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Bu T, Gao X, Zhang R, Xu Y. FGF1 as a New Promising Therapeutic Target in Type 2 Diabetes: Advances in Research and Clinical Trials. Diabetes Metab Syndr Obes 2025; 18:1137-1149. [PMID: 40260262 PMCID: PMC12010074 DOI: 10.2147/dmso.s505285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Accepted: 04/07/2025] [Indexed: 04/23/2025] Open
Abstract
Type 2 diabetes mellitus (T2DM) represents a global health crisis, characterized by insulin resistance, β-cell dysfunction, and metabolic disturbances. Current treatments, such as insulin and metformin, often fail to address the dual challenges of β-cell preservation and insulin resistance, leading to suboptimal long-term outcomes. Fibroblast growth factor 1 (FGF1) has recently gained attention as a new promising therapeutic target due to its unique ability to regulate glucose homeostasis, enhance insulin sensitivity, and protect β-cells without inducing hypoglycemia. This review critically examines the mechanisms of FGF1 action, including its signaling pathways, interactions with metabolic regulators, and roles in key organs involved in glucose metabolism. Additionally, we summarize findings from preclinical and clinical studies and evaluate the challenges associated with its therapeutic application, including pharmacokinetic limitations, delivery strategies, and long-term safety concerns. By addressing these issues, FGF1 holds the potential to advance beyond symptom management to become a disease-modifying therapy for T2DM.
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Affiliation(s)
- Tiansheng Bu
- Department of Traditional Chinese Medicine, The Third Affiliated Hospital of Gansu University of Chinese Medicine, Baiyin, Gansu, People’s Republic of China
| | - Xiaojuan Gao
- Department of Traditional Chinese Medicine, The Third Affiliated Hospital of Gansu University of Chinese Medicine, Baiyin, Gansu, People’s Republic of China
| | - Ruina Zhang
- Department of Traditional Chinese Medicine, The Third Affiliated Hospital of Gansu University of Chinese Medicine, Baiyin, Gansu, People’s Republic of China
| | - Ying Xu
- Department of Traditional Chinese Medicine, The Third Affiliated Hospital of Gansu University of Chinese Medicine, Baiyin, Gansu, People’s Republic of China
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Maines LW, Keller SN, Smith RA, Smith CD. Opaganib Promotes Weight Loss and Suppresses High-Fat Diet-Induced Obesity and Glucose Intolerance. Diabetes Metab Syndr Obes 2025; 18:969-983. [PMID: 40191829 PMCID: PMC11971975 DOI: 10.2147/dmso.s514548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2024] [Accepted: 03/22/2025] [Indexed: 04/09/2025] Open
Abstract
Introduction Sphingolipid metabolism has been implicated in many diseases including cancer, pathologic inflammation, viral infection, neurologic pathologies and metabolic pathologies, including obesity and diabetes. We have previously shown that opaganib (aka ABC294640) inhibits three key enzymes in the sphingolipid metabolism pathway: sphingosine kinase-2, dihydroceramide desaturase and glucosylceramide synthase. We and others have demonstrated anticancer, anti-inflammatory and antiviral activities of opaganib in multiple experimental models. Furthermore, opaganib has been studied in clinical trials with patients having cancer or severe Covid-19. In the present studies, the effects of opaganib in the well-established model of High-Fat Diet (HFD)-induced obesity have been studied. Methods Male or female C57BL/6 mice were fed Control Diet (CD) or HFD and treated with vehicle or opaganib by oral gavage once daily, 5 days per week. Body weights were monitored and glucose tolerance was measured periodically for up to 16 weeks. In some experiments, obese HFD-fed mice were treated with vehicle, opaganib alone, semaglutide alone or opaganib plus semaglutide. Results Treatment with opaganib markedly suppressed weight gain in male mice fed the HFD but not in mice given the CD. Compared with mice given CD, mice on the HFD demonstrated poor glucose tolerance at 8, 12 and 16 weeks, consistent with the progression of obesity. Importantly, opaganib treatment of the HFD-fed mice abolished this developing glucose intolerance at all times of measurement. Opaganib treatment also reduced the elevation of hemoglobin A1c and the deposition of inguinal fat in HFD-fed mice. Similar results were obtained with female mice, indicating equivalent efficacy of opaganib in both sexes. Additionally, opaganib and semaglutide were equally effective in promoting body weight loss and improving glucose tolerance in obese mice. Opaganib administered either concurrently with semaglutide or as a single drug following cessation of semaglutide treatment eliminated weight rebound. Conclusion Overall, the data indicate that opaganib effectively suppresses the loss of metabolic control in mice on HFD, suggesting that opaganib may be useful alone or in combination with existing therapies for weight management and improve conditions associated with obesity and diabetes.
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Affiliation(s)
- Lynn W Maines
- Apogee Biotechnology Corporation, Hummelstown, PA, USA
| | | | - Ryan A Smith
- Apogee Biotechnology Corporation, Hummelstown, PA, USA
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Rubinelli L, Manzo OL, Sungho J, Del Gaudio I, Bareja R, Marino A, Palikhe S, Di Mauro V, Bucci M, Falcone DJ, Elemento O, Ersoy B, Diano S, Sasset L, Di Lorenzo A. Suppression of endothelial ceramide de novo biosynthesis by Nogo-B contributes to cardiometabolic diseases. Nat Commun 2025; 16:1968. [PMID: 40000621 PMCID: PMC11862206 DOI: 10.1038/s41467-025-56869-9] [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] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 02/04/2025] [Indexed: 02/27/2025] Open
Abstract
Accrual of ceramides, membrane and bioactive sphingolipids, has been implicated in endothelial dysfunction preceding cardiometabolic diseases. Yet, direct in vivo evidence, underlying mechanisms, and pathological implications are lacking. Here we show that suppression of ceramides and sphingosine-1-phosphate (S1P), a product of ceramide degradation, are causally linked to endothelial dysfunction and activation, contributing to vascular and metabolic disorders in high fat diet fed (HFD) male mice. Mechanistically, the upregulation of Nogo-B and ORMDL proteins suppress ceramide de novo biosynthesis in endothelial cells (EC) of HFD mice, resulting in vascular and metabolic dysfunctions. Systemic and endothelial specific deletion of Nogo-B restore sphingolipid signaling and functions, lowers hypertension, and hepatic glucose production in HFD. Our results demonstrate in vivo that ceramide and S1P suppression rather than accrual contributes to endothelial dysfunction and cardiometabolic diseases in HFD mice. Our study also sets a framework for the development of therapeutic strategies to treat these conditions.
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Affiliation(s)
- Luisa Rubinelli
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
- Cardiovascular Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Onorina Laura Manzo
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
- Cardiovascular Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Jin Sungho
- Institute of Human Nutrition, Columbia University Irving Medical Center, New York, NY, USA
| | - Ilaria Del Gaudio
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
- Cardiovascular Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Rohan Bareja
- The Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and New York-Presbyterian Hospital, New York, NY, USA
| | - Alice Marino
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
- Cardiovascular Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Sailesh Palikhe
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
- Cardiovascular Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Vittoria Di Mauro
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
- Cardiovascular Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Mariarosaria Bucci
- Department of Pharmacy, School of Medicine, University of Naples Federico II, Naples, Italy
| | - Domenick J Falcone
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Olivier Elemento
- The Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and New York-Presbyterian Hospital, New York, NY, USA
| | - Baran Ersoy
- Joan & Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Sabrina Diano
- Institute of Human Nutrition, Columbia University Irving Medical Center, New York, NY, USA
| | - Linda Sasset
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA
- Cardiovascular Research Institute, Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA
| | - Annarita Di Lorenzo
- Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
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Zhu Y, Yang P, Ren T, Chen Z, Tian H, Wang M, Zhang C. Integrated metabolomics and transcriptomics reveal the potential of hydroxy-alpha-sanshool in alleviating insulin resistance. Mol Med 2025; 31:76. [PMID: 39984861 PMCID: PMC11846303 DOI: 10.1186/s10020-025-01129-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2024] [Accepted: 02/12/2025] [Indexed: 02/23/2025] Open
Abstract
Hydroxy-alpha-sanshool (HAS) has attracted attention because of its various biological activities, such as hypoglycemic, hypolipidemic, and antioxidant activities. In this study, we investigated the effects of HAS on insulin resistance (IR) and its mechanism. HAS reduced fasting blood glucose (FBG), promoted insulin (INS) secretion, significantly decreased levels of interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-α and monocyte chemoattractant protein-1 (MCP-1), and increased the IL-2 level in serum of IR model mice. HAS regulated the mRNA levels of protein kinase B (Akt), B-cell lymphoma extra-large (Bcl-xL), stearoyl-CoA desaturase-1 (SCD1), nuclear factor kappa B (NF-κB), and eukaryotic translation initiation factor 4E (eIF4E). Additionally, differentially abundant metabolites in IR model mice treated with HAS were involved in these signaling pathways including prion disease, choline metabolism in cancer, regulation of lipolysis in adipocytes and the pentose phosphate pathway and positively regulated betaine abundance. In conclusion, HAS activated the phosphatidylinositol-3 kinase (PI3K)/Akt insulin and NF-κB signaling pathways to maintain glucose homeostasis and regulate IR.
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Affiliation(s)
- Yuping Zhu
- School of Basic Medicine, Guizhou Medical University, Guiyang, 550025, China
| | - Pan Yang
- School of Basic Medicine, Guizhou Medical University, Guiyang, 550025, China
| | - Tingyuan Ren
- College of Brewing and Food Engineering, Guizhou University, Guiyang, 550025, China
| | - Zhuqi Chen
- School of Clinical Medicine, Guizhou Medical University, Guiyang, 550025, China
| | - Huanhuan Tian
- School of Clinical Medicine, Guizhou Medical University, Guiyang, 550025, China
| | - Mingfen Wang
- School of Clinical Medicine, Guizhou Medical University, Guiyang, 550025, China
| | - Chunlin Zhang
- School of Basic Medicine, Guizhou Medical University, Guiyang, 550025, China.
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5
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Xie YX, Yao H, Peng JF, Ni D, Liu WT, Li CQ, Yi GH. Insight into modulators of sphingosine-1-phosphate receptor and implications for cardiovascular therapeutics. J Drug Target 2024; 32:300-310. [PMID: 38269855 DOI: 10.1080/1061186x.2024.2309577] [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: 04/26/2023] [Accepted: 10/21/2023] [Indexed: 01/26/2024]
Abstract
Cardiovascular disease is the leading cause of death worldwide, and it's of great importance to understand its underlying mechanisms and find new treatments. Sphingosine 1-phosphate (S1P) is an active lipid that exerts its effects through S1P receptors on the cell surface or intracellular signal, and regulates many cellular processes such as cell growth, cell proliferation, cell migration, cell survival, and so on. S1PR modulators are a class of modulators that can interact with S1PR subtypes to activate receptors or block their activity, exerting either agonist or functional antagonist effects. Many studies have shown that S1P plays a protective role in the cardiovascular system and regulates cardiac physiological functions mainly through interaction with cell surface S1P receptors (S1PRs). Therefore, S1PR modulators may play a therapeutic role in cardiovascular diseases. Here, we review five S1PRs and their functions and the progress of S1PR modulators. In addition, we focus on the effects of S1PR modulators on atherosclerosis, myocardial infarction, myocardial ischaemia/reperfusion injury, diabetic cardiovascular diseases, and myocarditis, which may provide valuable insights into potential therapeutic strategies for cardiovascular disease.
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Affiliation(s)
- Yu-Xin Xie
- Hunan province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, University of South China, Hengyang, Hunan, China
- Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, Institute of Cardiovascular Disease, University of South China, Hengyang, Hunan, China
| | - Hui Yao
- Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, Institute of Cardiovascular Disease, University of South China, Hengyang, Hunan, China
| | - Jin-Fu Peng
- Hunan province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, University of South China, Hengyang, Hunan, China
- Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, Institute of Cardiovascular Disease, University of South China, Hengyang, Hunan, China
| | - Dan Ni
- Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, Institute of Cardiovascular Disease, University of South China, Hengyang, Hunan, China
| | - Wan-Ting Liu
- Hunan province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, University of South China, Hengyang, Hunan, China
- Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, Institute of Cardiovascular Disease, University of South China, Hengyang, Hunan, China
| | - Chao-Quan Li
- Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, Institute of Cardiovascular Disease, University of South China, Hengyang, Hunan, China
| | - Guang-Hui Yi
- Hunan province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology, University of South China, Hengyang, Hunan, China
- Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, Institute of Cardiovascular Disease, University of South China, Hengyang, Hunan, China
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Kiyuna LA, Krishnamurthy KA, Homan EB, Langelaar-Makkinje M, Gerding A, Bos T, Oosterhuis D, Overduin RJ, Schreuder AB, de Meijer VE, Olinga P, Derks TGJ, van Eunen K, Bakker BM, Oosterveer MH. Precision-cut liver slices as an ex vivo model to assess impaired hepatic glucose production. Commun Biol 2024; 7:1479. [PMID: 39521914 PMCID: PMC11550398 DOI: 10.1038/s42003-024-07070-z] [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] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 10/14/2024] [Indexed: 11/16/2024] Open
Abstract
Fasting hypoglycemia is a severe and incompletely understood symptom of various inborn errors of metabolism (IEM). Precision-cut liver slices (PCLS) represent a promising model for studying glucose production ex vivo. This study quantified the net glucose production of human and murine PCLS in the presence of different gluconeogenic precursors. Dihydroxyacetone-supplemented slices from the fed mice yielded the highest rate, further stimulated by forskolin and dibutyryl-cAMP. Moreover, using 13C isotope tracing, we assessed the contribution of glycogenolysis and gluconeogenesis to net glucose production over time. Pharmacological inhibition of the glucose 6-phosphate transporter SLC37A4 markedly reduced net glucose production and increased lactate secretion and glycogen storage, while glucose production was completely abolished in PCLS from glycogen storage disease type Ia and Ib patients. In conclusion, this study identifies PCLS as an effective ex vivo model to study hepatic glucose production and opens opportunities for its future application in IEM research and beyond.
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Affiliation(s)
- Ligia Akemi Kiyuna
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | | | - Esther B Homan
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Miriam Langelaar-Makkinje
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Albert Gerding
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Trijnie Bos
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Dorenda Oosterhuis
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands
| | - Ruben J Overduin
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Metabolic Diseases, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Andrea B Schreuder
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Metabolic Diseases, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Vincent E de Meijer
- Section of HPB Surgery and Liver Transplantation, Department of Surgery, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Peter Olinga
- Department of Pharmaceutical Technology and Biopharmacy, University of Groningen, Groningen, The Netherlands
| | - Terry G J Derks
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Metabolic Diseases, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Karen van Eunen
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Barbara M Bakker
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
| | - Maaike H Oosterveer
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
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7
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Jiang YC, Lai K, Muirhead RP, Chung LH, Huang Y, James E, Liu XT, Wu J, Atkinson FS, Yan S, Fogelholm M, Raben A, Don AS, Sun J, Brand-Miller JC, Qi Y. Deep serum lipidomics identifies evaluative and predictive biomarkers for individualized glycemic responses following low-energy diet-induced weight loss: a PREVention of diabetes through lifestyle Intervention and population studies in Europe and around the World (PREVIEW) substudy. Am J Clin Nutr 2024; 120:864-878. [PMID: 39182617 DOI: 10.1016/j.ajcnut.2024.08.015] [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: 03/27/2024] [Revised: 07/12/2024] [Accepted: 08/19/2024] [Indexed: 08/27/2024] Open
Abstract
BACKGROUND Weight loss through lifestyle interventions, notably low-energy diets, offers glycemic benefits in populations with overweight-associated prediabetes. However, >50% of these individuals fail to achieve normoglycemia after weight loss. Circulating lipids hold potential for evaluating dietary impacts and predicting diabetes risk. OBJECTIVES This study sought to identify serum lipids that could serve as evaluative or predictive biomarkers for individual glycemic changes following diet-induced weight loss. METHODS We studied 104 participants with overweight-associated prediabetes, who lost ≥8% weight via a low-energy diet over 8 wk. High-coverage lipidomics was conducted in serum samples before and after the dietary intervention. The lipidomic recalibration was assessed using differential lipid abundance comparisons and partial least squares discriminant analyses. Associations between lipid changes and clinical characteristics were determined by Spearman correlation and Bootstrap Forest of ensemble machine learning model. Baseline lipids, predictive of glycemic parameters changes postweight loss, were assessed using Bootstrap Forest analyses. RESULTS We quantified 439 serum lipid species and 9 related organic acids. Dietary intervention significantly reduced diacylglycerols, ceramides, lysophospholipids, and ether-linked phosphatidylethanolamine. In contrast, acylcarnitines, short-chain fatty acids, organic acids, and ether-linked phosphatidylcholine increased significantly. Changes in certain lipid species (e.g., saturated and monounsaturated fatty acid-containing glycerolipids, sphingadienine-based very long-chain sphingolipids, and organic acids) were closely associated with clinical glycemic parameters. Six baseline bioactive sphingolipids primarily predicted changes in fasting plasma glucose. In addition, a number of baseline lipid species, mainly diacylglycerols and triglycerides, were predictive of clinical changes in hemoglobin A1c, insulin and homeostasis model assessment of insulin resistance. CONCLUSIONS Newly discovered serum lipidomic alterations and the associated changes in lipid-clinical variables suggest broad metabolic reprogramming related to diet-mediated glycemic control. Novel lipid predictors of glycemic outcomes could facilitate early stratification of individuals with prediabetes who are metabolically less responsive to weight loss, enabling more tailored intervention strategies beyond 1-size-fits-all lifestyle modification advice. The PREVIEW lifestyle intervention study was registered at clinicaltrials.gov as NCT01777893 (https://clinicaltrials.gov/study/NCT01777893).
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Affiliation(s)
- Yingxin Celia Jiang
- Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia
| | - Kaitao Lai
- Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia; ANZAC Research Institute, The University of Sydney, Sydney, New South Wales, Australia
| | - Roslyn Patricia Muirhead
- Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia; Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Long Hoa Chung
- Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia
| | - Yu Huang
- Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia
| | - Elizaveta James
- Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Xin Tracy Liu
- Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia
| | - Julian Wu
- Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia; Barker College, Hornsby, New South Wales, Australia
| | - Fiona S Atkinson
- Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia; School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney, New South Wales, Australia
| | - Shuang Yan
- Department of Endocrinology and Metabolism Diseases, The 4th Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Mikael Fogelholm
- Department of Food and Nutrition, University of Helsinki, Helsinki, Finland
| | - Anne Raben
- Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark; Clinical Research, Copenhagen University Hospital-Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Anthony Simon Don
- Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia
| | - Jing Sun
- Rural Health Research Institute, Charles Sturt University, Leeds Parade, New South Wales, Australia; School of Medicine and Dentistry, Menzies Health Institute Queensland, Institute for Integrated Intelligence and Systems, Griffith University, Southport, Queensland, Australia.
| | - Jennie Cecile Brand-Miller
- Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia; School of Life and Environmental Sciences, Faculty of Science, The University of Sydney, Sydney, New South Wales, Australia.
| | - Yanfei Qi
- Centenary Institute, The University of Sydney, Sydney, New South Wales, Australia; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia; School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
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Foran D, Antoniades C, Akoumianakis I. Emerging Roles for Sphingolipids in Cardiometabolic Disease: A Rational Therapeutic Target? Nutrients 2024; 16:3296. [PMID: 39408263 PMCID: PMC11478599 DOI: 10.3390/nu16193296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 09/19/2024] [Accepted: 09/25/2024] [Indexed: 10/20/2024] Open
Abstract
Cardiovascular disease is a leading cause of morbidity and mortality. New research elucidates increasingly complex relationships between cardiac and metabolic health, giving rise to new possible therapeutic targets. Sphingolipids are a heterogeneous class of bioactive lipids with critical roles in normal human physiology. They have also been shown to play both protective and deleterious roles in the pathogenesis of cardiovascular disease. Ceramides are implicated in dysregulating insulin signalling, vascular endothelial function, inflammation, oxidative stress, and lipoprotein aggregation, thereby promoting atherosclerosis and vascular disease. Ceramides also advance myocardial disease by enhancing pathological cardiac remodelling and cardiomyocyte death. Glucosylceramides similarly contribute to insulin resistance and vascular inflammation, thus playing a role in atherogenesis and cardiometabolic dysfunction. Sphingosing-1-phosphate, on the other hand, may ameliorate some of the pathological functions of ceramide by protecting endothelial barrier integrity and promoting cell survival. Sphingosine-1-phosphate is, however, implicated in the development of cardiac fibrosis. This review will explore the roles of sphingolipids in vascular, cardiac, and metabolic pathologies and will evaluate the therapeutic potential in targeting sphingolipids with the aim of prevention and reversal of cardiovascular disease in order to improve long-term cardiovascular outcomes.
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Affiliation(s)
| | | | - Ioannis Akoumianakis
- Cardiovascular Medicine Division, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK; (D.F.); (C.A.)
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Green CD, Brown RDR, Uranbileg B, Weigel C, Saha S, Kurano M, Yatomi Y, Spiegel S. Sphingosine kinase 2 and p62 regulation are determinants of sexual dimorphism in hepatocellular carcinoma. Mol Metab 2024; 86:101971. [PMID: 38925249 PMCID: PMC11261290 DOI: 10.1016/j.molmet.2024.101971] [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: 04/13/2024] [Revised: 06/16/2024] [Accepted: 06/18/2024] [Indexed: 06/28/2024] Open
Abstract
OBJECTIVE Hepatocellular carcinoma (HCC) is the third leading cause of cancer mortality, and its incidence is increasing due to endemic obesity. HCC is sexually dimorphic in both humans and rodents with higher incidence in males, although the mechanisms contributing to these correlations remain unclear. Here, we examined the role of sphingosine kinase 2 (SphK2), the enzyme that regulates the balance of bioactive sphingolipid metabolites, sphingosine-1-phosphate (S1P) and ceramide, in gender specific MASH-driven HCC. METHODS Male and female mice were fed a high fat diet with sugar water, a clinically relevant model that recapitulates MASH-driven HCC in humans followed by physiological, biochemical cellular and molecular analyses. In addition, correlations with increased risk of HCC recurrence were determined in patients. RESULTS Here, we report that deletion of SphK2 protects both male and female mice from Western diet-induced weight gain and metabolic dysfunction without affecting hepatic lipid accumulation or fibrosis. However, SphK2 deficiency decreases chronic diet-induced hepatocyte proliferation in males but increases it in females. Remarkably, SphK2 deficiency reverses the sexual dimorphism of HCC, as SphK2-/- male mice are protected whereas the females develop liver cancer. Only in male mice, chronic western diet induced accumulation of the autophagy receptor p62 and its downstream mediators, the antioxidant response target NQO1, and the oncogene c-Myc. SphK2 deletion repressed these known drivers of HCC development. Moreover, high p62 expression correlates with poor survival in male HCC patients but not in females. In hepatocytes, lipotoxicity-induced p62 accumulation is regulated by sex hormones and prevented by SphK2 deletion. Importantly, high SphK2 expression in male but not female HCC patients is associated with a more aggressive HCC differentiation status and increased risk of cancer recurrence. CONCLUSIONS This work identifies SphK2 as a potential regulator of HCC sexual dimorphism and suggests SphK2 inhibitors now in clinical trials could have opposing, gender-specific effects in patients.
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Affiliation(s)
- Christopher D Green
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
| | - Ryan D R Brown
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Baasanjav Uranbileg
- Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan
| | - Cynthia Weigel
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Sumit Saha
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Makoto Kurano
- Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan; CREST, JST, Japan
| | - Yutaka Yatomi
- Department of Clinical Laboratory Medicine, The University of Tokyo, Tokyo, Japan; CREST, JST, Japan
| | - Sarah Spiegel
- Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
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10
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Rustamov J, Roh YS, Hong JT, Yoo HS. GT-11 impairs insulin signaling through modulation of sphingolipid metabolism in C2C12 myotubes. Life Sci 2024; 342:122534. [PMID: 38408637 DOI: 10.1016/j.lfs.2024.122534] [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: 09/08/2023] [Revised: 02/18/2024] [Accepted: 02/22/2024] [Indexed: 02/28/2024]
Abstract
AIMS Sphingolipids are involved in the regulation of insulin signaling, which is linked to the development of insulin resistance, leading to diabetes mellitus. We aimed to study whether modulation of sphingolipid levels by GT-11 may regulate insulin signaling in C2C12 myotubes. MAIN METHODS We investigated the effects of sphingolipid metabolism on Akt phosphorylation and glucose uptake using C2C12 myotubes. Either GT-11, an inhibitor of dihydroceramide desaturase 1 and S1P lyase, or siRNA targeting Sgpl1, the gene encoding the enzyme, was employed to determine the effect of sphingolipid metabolism modulation on insulin signaling. Western blotting and glucose uptake assays were used to evaluate the effect of treatments on insulin signaling. Sphingolipid metabolites were analyzed by high performance liquid chromatography (HPLC). KEY FINDINGS Treatment with GT-11 resulted in decreased Akt phosphorylation and reduced glucose uptake. Silencing the Sgpl1 gene, which encodes S1P lyase, mimicked these findings, suggesting the potential for regulating insulin signaling through S1P lyase modulation. GT-11 modulated sphingolipid metabolism, inducing the accumulation of sphingolipids. Using PF-543 and ARN14974 to inhibit sphingosine kinases and acid ceramidase, respectively, we identified a significant interplay between sphingosine, S1P lyase, and insulin signaling. Treatment with either exogenous sphingosine or palmitic acid inhibited Akt phosphorylation, and reduced S1P lyase activity. SIGNIFICANCE Our findings highlight the importance of close relationship between sphingolipid metabolism and insulin signaling in C2C12 myotubes, pointing to its potential therapeutic relevance for diabetes mellitus.
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Affiliation(s)
- Javokhir Rustamov
- College of Pharmacy, Chungbuk National University, Osongsaengmyeong 1-ro, Heungduk-gu, Cheongju, Republic of Korea
| | - Yoon-Seok Roh
- College of Pharmacy, Chungbuk National University, Osongsaengmyeong 1-ro, Heungduk-gu, Cheongju, Republic of Korea
| | - Jin Tae Hong
- College of Pharmacy, Chungbuk National University, Osongsaengmyeong 1-ro, Heungduk-gu, Cheongju, Republic of Korea
| | - Hwan-Soo Yoo
- College of Pharmacy, Chungbuk National University, Osongsaengmyeong 1-ro, Heungduk-gu, Cheongju, Republic of Korea.
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11
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Ha HT, Liu S, Nguyen XT, Vo LK, Leong NC, Nguyen DT, Balamurugan S, Lim PY, Wu Y, Seong E, Nguyen TQ, Oh J, Wenk MR, Cazenave-Gassiot A, Yapici Z, Ong WY, Burmeister M, Nguyen LN. Lack of SPNS1 results in accumulation of lysolipids and lysosomal storage disease in mouse models. JCI Insight 2024; 9:e175462. [PMID: 38451736 PMCID: PMC11141868 DOI: 10.1172/jci.insight.175462] [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: 09/05/2023] [Accepted: 03/05/2024] [Indexed: 03/09/2024] Open
Abstract
Accumulation of sphingolipids, especially sphingosines, in the lysosomes is a key driver of several lysosomal storage diseases. The transport mechanism for sphingolipids from the lysosome remains unclear. Here, we identified SPNS1, which shares the highest homology to SPNS2, a sphingosine-1-phosphate (S1P) transporter, functions as a transporter for lysolipids from the lysosome. We generated Spns1-KO cells and mice and employed lipidomic and metabolomic approaches to reveal SPNS1 ligand identity. Global KO of Spns1 caused embryonic lethality between E12.5 and E13.5 and an accumulation of sphingosine, lysophosphatidylcholines (LPC), and lysophosphatidylethanolamines (LPE) in the fetal livers. Similarly, metabolomic analysis of livers from postnatal Spns1-KO mice presented an accumulation of sphingosines and lysoglycerophospholipids including LPC and LPE. Subsequently, biochemical assays showed that SPNS1 is required for LPC and sphingosine release from lysosomes. The accumulation of these lysolipids in the lysosomes of Spns1-KO mice affected liver functions and altered the PI3K/AKT signaling pathway. Furthermore, we identified 3 human siblings with a homozygous variant in the SPNS1 gene. These patients suffer from developmental delay, neurological impairment, intellectual disability, and cerebellar hypoplasia. These results reveal a critical role of SPNS1 as a promiscuous lysolipid transporter in the lysosomes and link its physiological functions with lysosomal storage diseases.
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Affiliation(s)
- Hoa T.T. Ha
- Department of Biochemistry, Yong Loo Lin School of Medicine
| | - SiYi Liu
- Department of Biochemistry, Yong Loo Lin School of Medicine
| | | | - Linh K. Vo
- Department of Biochemistry, Yong Loo Lin School of Medicine
| | | | - Dat T. Nguyen
- Department of Biochemistry, Yong Loo Lin School of Medicine
| | | | - Pei Yen Lim
- Department of Biochemistry, Yong Loo Lin School of Medicine
- Singapore Lipidomics Incubator (SLING), Life Sciences Institute, and
| | - YaJun Wu
- Department of Anatomy, Yong Loo-Lin School of Medicine, National University of Singapore, Singapore
| | - Eunju Seong
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, USA
| | - Toan Q. Nguyen
- Department of Biochemistry, Yong Loo Lin School of Medicine
| | - Jeongah Oh
- Department of Biochemistry, Yong Loo Lin School of Medicine
- Singapore Lipidomics Incubator (SLING), Life Sciences Institute, and
| | - Markus R. Wenk
- Department of Biochemistry, Yong Loo Lin School of Medicine
- Singapore Lipidomics Incubator (SLING), Life Sciences Institute, and
| | - Amaury Cazenave-Gassiot
- Department of Biochemistry, Yong Loo Lin School of Medicine
- Singapore Lipidomics Incubator (SLING), Life Sciences Institute, and
| | - Zuhal Yapici
- Department of Neurology, Faculty of Medicine, Istanbul University, Istanbul, Turkey
| | - Wei-Yi Ong
- Department of Anatomy, Yong Loo-Lin School of Medicine, National University of Singapore, Singapore
| | - Margit Burmeister
- Michigan Neuroscience Institute, University of Michigan, Ann Arbor, USA
- Departments of Computational Medicine and Biochemistry, Psychiatry, and Human Genetics, University of Michigan, Ann Arbor, USA
| | - Long N. Nguyen
- Department of Biochemistry, Yong Loo Lin School of Medicine
- Singapore Lipidomics Incubator (SLING), Life Sciences Institute, and
- Cardiovascular Disease Research (CVD) Programme, Yong Loo Lin School of Medicine
- Immunology Program, Life Sciences Institute, and
- Immunology Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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12
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Yu G, Sun M, Zhang T, Xu H, Wang J, Ye W, Wang P, Zhang S, Zhang C, Sun Y. Lanhuashen stimulates the positive cross-regulation mediated by the S1P axis to ameliorate the disorder of glucolipid metabolism induced by the high sucrose diet in Drosophila melanogaster. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117248. [PMID: 37804923 DOI: 10.1016/j.jep.2023.117248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Revised: 09/11/2023] [Accepted: 09/28/2023] [Indexed: 10/09/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Herba Wanlenbergiae, named 'Lanhuashen' (LHS) in Chinese, is derived from the dried herba of Wahlenbergia marginata (Thunb.) A.DC. It is an abundant resource that has been used in traditional Chinese medicine (TCM) for over 600 years. LHS has the effects of enriching consumptive disease and relieving deficient heat, consistent with the therapy for type 2 diabetes mellitus (T2DM) in TCM. As the basic remedy of Yulan Jiangtang capsules, a listed Chinese medicine specifically for treating T2DM, LHS is a potential candidate for an anti-T2DM drug. However, due to the lack of pharmacodynamic studies and chemical component analysis, the application and development of LHS as a treatment for T2DM have been hindered. AIM OF THE STUDY To evaluate the regulation of the disorder of glucolipid metabolism using LHS extracts and its therapeutic potential in T2DM. MATERIALS AND METHODS Chemical components in LHS extracts were analysed using UPLC-Q Exactive-Orbitrap-MS. Subsequently, high sucrose diet (HSD)-induced Drosophila melanogaster were used as suitable models for T2DM in vivo. Behavioural and biochemical tests were performed to evaluate the regulation of the disorder of glucolipid metabolism using LHS in T2DM flies. Furthermore, integrative metabolomic and transcriptomic analysis was applied to reveal the specific effects of LHS extracts on metabolites and genes. Meanwhile, bioinformatic analysis was carried out to predict the targeted transcription factors (TFs) and potentially effective components of LHS extracts. RESULTS We redefined the chemical profile of LHS with 76 identified chemical components, including 65 chemical components for the first time. As indicated by decreased trehalose, glucose and triglyceride levels and increased total protein levels, LHS extracts were perceived to alleviate the disorder of glucolipid metabolism in HSD-induced T2DM fruit flies. Integrative metabolomic and transcriptomic analysis revealed that LHS extracts eliminated the accumulation of sphingolipids and subsequently stimulated the positive cross-regulation mediated by the sphingosine 1-phosphate (S1P) axis, resulting in the activation of the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt) signalling pathway and inhibition of lysosome-mediated apoptosis. Bioinformatic analysis revealed that the upstream TFs, transcriptional enhancer factor TEF-5 (TEAD3) and peroxisome proliferator-activated receptor alpha (PPARA), were the potential targets of atractylenolide III, dihydrokaempferol and syringaldehyde, the potentially effective components of LHS extracts. Therefore, this TF network was plausibly the basis for the efficacy. CONCLUSIONS LHS extracts broadly modulated TF-dependent gene expression and subsequently stimulated the positive cross-regulation mediated by the S1P axis to ameliorate the disorder of glucolipid metabolism. Our study provides critical evidence considering LHS as a potential drug candidate for T2DM, inspiring the discovery and development of innovative therapeutic agents based on the cross-regulation mediated by the S1P axis for treating T2DM and related complications.
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Affiliation(s)
- Gengyuan Yu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China.
| | - Mo Sun
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA 30332, USA.
| | - Tonghua Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China.
| | - Haoran Xu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China.
| | - Jiaqi Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China.
| | - Wanting Ye
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China.
| | - Peng Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China.
| | - Shiyun Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China.
| | - Chenning Zhang
- Department of Pharmacy, Xiangyang No. 1 People's Hospital Affiliated to Hubei University of Medicine, Xiangyang 441000, China.
| | - Yikun Sun
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 102488, China.
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13
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Kajita K, Ishii I, Mori I, Asano M, Fuwa M, Morita H. Sphingosine 1-Phosphate Regulates Obesity and Glucose Homeostasis. Int J Mol Sci 2024; 25:932. [PMID: 38256005 PMCID: PMC10816022 DOI: 10.3390/ijms25020932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 01/04/2024] [Accepted: 01/05/2024] [Indexed: 01/24/2024] Open
Abstract
One of the major global health and welfare issues is the treatment of obesity and associated metabolic disorders, such as type 2 diabetes mellitus and nonalcoholic fatty liver disease. Obesity, caused by the excessive accumulation of triglycerides in adipose tissues, induces adipocyte dysfunction, followed by inflammation, in adipose tissues and lipotoxicity in nonadipose tissues. Several studies have shown that obesity and glucose homeostasis are influenced by sphingolipid mediators, including ceramide and sphingosine 1-phosphate (S1P). Cellular accumulation of ceramide impairs pancreatic β-cell survival, confers insulin resistance in the liver and the skeletal muscle, and deteriorates adipose tissue inflammation via unknown molecular mechanisms. The roles of S1P are more complicated, because there are five cell-surface S1P receptors (S1PRs: S1P1-5) which have altered functions, different cellular expression patterns, and inapparent intracellular targets. Recent findings, including those by our group, support the notable concept that the pharmacological activation of S1P1 or S1P3 improves obesity and associated metabolic disorders, whereas that of S1P2 has the opposite effect. In addition, the regulation of S1P production by sphingosine kinase (SphK) is an essential factor affecting glucose homeostasis. This review summarizes the current knowledge on SphK/S1P/S1PR signaling in and against obesity, insulin resistance, and associated disorders.
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Affiliation(s)
- Kazuo Kajita
- Department of Health and Nutrition, Faculty of Home Economics, Gifu Women’s University, 80 Taromaru, Gifu 501-2592, Japan
| | - Isao Ishii
- Department of Health Chemistry, Showa Pharmaceutical University, 3-3165 Higashitamagawagakuen, Machida 194-8543, Japan
| | - Ichiro Mori
- Department of General Medicine and General Internal Medicine, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; (I.M.); (M.A.); (M.F.); (H.M.)
| | - Motochika Asano
- Department of General Medicine and General Internal Medicine, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; (I.M.); (M.A.); (M.F.); (H.M.)
| | - Masayuki Fuwa
- Department of General Medicine and General Internal Medicine, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; (I.M.); (M.A.); (M.F.); (H.M.)
| | - Hiroyuki Morita
- Department of General Medicine and General Internal Medicine, Graduate School of Medicine, Gifu University, 1-1 Yanagido, Gifu 501-1194, Japan; (I.M.); (M.A.); (M.F.); (H.M.)
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14
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Liu XT, Huang Y, Liu D, Jiang YC, Zhao M, Chung LH, Han XD, Zhao Y, Chen J, Coleman P, Ting KK, Tran C, Su Y, Dennis CV, Bhatnagar A, Liu K, Don AS, Vadas MA, Gorrell MD, Zhang S, Murray M, Kavurma MM, McCaughan GW, Gamble JR, Qi Y. Targeting the SphK1/S1P/PFKFB3 axis suppresses hepatocellular carcinoma progression by disrupting glycolytic energy supply that drives tumor angiogenesis. J Transl Med 2024; 22:43. [PMID: 38200582 PMCID: PMC10782643 DOI: 10.1186/s12967-023-04830-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 12/24/2023] [Indexed: 01/12/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) remains a leading life-threatening health challenge worldwide, with pressing needs for novel therapeutic strategies. Sphingosine kinase 1 (SphK1), a well-established pro-cancer enzyme, is aberrantly overexpressed in a multitude of malignancies, including HCC. Our previous research has shown that genetic ablation of Sphk1 mitigates HCC progression in mice. Therefore, the development of PF-543, a highly selective SphK1 inhibitor, opens a new avenue for HCC treatment. However, the anti-cancer efficacy of PF-543 has not yet been investigated in primary cancer models in vivo, thereby limiting its further translation. METHODS Building upon the identification of the active form of SphK1 as a viable therapeutic target in human HCC specimens, we assessed the capacity of PF-543 in suppressing tumor progression using a diethylnitrosamine-induced mouse model of primary HCC. We further delineated its underlying mechanisms in both HCC and endothelial cells. Key findings were validated in Sphk1 knockout mice and lentiviral-mediated SphK1 knockdown cells. RESULTS SphK1 activity was found to be elevated in human HCC tissues. Administration of PF-543 effectively abrogated hepatic SphK1 activity and significantly suppressed HCC progression in diethylnitrosamine-treated mice. The primary mechanism of action was through the inhibition of tumor neovascularization, as PF-543 disrupted endothelial cell angiogenesis even in a pro-angiogenic milieu. Mechanistically, PF-543 induced proteasomal degradation of the critical glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, thus restricting the energy supply essential for tumor angiogenesis. These effects of PF-543 could be reversed upon S1P supplementation in an S1P receptor-dependent manner. CONCLUSIONS This study provides the first in vivo evidence supporting the potential of PF-543 as an effective anti-HCC agent. It also uncovers previously undescribed links between the pro-cancer, pro-angiogenic and pro-glycolytic roles of the SphK1/S1P/S1P receptor axis. Importantly, unlike conventional anti-HCC drugs that target individual pro-angiogenic drivers, PF-543 impairs the PFKFB3-dictated glycolytic energy engine that fuels tumor angiogenesis, representing a novel and potentially safer therapeutic strategy for HCC.
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Affiliation(s)
- Xin Tracy Liu
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, 2050, Australia
| | - Yu Huang
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, 2050, Australia
| | - Da Liu
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, 2050, Australia
| | - Yingxin Celia Jiang
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, 2050, Australia
| | - Min Zhao
- School of Science, Technology and Engineering, University of the Sunshine Coast, Maroochydore DC, QLD, 4558, Australia
| | - Long Hoa Chung
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, 2050, Australia
| | - Xingxing Daisy Han
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, 2050, Australia
| | - Yinan Zhao
- Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian, 116600, Liaoning, China
| | - Jinbiao Chen
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, 2050, Australia
| | - Paul Coleman
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, 2050, Australia
| | - Ka Ka Ting
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, 2050, Australia
| | - Collin Tran
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Yingying Su
- Sydney Microscopy and Microanalysis, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Claude Vincent Dennis
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney Local Health District, Sydney, NSW, 2050, Australia
| | - Atul Bhatnagar
- Sydney Mass Spectrometry, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Ken Liu
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney Local Health District, Sydney, NSW, 2050, Australia
| | - Anthony Simon Don
- School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia
| | - Mathew Alexander Vadas
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, 2050, Australia
| | - Mark Douglas Gorrell
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, 2050, Australia
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney Local Health District, Sydney, NSW, 2050, Australia
| | - Shubiao Zhang
- Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian, 116600, Liaoning, China
| | - Michael Murray
- Sydney Pharmacy School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, 2006, Australia
| | | | - Geoffrey William McCaughan
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, 2050, Australia
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney Local Health District, Sydney, NSW, 2050, Australia
| | - Jennifer Ruth Gamble
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, 2050, Australia
| | - Yanfei Qi
- Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, 2050, Australia.
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15
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Chen Q, Jiang FJ, Gao X, Li XY, Xia P. Steatotic hepatocyte-derived extracellular vesicles promote β-cell apoptosis and diabetes via microRNA-126a-3p. Liver Int 2023; 43:2560-2570. [PMID: 37337778 DOI: 10.1111/liv.15654] [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: 08/07/2022] [Revised: 06/08/2023] [Accepted: 06/10/2023] [Indexed: 06/21/2023]
Abstract
Extracellular vesicles (EVs) have emerged as a unique mediator of interorgan communications, playing important roles in the pathophysiologic process of various diseases, including diabetes and other metabolic diseases. Here, we reported that the EVs released by steatotic hepatocytes exerted a detrimental effect on pancreatic β cells, leading to β-cell apoptosis and dysfunction. The effect was profoundly attributable to an up-regulation of miR-126a-3p in the steatotic hepatocyte-derived EVs. Accordingly, overexpression of miR-126a-3p promoted, whereas inhibition of miR-126a-3p prevented β-cell apoptosis, through a mechanism related to its target gene, insulin receptor substrate-2. Moreover, inhibition of miR-126a-3p by its specific antagomir was able to partially reverse the loss of β-cell mass and ameliorate hyperglycaemia in diabetic mice. Thus, the findings reveal a novel pathogenic role of steatotic hepatocyte-derived EVs, which mechanistically links nonalcoholic fatty liver disease to the development of diabetes.
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Affiliation(s)
- Qi Chen
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Fang-Jie Jiang
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xin Gao
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xiao-Ying Li
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Pu Xia
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
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16
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Zhang C, Sui Y, Liu S, Yang M. Molecular mechanisms of metabolic disease-associated hepatic inflammation in non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. EXPLORATION OF DIGESTIVE DISEASES 2023:246-275. [DOI: https:/doi.org/10.37349/edd.2023.00029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 08/05/2023] [Indexed: 11/27/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the leading chronic liver disease worldwide, with a progressive form of non-alcoholic steatohepatitis (NASH). It may progress to advanced liver diseases, including liver fibrosis, cirrhosis, and hepatocellular carcinoma. NAFLD/NASH is a comorbidity of many metabolic disorders such as obesity, insulin resistance, type 2 diabetes, cardiovascular disease, and chronic kidney disease. These metabolic diseases are often accompanied by systemic or extrahepatic inflammation, which plays an important role in the pathogenesis and treatment of NAFLD or NASH. Metabolites, such as short-chain fatty acids, impact the function, inflammation, and death of hepatocytes, the primary parenchymal cells in the liver tissue. Cholangiocytes, the epithelial cells that line the bile ducts, can differentiate into proliferative hepatocytes in chronic liver injury. In addition, hepatic non-parenchymal cells, including liver sinusoidal endothelial cells, hepatic stellate cells, and innate and adaptive immune cells, are involved in liver inflammation. Proteins such as fibroblast growth factors, acetyl-coenzyme A carboxylases, and nuclear factor erythroid 2-related factor 2 are involved in liver metabolism and inflammation, which are potential targets for NASH treatment. This review focuses on the effects of metabolic disease-induced extrahepatic inflammation, liver inflammation, and the cellular and molecular mechanisms of liver metabolism on the development and progression of NAFLD and NASH, as well as the associated treatments.
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Affiliation(s)
- Chunye Zhang
- Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA
| | - Yuxiang Sui
- School of Life Science, Shanxi Normal University, Linfen 041004, Shanxi Province, China
| | - Shuai Liu
- The First Affiliated Hospital, Zhejiang University, Hangzhou 310006, Zhejiang Province, China
| | - Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65211, USA
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Zhang L, Ma P, Wang Z, Xu T, Lam SM, Shui G, Wang Y, Xie J, Qiang G. Multiomics Approaches Identify Biomarkers for BAT Thermogenesis. J Proteome Res 2023; 22:3332-3347. [PMID: 37616386 DOI: 10.1021/acs.jproteome.3c00423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/26/2023]
Abstract
Brown adipose tissue (BAT) thermogenesis confers beneficial effects on metabolic diseases such as obesity and type-2 diabetes. Nevertheless, the mechanism and lipid driving the process that evokes this response have not been investigated yet. Here, a multiomics approach of integrative transcriptomics and lipidomics is used to explore the mechanism of regulating thermogenesis in BAT and providing promising lipid biomarkers and biomarker genes for thermogenic activators as antiobesity drugs. Lipidomics analysis demonstrated that a high abundance of glycerophospholipids and sphingolipids was more significant in BAT than in WAT. Enrichment analysis of upregulated DEGs between WAT and BAT screened suggested that the differences were mainly involved in lipid metabolism. Besides, β3-adrenergic agonist stimulation reduced the levels of TAG and DAG and increased the content of PC, PE, CL, and LPC and expression of genes involved in thermogenesis, fatty acid elongation, and glycerophospholipid metabolism in BAT. In this study, based on interpreting the inherent characterization of BAT as thermogenic tissue through comparison with WAT as fat storage tissue, adrenergic stimulation-induced BAT thermogenesis further identified specific lipid biomarkers (7 TAG species, 10 PC species, 1 LPC species, and 1 CL species) and Elovl3 and Crat gene biomarkers, which may provide targets for combating obesity by boosting BAT thermogenesis.
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Affiliation(s)
- Li Zhang
- Inner Mongolia Clinical College, Inner Mongolia Medical University, Hohhot 010110, China
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing 100050, China
| | - Peng Ma
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing 100050, China
| | - Zijing Wang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing 100050, China
| | - Tianshu Xu
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing 100050, China
| | - Sin Man Lam
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Guanghou Shui
- State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China
| | - Yuzhen Wang
- College of Life Science, Inner Mongolia Agricultural University, Hohhot 010018, China
| | - Jiming Xie
- Inner Mongolia Clinical College, Inner Mongolia Medical University, Hohhot 010110, China
- Clinical Laboratory, Inner Mongolia People's Hospital, Hohhot 010020, China
| | - Guifen Qiang
- State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College and Beijing Key Laboratory of Drug Target and Screening Research, Beijing 100050, China
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18
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Hoseini Z, Behpour N, Hoseini R. Vitamin D improves the antidiabetic effectiveness of aerobic training via modulation of Akt, PEPCK, and G6Pase expression. Diabetol Metab Syndr 2023; 15:184. [PMID: 37689713 PMCID: PMC10492382 DOI: 10.1186/s13098-023-01158-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 08/31/2023] [Indexed: 09/11/2023] Open
Abstract
BACKGROUND Although the effect of Vitamin D Supplementation (Vit D) on several chronic diseases has been well conceded, its role in diabetes remains ambiguous. The present study investigated the interactive effects of Aerobic Training (AT) and different Vit D doses on Protein Kinase B (Akt), Phosphoenolpyruvate Carboxylase (PEPCK), and Glucose-6-Phosphatase (G6Pase) protein expressions in hepatocytes of type-2 diabetic rats. METHODS Fifty-six male Wistar rats were divided into 2 groups SHAM (non-diabetic control; n = 8), and diabetic (n = 48). Then, diabetic rats were divided into six groups: AT with high doses of Vit D (D + AT + HD), AT with moderate doses of Vit D (D + AT + MD), high doses of Vit D (D + HD), moderate doses of Vit D (D + MD), AT receiving vehicle (sesame oil; D + AT + oil), and control (oil-receiving). D + AT + HD and D + HD groups received 10,000 IU of Vit D; while D + AT + MD and D + MD groups receive 5000 IU of Vit D once a week by injection; D + AT + oil and SHAM groups received sesame oil. Diabetes was induced via intraperitoneal (IP) injection of streptozotocin (50 mg/kg body weight). After 2 months of intervention, serum insulin, glucose, and visceral fat were measured; protein expressions of Akt, PEPCK, and G6Pase were assessed by western blotting. The paired t-test, one-way analysis of variance (One-Way ANOVA), and the Tukey post hoc test were used at the signification level of P < 0.05. RESULTS Our data indicate that the diabeticization of rats increased the level of insulin, glucose, and PEPCK and G6Pase protein expressions and decreased the expression of the Akt (P < 0.05 for all variables). Combined AT and moderate or high Vit D significantly reduced body weight (P = 0.001; P = 0.001), body mass index (P = 0.001; P = 0.002), food intake (P = 0.001; P = 0.001) comparing the pre-test with the post-test, respectively. Also, AT and either high or moderate Vit D alone therapies lead to the improvement of the metabolic state, however, their combination had a more significant effect on the treatment of type 2 diabetes. CONCLUSIONS Findings from the present study suggested that combined Vit D supplementation and AT successfully improve liver function and attenuate insulin resistance via upregulating Akt and downregulating PEPCK and G6Pase expressions, compared with monotherapy.
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Affiliation(s)
- Zahra Hoseini
- Department of Exercise Physiology, Faculty of Sport Sciences, Razi University, P.O. Box. 6714967346, Kermanshah, Iran
| | - Nasser Behpour
- Department of Exercise Physiology, Faculty of Sport Sciences, Razi University, P.O. Box. 6714967346, Kermanshah, Iran.
| | - Rastegar Hoseini
- Department of Exercise Physiology, Faculty of Sport Sciences, Razi University, P.O. Box. 6714967346, Kermanshah, Iran
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19
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Khandelwal M, Krishna G, Ying Z, Gomez-Pinilla F. Liver acts as a metabolic gate for the traumatic brain injury pathology: Protective action of thyroid hormone. Biochim Biophys Acta Mol Basis Dis 2023; 1869:166728. [PMID: 37137432 PMCID: PMC10601893 DOI: 10.1016/j.bbadis.2023.166728] [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: 01/23/2023] [Revised: 04/16/2023] [Accepted: 04/25/2023] [Indexed: 05/05/2023]
Abstract
Clinical evidence indicates that injury to the brain elicits systemic metabolic disturbances that contributes to the brain pathology. Since dietary fructose is metabolized in the liver, we explored mechanisms by which traumatic brain injury (TBI) and dietary fructose influence liver function and their possible repercussions to brain. Consumption of fructose contributed to the detrimental effects of TBI on liver operation, in terms of glucose and lipid metabolism, de novo lipogenesis, lipid peroxidation. Thyroid hormone (T4) is metabolized in the liver and found that T4 supply improved lipid metabolism by reducing de novo lipogenesis, lipid accumulation, lipogenic enzymes (ACC, AceCS1, FAS), lipid peroxidation in liver in response to fructose and fructose-TBI. T4 supply also helped to normalize glucose metabolism and improve insulin sensitivity. Furthermore, T4 counteracted elevations of the pro-inflammatory cytokines, Tnfα and Mcp-1 after TBI and/or fructose intake in liver and circulation. T4 also exerted an effect on isolated primary hepatocytes by potentiating phosphorylation of AMPKα and AKT substrate, AS160, leading to increased glucose uptake. In addition, T4 restored the metabolism of DHA in the liver disrupted by TBI and fructose, adding important information to optimize the action of DHA in therapeutics. The overall evidence seems to indicate that the liver works as a gate for the regulation of the effects of brain injury and foods on brain pathologies.
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Affiliation(s)
- Mayuri Khandelwal
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
| | - Gokul Krishna
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
| | - Zhe Ying
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA
| | - Fernando Gomez-Pinilla
- Department of Integrative Biology and Physiology, University of California, Los Angeles, CA, USA; Department of Neurosurgery, UCLA Brain Injury Research Center, Los Angeles, CA, USA.
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20
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Li K, Li H, Song X, Kuang X, Liu S, Zhu S, Li D. The preventive effect of mussel oil on gestational diabetes mellitus in pregnant mice fed by a high-fat and high-sucrose diet. Food Funct 2023; 14:1198-1208. [PMID: 36602239 DOI: 10.1039/d2fo03320h] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The present study aimed to investigate the preventive effect of mussel oil (MO) on gestational diabetes mellitus (GDM) in mice fed by a high-fat and high-sucrose (HFHS) diet. Pregnant mice were allocated to four groups: normal diet + corn oil (CO), HFHS + CO, HFHS + fish oil (FO), and HFHS + MO. The total n-3 polyunsaturated fatty acids (PUFAs) in MO (51.30%) and FO (48.25%) were comparable (mainly C22:6n-3 and C20:5n-3). HFHS + MO and HHFS + FO had a significantly lower area under the curve (AUC) for the oral glucose tolerance test (OGTT) than the HFHS + CO group. The HFHS + MO group but not HFHS + FO group had a significantly lower AUC for the insulin tolerance test (ITT) than the HFHS + CO group. The HFHS + MO group had significantly lower homeostasis model assessment-insulin resistance (HOMA-IR) and fasting serum insulin than the HHFS + FO and HFHS + CO groups. Liver sphingosine kinase 1 (SphK1) was significantly higher, while SphK2, Akt, and P-Akt were significantly lower in the HFHS + CO group compared with the normal diet + CO group. The HFHS + MO group but not the HFHS + FO group had significantly higher SphK2, Akt, and P-Akt than the HFHS + CO group. SphK2 had a strong negative correlation with the AUC for the OGTT (r = -0.759, p = 0.001) and insulin tolerance test (ITT) (r = -0.637; p = 0.008), fasting serum insulin (r = -0.594, p = 0.015), fasting blood glucose (r = -0.587, p = 0.017) and HOMA-IR (r = -0.629, p = 0.009) and a strong positive correlation with Akt (r = 0.594, p = 0.015) and P-Akt (r = 0.676, p = 0.004). In conclusion, mussel oil improved glucose intolerance and insulin resistance during mice pregnancy, which was superior to the effects of fish oil.
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Affiliation(s)
- Kelei Li
- Institute of Nutrition and Health, Qingdao University, Qingdao, China.,School of Public Health, Qingdao University, Qingdao, China.
| | - Huiying Li
- Institute of Nutrition and Health, Qingdao University, Qingdao, China.,School of Public Health, Qingdao University, Qingdao, China.
| | - Xiaolei Song
- Institute of Nutrition and Health, Qingdao University, Qingdao, China.,School of Public Health, Qingdao University, Qingdao, China.
| | - Xiaotong Kuang
- Institute of Nutrition and Health, Qingdao University, Qingdao, China.,School of Public Health, Qingdao University, Qingdao, China.
| | - Shiyi Liu
- Institute of Nutrition and Health, Qingdao University, Qingdao, China.,School of Public Health, Qingdao University, Qingdao, China.
| | - Suqing Zhu
- Institute of Nutrition and Health, Qingdao University, Qingdao, China.,School of Public Health, Qingdao University, Qingdao, China.
| | - Duo Li
- Institute of Nutrition and Health, Qingdao University, Qingdao, China.,School of Public Health, Qingdao University, Qingdao, China.
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21
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Di Pietro P, Izzo C, Abate AC, Iesu P, Rusciano MR, Venturini E, Visco V, Sommella E, Ciccarelli M, Carrizzo A, Vecchione C. The Dark Side of Sphingolipids: Searching for Potential Cardiovascular Biomarkers. Biomolecules 2023; 13:168. [PMID: 36671552 PMCID: PMC9855992 DOI: 10.3390/biom13010168] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 12/31/2022] [Accepted: 01/11/2023] [Indexed: 01/14/2023] Open
Abstract
Cardiovascular diseases (CVDs) are the leading cause of death and illness in Europe and worldwide, responsible for a staggering 47% of deaths in Europe. Over the past few years, there has been increasing evidence pointing to bioactive sphingolipids as drivers of CVDs. Among them, most studies place emphasis on the cardiovascular effect of ceramides and sphingosine-1-phosphate (S1P), reporting correlation between their aberrant expression and CVD risk factors. In experimental in vivo models, pharmacological inhibition of de novo ceramide synthesis averts the development of diabetes, atherosclerosis, hypertension and heart failure. In humans, levels of circulating sphingolipids have been suggested as prognostic indicators for a broad spectrum of diseases. This article provides a comprehensive review of sphingolipids' contribution to cardiovascular, cerebrovascular and metabolic diseases, focusing on the latest experimental and clinical findings. Cumulatively, these studies indicate that monitoring sphingolipid level alterations could allow for better assessment of cardiovascular disease progression and/or severity, and also suggest them as a potential target for future therapeutic intervention. Some approaches may include the down-regulation of specific sphingolipid species levels in the circulation, by inhibiting critical enzymes that catalyze ceramide metabolism, such as ceramidases, sphingomyelinases and sphingosine kinases. Therefore, manipulation of the sphingolipid pathway may be a promising strategy for the treatment of cardio- and cerebrovascular diseases.
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Affiliation(s)
- Paola Di Pietro
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy
| | - Carmine Izzo
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy
| | - Angela Carmelita Abate
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy
| | - Paola Iesu
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy
| | - Maria Rosaria Rusciano
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy
| | | | - Valeria Visco
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy
| | - Eduardo Sommella
- Department of Pharmacy, University of Salerno, 84084 Fisciano, Italy
| | - Michele Ciccarelli
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy
| | - Albino Carrizzo
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy
- Vascular Physiopathology Unit, IRCCS Neuromed, 86077 Pozzilli, Italy
| | - Carmine Vecchione
- Department of Medicine, Surgery and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy
- Vascular Physiopathology Unit, IRCCS Neuromed, 86077 Pozzilli, Italy
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22
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Liu XT, Chung LH, Liu D, Chen J, Huang Y, Teo JD, Han XD, Zhao Y, Guan FHX, Tran C, Lee JY, Couttas TA, Liu K, McCaughan GW, Gorrell MD, Don AS, Zhang S, Qi Y. Ablation of sphingosine kinase 2 suppresses fatty liver-associated hepatocellular carcinoma via downregulation of ceramide transfer protein. Oncogenesis 2022; 11:67. [PMID: 36333295 PMCID: PMC9636415 DOI: 10.1038/s41389-022-00444-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 10/18/2022] [Accepted: 10/21/2022] [Indexed: 11/06/2022] Open
Abstract
Hepatocellular carcinoma (HCC) accounts for 90% of primary liver cancer, the third leading cause of cancer-associated death worldwide. With the increasing prevalence of metabolic conditions, non-alcoholic fatty liver disease (NAFLD) is emerging as the fastest-growing HCC risk factor, and it imposes an additional layer of difficulty in HCC management. Dysregulated hepatic lipids are generally believed to constitute a deleterious environment cultivating the development of NAFLD-associated HCC. However, exactly which lipids or lipid regulators drive this process remains elusive. We report herein that sphingosine kinase 2 (SphK2), a key sphingolipid metabolic enzyme, plays a critical role in NAFLD-associated HCC. Ablation of Sphk2 suppressed HCC development in NAFLD livers via inhibition of hepatocyte proliferation both in vivo and in vitro. Mechanistically, SphK2 deficiency led to downregulation of ceramide transfer protein (CERT) that, in turn, decreased the ratio of pro-cancer sphingomyelin (SM) to anti-cancer ceramide. Overexpression of CERT restored hepatocyte proliferation, colony growth and cell cycle progression. In conclusion, the current study demonstrates that SphK2 is an essential lipid regulator in NAFLD-associated HCC, providing experimental evidence to support clinical trials of SphK2 inhibitors as systemic therapies against HCC.
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Affiliation(s)
- Xin Tracy Liu
- Centenary Institute, The University of Sydney, Sydney, NSW, Australia
| | - Long Hoa Chung
- Centenary Institute, The University of Sydney, Sydney, NSW, Australia
| | - Da Liu
- Centenary Institute, The University of Sydney, Sydney, NSW, Australia
| | - Jinbiao Chen
- Centenary Institute, The University of Sydney, Sydney, NSW, Australia
| | - Yu Huang
- Centenary Institute, The University of Sydney, Sydney, NSW, Australia
| | - Jonathan D Teo
- School of Medical Sciences and Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | | | - Yinan Zhao
- Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian, Liaoning, China
| | - Fiona H X Guan
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney Local Health District, Sydney, NSW, Australia
| | - Collin Tran
- School of Medical Sciences and Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Jun Yup Lee
- School of Medical Sciences and Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Timothy A Couttas
- Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Ken Liu
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney Local Health District, Sydney, NSW, Australia
| | - Geoffery W McCaughan
- Centenary Institute, The University of Sydney, Sydney, NSW, Australia
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney Local Health District, Sydney, NSW, Australia
| | - Mark D Gorrell
- Centenary Institute, The University of Sydney, Sydney, NSW, Australia
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, Sydney Local Health District, Sydney, NSW, Australia
| | - Anthony S Don
- School of Medical Sciences and Charles Perkins Centre, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia.
| | - Shubiao Zhang
- Key Laboratory of Biotechnology and Bioresources Utilization of Ministry of Education, Dalian Minzu University, Dalian, Liaoning, China.
| | - Yanfei Qi
- Centenary Institute, The University of Sydney, Sydney, NSW, Australia.
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23
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Li ZY, Wu G, Qiu C, Zhou ZJ, Wang YP, Song GH, Xiao C, Zhang X, Deng GL, Wang RT, Yang YL, Wang XL. Mechanism and therapeutic strategy of hepatic TM6SF2-deficient non-alcoholic fatty liver diseases via in vivo and in vitro experiments. World J Gastroenterol 2022; 28:2937-2954. [PMID: 35978872 PMCID: PMC9280743 DOI: 10.3748/wjg.v28.i25.2937] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 04/15/2022] [Accepted: 05/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The lack of effective pharmacotherapies for nonalcoholic fatty liver disease (NAFLD) is mainly attributed to insufficient research on its pathogenesis. The pathogenesis of TM6SF2-efficient NAFLD remains unclear, resulting in a lack of therapeutic strategies for TM6SF2-deficient patients.
AIM To investigate the role of TM6SF2 in fatty acid metabolism in the context of fatty liver and propose possible therapeutic strategies for NAFLD caused by TM6SF2 deficiency.
METHODS Liver samples collected from both NAFLD mouse models and human participants (80 cases) were used to evaluate the expression of TM6SF2 by using western blotting, immunohistochemistry, and quantitative polymerase chain reaction. RNA-seq data retrieved from the Gene Expression Omnibus database were used to confirm the over-expression of TM6SF2. Knockdown and overexpression of TM6SF2 were performed to clarify the mechanistic basis of hepatic lipid accumulation in NAFLD. MK-4074 administration was used as a therapeutic intervention to evaluate its effect on NAFLD caused by TM6SF2 deficiency.
RESULTS Hepatic TM6SF2 levels were elevated in patients with NAFLD and NAFLD mouse models. TM6SF2 overexpression can reduce hepatic lipid accumulation, suggesting a protective role for TM6SF2 in a high-fat diet (HFD). Downregulation of TM6SF2, simulating the TM6SF2 E167K mutation condition, increases intracellular lipid deposition due to dysregulated fatty acid metabolism and is characterized by enhanced fatty acid uptake and synthesis, accompanied by impaired fatty acid oxidation. Owing to the potential effect of TM6SF2 deficiency on lipid metabolism, the application of an acetyl-CoA carboxylase inhibitor (MK-4074) could reverse the NAFLD phenotypes caused by TM6SF2 deficiency.
CONCLUSION TM6SF2 plays a protective role in the HFD condition; its deficiency enhanced hepatic lipid accumulation through dysregulated fatty acid metabolism, and MK-4074 treatment could alleviate the NAFLD phenotypes caused by TM6SF2 deficiency.
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Affiliation(s)
- Zu-Yin Li
- Department of Hepatobiliary Surgery, Peking University People’s Hospital, Beijing 100034, China
| | - Gang Wu
- Department of Gastrointestinal Surgery, Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
| | - Chen Qiu
- Institute of Gallstone Disease, Shanghai East Hospital, Shanghai 200120, China
| | - Zhi-Jie Zhou
- Department of General Surgery, Huashan Hospital North, Shanghai 201907, China
| | - Yu-Peng Wang
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Guo-He Song
- Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Chao Xiao
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200041, China
| | - Xin Zhang
- Department of General Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai 201700, China
| | - Gui-Long Deng
- Department of General Surgery, Shanghai General Hospital, Shanghai 201600, China
| | - Rui-Tao Wang
- Department of General Surgery, Shanghai General Hospital, Shanghai 201600, China
| | - Yu-Long Yang
- Institute of Gallstone Disease, Center of Gallbladder Disease, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
| | - Xiao-Liang Wang
- Department of General Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai 201700, China
- Department of Hepatobiliary Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China
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24
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Duan M, Gao P, Chen SX, Novák P, Yin K, Zhu X. Sphingosine-1-phosphate in mitochondrial function and metabolic diseases. Obes Rev 2022; 23:e13426. [PMID: 35122459 DOI: 10.1111/obr.13426] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Revised: 01/02/2022] [Accepted: 01/02/2022] [Indexed: 01/23/2023]
Abstract
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite. The past decade has witnessed exponential growth in the field of S1P research, partly attributed to drugs targeting its receptors or kinases. Accumulating evidence indicates that changes in the S1P axis (i.e., S1P production, transport, and receptors) may modify metabolism and eventually mediate metabolic diseases. Dysfunction of the mitochondria on a master monitor of cellular metabolism is considered the leading cause of metabolic diseases, with aberrations typically induced by abnormal biogenesis, respiratory chain complex disorders, reactive oxygen species overproduction, calcium deposition, and mitophagy impairment. Accordingly, we discuss decades of investigation into changes in the S1P axis and how it controls mitochondrial function. Furthermore, we summarize recent scientific advances in disorders associated with the S1P axis and their involvement in the pathogenesis of metabolic diseases in humans, including type 2 diabetes mellitus and cardiovascular disease, from the perspective of mitochondrial function. Finally, we review potential challenges and prospects for S1P axis application to the regulation of mitochondrial function and metabolic diseases; these data may provide theoretical guidance for the treatment of metabolic diseases.
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Affiliation(s)
- Meng Duan
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi, China
| | - Pan Gao
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi, China
| | - Sheng-Xi Chen
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi, China
| | - Petr Novák
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi, China
| | - Kai Yin
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi, China.,Department of Cardiology, The Second Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Xiao Zhu
- Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, Guangxi, China
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25
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Abstract
PURPOSE OF REVIEW Multiple studies have shown a strong association between lipids and diabetes. These are usually described through the effects of cholesterol content of lipid particles and in particular low-density lipoprotein. However, lipoprotein particles contain other components, such as phospholipids and more complex lipid species, such as ceramides and sphingolipids. Ceramides, such as sphingolipids are also produced intracellularly and have signalling actions in regulating cell metabolism including effects on inflammation, and potentially have a mechanistic role in the development of insulin resistance. RECENT FINDINGS Recently, techniques have been developed to analyse detailed molecular profiles of lipid particles - lipidomics. Proteomics has confirmed the different proteins associated with different particles but far less is known about the relationship of individual lipid species with diabetes and cardiovascular risk. A number of studies have now shown that the plasma lipidome, and in particular, ceramides and sphingolipids may predict the development of diabetes. SUMMARY Lipidomics had identified ceramides and sphingolipids as potential mediators of cellular dysfunction in diabetes. Further work is required to ascertain whether they have clinical utility.
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Affiliation(s)
- Eun Ji Kim
- Department of Metabolic Medicine/Chemical Pathology Guy's & St Thomas' Hospitals, London, UK
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26
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Jiang X, Xu Q, Zhang A, Liu Y, Li Z, Tang H, Cao D, Zhang D. Revealing the Hypoglycemic Effects and Mechanism of GABA-Rich Germinated Adzuki Beans on T2DM Mice by Untargeted Serum Metabolomics. Front Nutr 2022; 8:791191. [PMID: 34970582 PMCID: PMC8712313 DOI: 10.3389/fnut.2021.791191] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 11/02/2021] [Indexed: 12/31/2022] Open
Abstract
Type 2 diabetes mellitus (T2DM) is one of the most common metabolic diseases, and exploring strategies to prevent and treat diabetes has become extremely important. In recent decades the search for new therapeutic strategies for T2DM involving dietary interventions has attracted public attention. We established a diabetic mouse model by feeding mice a high-fat diet combined with injection of low-dose streptozotocin, intending to elucidate the effects and possible mechanisms of different dosages of γ-aminobutyric acid (GABA)-rich germinated adzuki beans on the treatment of diabetes in mice. The mice were treated for 6 weeks either with increasing doses of GABA-enriched germinated adzuki beans, with non-germinated adzuki beans, with GABA, or with the positive control drug metformin. Then, the blood glucose levels and blood lipid biochemical indicators of all the mice were measured. At the same time, serum differential metabolite interactions were explored by UPLC-Q/TOF-MS-based serum metabolomic analysis. The results showed that body weight and fasting blood glucose levels were significantly reduced (P < 0.05). We also report improved levels of total cholesterol, triglycerides, aspartate aminotransferase, alanine aminotransferase, urea, and serum creatinine. We observed a significant improvement in the homeostasis model assessment of the beta cell function and insulin resistance (HOMA-β and HOMA-IR) scores (P < 0.05) in the group of mice treated with the highest dose of GABA-enriched germinated adzuki beans. In addition, the metabolic profiles of the serum were analyzed, and 31 differential metabolites including amino acids and lipids were obtained. According to the Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, this was found to be correlated with nine significantly enriched metabolic pathways involving the up-regulation of levels of L-serine, SM (d18:1/22:1(13Z)), L-histidine, creatine, and 3-indoleacetic acid. Our data suggest that the hypoglycemic effect of GABA-enriched germinated adzuki beans on diabetic mice may be related to improving tryptophan metabolism, glycerol phospholipid metabolism, sphingosline metabolism, and the glycine, serine, and threonine metabolic pathways. This study provides a reference for the application of GABA-enriched germinated foods in type 2 diabetes and could provide a cue for searching biomarkers to be adopted for T2DM diagnosis.
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Affiliation(s)
- Xiujie Jiang
- National Coarse Cereals Engineering Research Center, Heilongjiang Bayi Agricultural University, Daqing, China.,College of Food Science, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Qingpeng Xu
- College of Food Science, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Aiwu Zhang
- College of Food Science, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Yong Liu
- Experimental Equipment Management Center, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Zhijiang Li
- College of Food Science, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Huacheng Tang
- National Coarse Cereals Engineering Research Center, Heilongjiang Bayi Agricultural University, Daqing, China.,College of Food Science, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Dongmei Cao
- College of Food Science, Heilongjiang Bayi Agricultural University, Daqing, China
| | - Dongjie Zhang
- National Coarse Cereals Engineering Research Center, Heilongjiang Bayi Agricultural University, Daqing, China.,College of Food Science, Heilongjiang Bayi Agricultural University, Daqing, China
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27
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Manifold Roles of Ceramide Metabolism in Non-Alcoholic Fatty Liver Disease and Liver Cancer. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1372:157-168. [DOI: 10.1007/978-981-19-0394-6_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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28
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Chung LH, Liu D, Liu XT, Qi Y. Ceramide Transfer Protein (CERT): An Overlooked Molecular Player in Cancer. Int J Mol Sci 2021; 22:13184. [PMID: 34947980 PMCID: PMC8705978 DOI: 10.3390/ijms222413184] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 12/02/2021] [Accepted: 12/05/2021] [Indexed: 12/26/2022] Open
Abstract
Sphingolipids are a class of essential lipids implicated in constructing cellular membranes and regulating nearly all cellular functions. Sphingolipid metabolic network is centered with the ceramide-sphingomyelin axis. Ceramide is well-recognized as a pro-apoptotic signal; while sphingomyelin, as the most abundant type of sphingolipids, is required for cell growth. Therefore, the balance between these two sphingolipids can be critical for cancer cell survival and functioning. Ceramide transfer protein (CERT) dictates the ratio of ceramide to sphingomyelin within the cell. It is the only lipid transfer protein that specifically delivers ceramide from the endoplasmic reticulum to the Golgi apparatus, where ceramide serves as the substrate for sphingomyelin synthesis. In the past two decades, an increasing body of evidence has suggested a critical role of CERT in cancer, but much more intensive efforts are required to draw a definite conclusion. Herein, we review all research findings of CERT, focusing on its molecular structure, cellular functions and implications in cancer. This comprehensive review of CERT will help to better understand the molecular mechanism of cancer and inspire to identify novel druggable targets.
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Affiliation(s)
- Long Hoa Chung
- Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Camperdown, NSW 2050, Australia; (D.L.); (X.T.L.)
| | | | | | - Yanfei Qi
- Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Camperdown, NSW 2050, Australia; (D.L.); (X.T.L.)
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29
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Xue R, Su L, Lai S, Wang Y, Zhao D, Fan J, Chen W, Hylemon PB, Zhou H. Bile Acid Receptors and the Gut-Liver Axis in Nonalcoholic Fatty Liver Disease. Cells 2021; 10:2806. [PMID: 34831031 PMCID: PMC8616422 DOI: 10.3390/cells10112806] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 09/28/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022] Open
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) has been significantly increased due to the global epidemic of obesity. The disease progression from simple steatosis (NAFL) to nonalcoholic steatohepatitis (NASH) is closely linked to inflammation, insulin resistance, and dysbiosis. Although extensive efforts have been aimed at elucidating the pathological mechanisms of NAFLD disease progression, current understanding remains incomplete, and no effective therapy is available. Bile acids (BAs) are not only important physiological detergents for the absorption of lipid-soluble nutrients in the intestine but also metabolic regulators. During the last two decades, BAs have been identified as important signaling molecules involved in lipid, glucose, and energy metabolism. Dysregulation of BA homeostasis has been associated with NAFLD disease severity. Identification of nuclear receptors and G-protein-coupled receptors activated by different BAs not only significantly expanded the current understanding of NAFLD/NASH disease progression but also provided the opportunity to develop potential therapeutics for NAFLD/NASH. In this review, we will summarize the recent studies with a focus on BA-mediated signaling pathways in NAFLD/NASH. Furthermore, the therapeutic implications of targeting BA-mediated signaling pathways for NAFLD will also be discussed.
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Affiliation(s)
- Rui Xue
- Department of Gastroenterology, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 210092, China; (R.X.); (J.F.)
| | - Lianyong Su
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23284, USA; (L.S.); (S.L.); (D.Z.); (P.B.H.)
| | - Shengyi Lai
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23284, USA; (L.S.); (S.L.); (D.Z.); (P.B.H.)
| | - Yanyan Wang
- School of Pharmaceutical Science, Anhui University of Chinese Medicine, Hefei 230031, China; (Y.W.); (W.C.)
| | - Derrick Zhao
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23284, USA; (L.S.); (S.L.); (D.Z.); (P.B.H.)
| | - Jiangao Fan
- Department of Gastroenterology, Shanghai Key Lab of Pediatric Gastroenterology and Nutrition, Shanghai 210092, China; (R.X.); (J.F.)
| | - Weidong Chen
- School of Pharmaceutical Science, Anhui University of Chinese Medicine, Hefei 230031, China; (Y.W.); (W.C.)
| | - Phillip B. Hylemon
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23284, USA; (L.S.); (S.L.); (D.Z.); (P.B.H.)
| | - Huiping Zhou
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, VA 23284, USA; (L.S.); (S.L.); (D.Z.); (P.B.H.)
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30
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Trapika IGMGSC, Liu XT, Chung LH, Lai F, Xie C, Zhao Y, Cui S, Chen J, Tran C, Wang Q, Zhang S, Don AS, Li GQ, Hanrahan JR, Qi Y. Ceramide Regulates Anti-Tumor Mechanisms of Erianin in Androgen-Sensitive and Castration-Resistant Prostate Cancers. Front Oncol 2021; 11:738078. [PMID: 34604081 PMCID: PMC8484793 DOI: 10.3389/fonc.2021.738078] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 09/02/2021] [Indexed: 01/09/2023] Open
Abstract
Prostate cancer is the second most prevalent malignancy worldwide. In the early stages, the development of prostate cancer is dependent on androgens. Over time with androgen deprivation therapy, 20% of prostate cancers progress to a castration-resistant form. Novel treatments for prostate cancers are still urgently needed. Erianin is a plant-derived bibenzyl compound. We report herein that erianin exhibits anti-tumor effects in androgen-sensitive and castration-resistant prostate cancer cells through different mechanisms. Erianin induces endoplasmic reticulum stress-associated apoptosis in androgen-sensitive prostate cancer cells. It also triggers pro-survival autophagic responses, as inhibition of autophagy predisposes to apoptosis. In contrast, erianin fails to induce apoptosis in castration-resistant prostate cancer cells. Instead, it results in cell cycle arrest at the M phase. Mechanistically, C16 ceramide dictates differential responses of androgen-sensitive and castration-resistant prostate cancer cells to erianin. Erianin elevates C16 ceramide level in androgen-sensitive but not castration-resistant prostate cancer cells. Overexpression of ceramide synthase 5 that specifically produces C16 ceramide enables erianin to induce apoptosis in castration-resistant prostate cancer cells. Our study provides both experimental evidence and mechanistic data showing that erianin is a potential treatment option for prostate cancers.
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Affiliation(s)
- I Gusti Md Gde Surya C. Trapika
- Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Camperdown, NSW, Australia,School of Pharmacy, Faculty of Health and Medicine, University of Sydney, Camperdown, NSW, Australia
| | - Xin Tracy Liu
- Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Camperdown, NSW, Australia
| | - Long Hoa Chung
- Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Camperdown, NSW, Australia
| | - Felcia Lai
- Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Camperdown, NSW, Australia,School of Pharmacy, Faculty of Health and Medicine, University of Sydney, Camperdown, NSW, Australia
| | - Chanlu Xie
- Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW, Australia,Chinese Medicine Anti-Cancer Evaluation Program, Central Clinical School, University of Sydney, Camperdown, NSW, Australia
| | - Yang Zhao
- Department of Biochemistry and Molecular Biology, School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shaohui Cui
- Key Laboratory of Biotechnology and Biorescources Utilization of Ministry of Education, Dalian Minzu University, Dalian, China
| | - Jinbiao Chen
- Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Camperdown, NSW, Australia
| | - Collin Tran
- Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Camperdown, NSW, Australia
| | - Qian Wang
- Translational Cancer Metabolism Laboratory, School of Medical Sciences and Prince of Wales Clinical School, UNSW, Sydney, NSW, Australia
| | - Shubiao Zhang
- Key Laboratory of Biotechnology and Biorescources Utilization of Ministry of Education, Dalian Minzu University, Dalian, China
| | - Anthony S. Don
- Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Camperdown, NSW, Australia,School of Medical Sciences, Faculty of Health and Medicine, University of Sydney, Camperdown, NSW, Australia
| | - George Qian Li
- School of Pharmacy, Faculty of Health and Medicine, University of Sydney, Camperdown, NSW, Australia
| | - Jane R. Hanrahan
- School of Pharmacy, Faculty of Health and Medicine, University of Sydney, Camperdown, NSW, Australia,*Correspondence: Yanfei Qi, ; Jane R. Hanrahan,
| | - Yanfei Qi
- Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Camperdown, NSW, Australia,*Correspondence: Yanfei Qi, ; Jane R. Hanrahan,
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31
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Chen Q, Wang W, Xia MF, Lu YL, Bian H, Yu C, Li XY, Vadas MA, Gao X, Lin HD, Xia P. Identification of circulating sphingosine kinase-related metabolites for prediction of type 2 diabetes. J Transl Med 2021; 19:393. [PMID: 34530846 PMCID: PMC8447705 DOI: 10.1186/s12967-021-03066-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 09/02/2021] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Sphingosine Kinase (SphK) that catalyzes sphingosine (Sph) to sphingosine 1-phosphate (S1P), plays a key role in both sphingolipid metabolism and cellular signaling. While SphK has been implicated in type 2 diabetes mellitus (T2DM), it is unexplored in humans. Herein, we investigated whether circulating SphK-related metabolites are associated with T2DM incidence in an established prospective cohort. METHODS Levels of SphK-related sphingolipid metabolites, including Sph, S1P, dihydrosphingosine (dhSph) and dihydro-S1P (dhS1P) in serum were measured by targeted-lipidomic analyses. By accessing to an established prospective cohort that involves a total of 2486 non-diabetic adults at baseline, 100 subjects who developed T2DM after a mean follow-up of 4.2-years, along with 100 control subjects matched strictly with age, sex, BMI and fasting glucose, were randomly enrolled for the present study. RESULTS Comparison with the control group, medians of serum dhS1P and dhS1P/dhSph ratio at baseline were elevated significantly prior to the onset of T2DM. Each SD increment of dhS1P and dhS1P/dhSph ratio was associated with 53.5% and 54.1% increased risk of incident diabetes, respectively. The predictive effect of circulating dhS1P and dhS1P/dhSph ratio on T2DM incidence was independent of conventional risk factors in multivariate regression models. Furthermore, combination of serum dhS1P and dhS1P/dhSph ratio with conventional clinical indices significantly improved the accuracy of T2DM prediction (AUROC, 0.726), especially for normoglycemic subjects (AUROC, 0.859). CONCLUSION Circulating levels of dhS1P and dhS1P/dhSph ratio are strongly associated with increased risk of T2DM, and could serve as a useful biomarker for prediction of incident T2DM in normoglycemic populations.
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Affiliation(s)
- Qi Chen
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Wei Wang
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Ming-Feng Xia
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - You-Li Lu
- Central Laboratory, Xuhui Central Hospital, Shanghai, China
| | - Hua Bian
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Chen Yu
- Central Laboratory, Xuhui Central Hospital, Shanghai, China
| | - Xiao-Ying Li
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Mathew A Vadas
- Centenary Institute, The University of Sydney, Sydney, Australia
| | - Xin Gao
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China
| | - Huan-Dong Lin
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
| | - Pu Xia
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032, China.
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32
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Green CD, Maceyka M, Cowart LA, Spiegel S. Sphingolipids in metabolic disease: The good, the bad, and the unknown. Cell Metab 2021; 33:1293-1306. [PMID: 34233172 PMCID: PMC8269961 DOI: 10.1016/j.cmet.2021.06.006] [Citation(s) in RCA: 170] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 05/05/2021] [Accepted: 06/11/2021] [Indexed: 01/10/2023]
Abstract
The bioactive sphingolipid metabolites ceramide and sphingosine-1-phosphate (S1P) are a recent addition to the lipids accumulated in obesity and have emerged as important molecular players in metabolic diseases. Here we summarize evidence that dysregulation of sphingolipid metabolism correlates with pathogenesis of metabolic diseases in humans. This review discusses the current understanding of how ceramide regulates signaling and metabolic pathways to exacerbate metabolic diseases and the Janus faces for its further metabolite S1P, the kinases that produce it, and the multifaceted and at times opposing actions of S1P receptors in various tissues. Gaps and limitations in current knowledge are highlighted together with the need to further decipher the full array of their actions in tissue dysfunction underlying metabolic pathologies, pointing out prospects to move this young field of research toward the development of effective therapeutics.
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Affiliation(s)
- Christopher D Green
- Department of Biochemistry and Molecular Biology, VCU School of Medicine and Massey Cancer Center, Richmond, VA 23298, USA
| | - Michael Maceyka
- Department of Biochemistry and Molecular Biology, VCU School of Medicine and Massey Cancer Center, Richmond, VA 23298, USA
| | - L Ashley Cowart
- Department of Biochemistry and Molecular Biology, VCU School of Medicine and Massey Cancer Center, Richmond, VA 23298, USA; Hunter Holmes McGuire VA Medical Center, Richmond, VA 23298, USA
| | - Sarah Spiegel
- Department of Biochemistry and Molecular Biology, VCU School of Medicine and Massey Cancer Center, Richmond, VA 23298, USA.
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33
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Ziegler AC, Gräler MH. Barrier maintenance by S1P during inflammation and sepsis. Tissue Barriers 2021; 9:1940069. [PMID: 34152926 DOI: 10.1080/21688370.2021.1940069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Sphingosine 1-phosphate (S1P) is a multifaceted lipid signaling molecule that activates five specific G protein-coupled S1P receptors. Despite the fact that S1P is known as one of the strongest barrier-enhancing molecules for two decades, no medical application is available yet. The reason for this lack of translation into clinical practice may be the complex regulatory network of S1P signaling, metabolism and transportation.In this review, we will provide an overview about the physiology and the network of S1P signaling with the focus on endothelial barrier maintenance in inflammation. We briefly describe the physiological role of S1P and the underlying S1P signaling in barrier maintenance, outline differences of S1P signaling and metabolism in inflammatory diseases, discuss potential targets and compounds for medical intervention, and summarize our current knowledge regarding the role of S1P in the maintenance of specialized barriers like the blood-brain barrier and the placenta.
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Affiliation(s)
- Anke C Ziegler
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.,Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany
| | - Markus H Gräler
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Jena, Germany.,Center for Molecular Biomedicine, Jena University Hospital, Jena, Germany.,Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany
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34
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Diaz Escarcega R, McCullough LD, Tsvetkov AS. The Functional Role of Sphingosine Kinase 2. Front Mol Biosci 2021; 8:683767. [PMID: 34055895 PMCID: PMC8160245 DOI: 10.3389/fmolb.2021.683767] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 04/30/2021] [Indexed: 12/19/2022] Open
Abstract
Sphingosine-1-phosphate (S1P) is a bioactive lipid molecule that is present in all eukaryotic cells and plays key roles in various extracellular, cytosolic, and nuclear signaling pathways. Two sphingosine kinase isoforms, sphingosine kinase 1 (SPHK1) and sphingosine kinase 2 (SPHK2), synthesize S1P by phosphorylating sphingosine. While SPHK1 is a cytoplasmic kinase, SPHK2 is localized to the nucleus, endoplasmic reticulum, and mitochondria. The SPHK2/S1P pathway regulates transcription, telomere maintenance, mitochondrial respiration, among many other processes. SPHK2 is under investigation as a target for treating many age-associated conditions, such as cancer, stroke, and neurodegeneration. In this review, we will focus on the role of SPHK2 in health and disease.
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Affiliation(s)
- Rocio Diaz Escarcega
- Department of Neurology, The University of Texas McGovern Medical School at Houston, Houston, TX, United States
| | - Louise D McCullough
- Department of Neurology, The University of Texas McGovern Medical School at Houston, Houston, TX, United States.,The University of Texas Graduate School of Biomedical Sciences, Houston, TX, United States
| | - Andrey S Tsvetkov
- Department of Neurology, The University of Texas McGovern Medical School at Houston, Houston, TX, United States.,The University of Texas Graduate School of Biomedical Sciences, Houston, TX, United States.,UTHealth Consortium on Aging, The University of Texas McGovern Medical School, Houston, TX, United States
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35
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Wigger D, Schumacher F, Schneider-Schaulies S, Kleuser B. Sphingosine 1-phosphate metabolism and insulin signaling. Cell Signal 2021; 82:109959. [PMID: 33631318 DOI: 10.1016/j.cellsig.2021.109959] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/17/2021] [Accepted: 02/18/2021] [Indexed: 12/19/2022]
Abstract
Insulin is the main anabolic hormone secreted by β-cells of the pancreas stimulating the assimilation and storage of glucose in muscle and fat cells. It modulates the postprandial balance of carbohydrates, lipids and proteins via enhancing lipogenesis, glycogen and protein synthesis and suppressing glucose generation and its release from the liver. Resistance to insulin is a severe metabolic disorder related to a diminished response of peripheral tissues to the insulin action and signaling. This leads to a disturbed glucose homeostasis that precedes the onset of type 2 diabetes (T2D), a disease reaching epidemic proportions. A large number of studies reported an association between elevated circulating fatty acids and the development of insulin resistance. The increased fatty acid lipid flux results in the accumulation of lipid droplets in a variety of tissues. However, lipid intermediates such as diacylglycerols and ceramides are also formed in response to elevated fatty acid levels. These bioactive lipids have been associated with the pathogenesis of insulin resistance. More recently, sphingosine 1-phosphate (S1P), another bioactive sphingolipid derivative, has also been shown to increase in T2D and obesity. Although many studies propose a protective role of S1P metabolism on insulin signaling in peripheral tissues, other studies suggest a causal role of S1P on insulin resistance. In this review, we critically summarize the current state of knowledge of S1P metabolism and its modulating role on insulin resistance. A particular emphasis is placed on S1P and insulin signaling in hepatocytes, skeletal muscle cells, adipocytes and pancreatic β-cells. In particular, modulation of receptors and enzymes that regulate S1P metabolism can be considered as a new therapeutic option for the treatment of insulin resistance and T2D.
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Affiliation(s)
- Dominik Wigger
- Institute of Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany; Institute of Nutritional Science, Nutritional Toxicology, University of Potsdam, Nuthetal, Germany
| | - Fabian Schumacher
- Institute of Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany; Institute of Nutritional Science, Nutritional Toxicology, University of Potsdam, Nuthetal, Germany
| | | | - Burkhard Kleuser
- Institute of Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany; Institute of Nutritional Science, Nutritional Toxicology, University of Potsdam, Nuthetal, Germany.
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36
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Qi Y, Wang W, Song Z, Aji G, Liu XT, Xia P. Role of Sphingosine Kinase in Type 2 Diabetes Mellitus. Front Endocrinol (Lausanne) 2021; 11:627076. [PMID: 33633691 PMCID: PMC7899982 DOI: 10.3389/fendo.2020.627076] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 12/21/2020] [Indexed: 12/15/2022] Open
Abstract
Sphingolipids are a class of essential lipids, functioning as both cell membrane constituents and signaling messengers. In the sphingolipid metabolic network, ceramides serve as the central hub that is hydrolyzed to sphingosine, followed by phosphorylation to sphingosine 1-phosphate (S1P) by sphingosine kinase (SphK). SphK is regarded as a "switch" of the sphingolipid rheostat, as it catalyzes the conversion of ceramide/sphingosine to S1P, which often exhibit opposing biological roles in the cell. Besides, SphK is an important signaling enzyme that has been implicated in the regulation of a wide variety of biological functions. In recent years, an increasing body of evidence has suggested a critical role of SphK in type 2 diabetes mellitus (T2D), although a certain level of controversy remains. Herein, we review recent findings related to SphK in the field of T2D research with a focus on peripheral insulin resistance and pancreatic β-cell failure. It is expected that a comprehensive understanding of the role of SphK and the associated sphingolipids in T2D will help to identify druggable targets for future anti-diabetes therapy.
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Affiliation(s)
- Yanfei Qi
- Lipid Cell Biology Laboratory, Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Sydney, NSW, Australia
| | - Wei Wang
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ziyu Song
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Gulibositan Aji
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xin Tracy Liu
- Lipid Cell Biology Laboratory, Centenary Institute of Cancer Medicine and Cell Biology, University of Sydney, Sydney, NSW, Australia
| | - Pu Xia
- Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
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