells10112978] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 10/25/2021] [Accepted: 10/30/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is currently among the most common liver diseases. Unfavorable data on the epidemiology of metabolic syndrome and obesity have increased the attention of clinicians and researchers to the problem of NAFLD. The research results allow us to emphasize the systemicity and multifactoriality of the pathogenesis of liver parenchyma lesion. At the same time, many aspects of its classification, etiology, and pathogenesis remain controversial. Local and systemic metabolic disorders are also a part of the pathogenesis of chronic obstructive pulmonary disease and can influence its course. The present article analyzes the metabolic pathways mediating the links of impaired lipid metabolism in NAFLD and chronic obstructive pulmonary disease (COPD). Free fatty acids, cholesterol, and ceramides are involved in key metabolic and inflammatory pathways underlying the pathogenesis of both diseases. Moreover, inflammation and lipid metabolism demonstrate close links in the comorbid course of NAFLD and COPD.
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Affiliation(s)
- Stanislav Kotlyarov
- Department of Nursing, Ryazan State Medical University, 390026 Ryazan, Russia;
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21
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SREBP-1c and lipogenesis in the liver: an update1. Biochem J 2021; 478:3723-3739. [PMID: 34673919 DOI: 10.1042/bcj20210071] [Citation(s) in RCA: 80] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 09/28/2021] [Accepted: 09/30/2021] [Indexed: 12/13/2022]
Abstract
Sterol Regulatory Element Binding Protein-1c is a transcription factor that controls the synthesis of lipids from glucose in the liver, a process which is of utmost importance for the storage of energy. Discovered in the early nineties by B. Spiegelman and by M. Brown and J. Goldstein, it has generated more than 5000 studies in order to elucidate its mechanism of activation and its role in physiology and pathology. Synthetized as a precursor found in the membranes of the endoplasmic reticulum, it has to be exported to the Golgi and cleaved by a mechanism called regulated intramembrane proteolysis. We reviewed in 2002 its main characteristics, its activation process and its role in the regulation of hepatic glycolytic and lipogenic genes. We particularly emphasized that Sterol Regulatory Element Binding Protein-1c is the mediator of insulin effects on these genes. In the present review, we would like to update these informations and focus on the response to insulin and to another actor in Sterol Regulatory Element Binding Protein-1c activation, the endoplasmic reticulum stress.
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22
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Hajduch E, Lachkar F, Ferré P, Foufelle F. Roles of Ceramides in Non-Alcoholic Fatty Liver Disease. J Clin Med 2021; 10:jcm10040792. [PMID: 33669443 PMCID: PMC7920467 DOI: 10.3390/jcm10040792] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 02/10/2021] [Accepted: 02/12/2021] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease is one of the most common chronic liver diseases, ranging from simple steatosis to steatohepatitis, fibrosis, and cirrhosis. Its prevalence is rapidly increasing and presently affects around 25% of the general population of Western countries, due to the obesity epidemic. Liver fat accumulation induces the synthesis of specific lipid species and particularly ceramides, a sphingolipid. In turn, ceramides have deleterious effects on hepatic metabolism, a phenomenon called lipotoxicity. We review here the evidence showing the role of ceramides in non-alcoholic fatty liver disease and the mechanisms underlying their effects.
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Affiliation(s)
- Eric Hajduch
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, 75006 Paris, France; (E.H.); (F.L.); (P.F.)
- Institute of Cardiometabolism and Nutrition (ICAN), Hôpital Pitié-Salpêtrière, AP-HP, 75013 Paris, France
| | - Floriane Lachkar
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, 75006 Paris, France; (E.H.); (F.L.); (P.F.)
- Institute of Cardiometabolism and Nutrition (ICAN), Hôpital Pitié-Salpêtrière, AP-HP, 75013 Paris, France
| | - Pascal Ferré
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, 75006 Paris, France; (E.H.); (F.L.); (P.F.)
- Institute of Cardiometabolism and Nutrition (ICAN), Hôpital Pitié-Salpêtrière, AP-HP, 75013 Paris, France
| | - Fabienne Foufelle
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, 75006 Paris, France; (E.H.); (F.L.); (P.F.)
- Institute of Cardiometabolism and Nutrition (ICAN), Hôpital Pitié-Salpêtrière, AP-HP, 75013 Paris, France
- Correspondence: ; Tel.: +33-1-44-27-24-25
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Lachkar F, Ferré P, Foufelle F, Papaioannou A. Dihydroceramides: their emerging physiological roles and functions in cancer and metabolic diseases. Am J Physiol Endocrinol Metab 2021; 320:E122-E130. [PMID: 33135459 DOI: 10.1152/ajpendo.00330.2020] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Dihydroceramides (DhCers) are a type of sphingolipids that for a long time were regarded as biologically inactive. They are metabolic intermediates of the de novo sphingolipid synthesis pathway, and are converted into ceramides (Cers) with the addition of a double bond. Ceramides are abundant in tissues and have well-established biological functions. On the contrary, dihydroceramides are less prevalent, and despite their hitherto characterization as inert lipids, studies of the past decade began to unravel their implication in various biological processes distinct from those involving ceramides. These processes include cellular stress responses and autophagy, cell growth, pro-death or pro-survival pathways, hypoxia, and immune responses. In addition, their plasma concentration has been related to metabolic diseases and shown as a long-term predictor of type 2 diabetes onset. They are thus important players and potential biomarkers in pathologies ranging from diabetes to cancer and neurodegenerative diseases. The purpose of this mini-review is to highlight the emergence of dihydroceramides as a new class of bioactive sphingolipids by reporting recent advances on their biological characterization and pathological implications, focusing on cancer and metabolic diseases.
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Affiliation(s)
- Floriane Lachkar
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France
- Institute of Cardiometabolism and Nutrition (ICAN), Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Pascal Ferré
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France
- Institute of Cardiometabolism and Nutrition (ICAN), Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
- Department of Oncology and Endocrine Biochemistry, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Fabienne Foufelle
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France
- Institute of Cardiometabolism and Nutrition (ICAN), Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Alexandra Papaioannou
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université de Paris, Paris, France
- Institute of Cardiometabolism and Nutrition (ICAN), Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
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Mah M, Febbraio M, Turpin-Nolan S. Circulating Ceramides- Are Origins Important for Sphingolipid Biomarkers and Treatments? Front Endocrinol (Lausanne) 2021; 12:684448. [PMID: 34385976 PMCID: PMC8353232 DOI: 10.3389/fendo.2021.684448] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 06/23/2021] [Indexed: 01/13/2023] Open
Abstract
Biomarkers are important tools for describing the adequacy or inadequacy of biological processes (to allow for the early and accurate diagnosis) and monitoring the biological effects of intervention strategies (to identify and develop optimal dose and treatment strategies). A number of lipid biomarkers are implicated in metabolic disease and the circulating levels of these biomarkers are used in clinical settings to predict and monitor disease severity. There is convincing evidence that specific circulating ceramide species can be used as biological predictors and markers of cardiovascular disease, atherosclerosis and type 2 diabetes mellitus. Here, we review the existing literature that investigated sphingolipids as biomarkers for metabolic disease prediction. What are the advantages and disadvantages? Are circulating ceramides predominantly produced in the liver? Will hepatic sphingolipid inhibitors be able to completely prevent and treat metabolic disease? As sphingolipids are being employed as biomarkers and potential metabolic disease treatments, we explore what is currently known and what still needs to be discovered.
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