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Lee JE, Im DS. GPR55 Antagonist CID16020046 Suppresses Collagen-Induced Rheumatoid Arthritis by Suppressing Th1/Th17 Cells in Mice. Int J Mol Sci 2025; 26:4680. [PMID: 40429822 DOI: 10.3390/ijms26104680] [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: 02/28/2025] [Revised: 05/03/2025] [Accepted: 05/09/2025] [Indexed: 05/29/2025] Open
Abstract
Lysophosphatidylinositols are degradation products of phosphatidylinositols within cell membranes and digestive metabolites of a high-fat diet in the gut. G-protein-coupled receptor 55 (GPR55) is a receptor that senses lysophosphatidylinositol and acts as an immune mediator, being primarily upregulated during immune cell activation. This study aimed to investigate the role of GPR55, using its antagonist, CID16020046, in a collagen-induced rheumatoid arthritis mouse model. It was observed that DBA-1J mice develop joint lesions characteristic of rheumatoid arthritis following immunization with bovine type II collagen. The administration of CID16020046 (1 mg/kg, intraperitoneally) alleviated rheumatoid arthritis symptoms and inflammatory responses. Histopathological analysis showed that CID16020046 reduced foot edema, proteoglycan loss, and bone erosion in the joints. CID16020046 also decreased rheumatoid-arthritis-induced serum IgG levels, as measured using enzyme-linked immunosorbent assays. The treatment reduced levels of pro-inflammatory cytokines (IL-1β and IL-6), Th1 cytokine (IFN-γ), and Th17 cytokine (IL-17A), along with matrix metalloproteinase-3 (MMP-3) and the receptor activator of nuclear factor-κB ligand (RANKL) in the feet. A significant reduction in splenomegaly was also observed, along with significant reductions in CD4+ T helper 1 (Th1) and Th17 cells in the spleen. Additionally, CID16020046 suppressed the differentiation of naïve T cells into CD4+IL-17+ Th17 cells. CID16020046 suppressed expression levels of inflammatory cytokine mRNAs in SW982 human synovial cells. In conclusion, blocking GPR55 alleviates collagen-induced rheumatoid arthritis symptoms by suppressing Th1 and Th17 cells in the spleen and pro-inflammatory cytokines in the joints, suggesting that GPR55 is a potential therapeutic target for autoimmune inflammatory diseases.
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MESH Headings
- Animals
- Th17 Cells/drug effects
- Th17 Cells/immunology
- Th17 Cells/metabolism
- Arthritis, Rheumatoid/drug therapy
- Arthritis, Rheumatoid/immunology
- Arthritis, Rheumatoid/metabolism
- Arthritis, Rheumatoid/pathology
- Arthritis, Rheumatoid/chemically induced
- Th1 Cells/drug effects
- Th1 Cells/immunology
- Th1 Cells/metabolism
- Mice
- Arthritis, Experimental/drug therapy
- Arthritis, Experimental/immunology
- Arthritis, Experimental/pathology
- Arthritis, Experimental/metabolism
- Mice, Inbred DBA
- Cytokines/metabolism
- Receptors, Cannabinoid/metabolism
- Male
- Receptors, G-Protein-Coupled/antagonists & inhibitors
- Humans
- Disease Models, Animal
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Affiliation(s)
- Jung-Eun Lee
- Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02446, Republic of Korea
| | - Dong-Soon Im
- Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02446, Republic of Korea
- Department of Basic Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02446, Republic of Korea
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2
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Cortes-Justo E, Ortiz-Butrón R, Vilches-Flores A. Cannabidiol oil delays pancreatic islet dysfunction in Wistar rats under hypercaloric diet. Biomed Pharmacother 2025; 186:117993. [PMID: 40106970 DOI: 10.1016/j.biopha.2025.117993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 03/09/2025] [Accepted: 03/13/2025] [Indexed: 03/22/2025] Open
Abstract
Hypercaloric diet (HCD) intake can lead to metabolic alterations, such as metabolic syndrome and type-2 diabetes mellitus. Phytocannabinoid cannabidiol (CBD) is a GPR55 receptor antagonist involved in insulin secretion and other functions in pancreatic islet. The therapeutic use of CBD has been suggested for diabetes, but little is known regarding its effects on pancreatic islet physiology. Our aim was to evaluate the effects of CBD oil on pancreatic islets, from Wistar rats under HCD. Male rats were divided in 4 groups: Normal diet vehicle-treated (control) and CBD-treated group. Rats under HCD were subdivided in treated with vehicle (HCD) and with CBD oil administered 21 mg/Kg orally, 0.5 ml in 3 days per week; controls received coconut oil as vehicle. Body weight, food intake, and water consumption were recorded. After 20 weeks, glucose tolerance curve was performed; serum insulin was determined by ELISA, and pancreas was removed for histological and gene expression analysis for insulin, glucagon, PDX-1, MafA and GPR55 receptor. CBD treatment reduced body weight and food intake but increased fluid consumption, independently of diets. In control group, CBD did not alter blood glucose and serum insulin, but modified expression for GPR55 receptor, glucagon, insulin and MafA. Rats under HCD and treated with CBD decreased glycaemia, insulinaemia, islets relative area, GPR55-positive cells, PDX-1 and MafA gene expression, meanwhile insulin and glucagon expression was increased. In conclusion, CBD ameliorated HCD effects through changes in insulin, glucagon and GPR55 receptor expressions. We assume CBD interacts with other receptors beside GPR55.
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Affiliation(s)
- Edgardo Cortes-Justo
- Posgrado e Investigación, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Mexico City, Mexico
| | - Rocío Ortiz-Butrón
- Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas. Instituto Politécnico Nacional, Ciudad de México, Mexico
| | - Alonso Vilches-Flores
- Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Mexico.
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3
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Claff T, Ebenhoch R, Kley JT, Magarkar A, Nar H, Weichert D. Structural basis for lipid-mediated activation of G protein-coupled receptor GPR55. Nat Commun 2025; 16:1973. [PMID: 40000629 PMCID: PMC11861906 DOI: 10.1038/s41467-025-57204-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 02/10/2025] [Indexed: 02/27/2025] Open
Abstract
GPR55 is an orphan G protein-coupled receptor (GPCR) and represents a promising drug target for cancer, inflammation, and metabolic diseases. The endogenous activation of lipid GPCRs can be solely mediated by membrane components and different lipids have been proposed as endogenous activators of GPR55, such as cannabinoids and lysophosphatidylinositols. Here, we determine high-resolution cryo-electron microscopy structures of the activated GPR55 in complex with heterotrimeric G13 and two structurally diverse ligands: the putative endogenous agonist 1-palmitoyl-2-lysophosphatidylinositol (LPI) and the synthetic agonist ML184. These results reveal insights into ligand recognition at GPR55, G protein coupling and receptor activation. Notably, an orthosteric binding site opening towards the membrane is observed in both structures, enabling direct interaction of the agonists with membrane lipids. The structural observations are supported by mutagenesis and functional experiments employing G protein dissociation assays. These findings will be of importance for the structure-based development of drugs targeting GPR55.
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Affiliation(s)
| | - Rebecca Ebenhoch
- Boehringer Ingelheim Pharma GmbH & Co. KG, Global Medicinal Chemistry, Biberach an der Riß, Germany
| | - Jörg T Kley
- Boehringer Ingelheim Pharma GmbH & Co. KG, Global Medicinal Chemistry, Biberach an der Riß, Germany
| | - Aniket Magarkar
- Boehringer Ingelheim Pharma GmbH & Co. KG, Global Medicinal Chemistry, Biberach an der Riß, Germany
| | - Herbert Nar
- Boehringer Ingelheim Pharma GmbH & Co. KG, Global Medicinal Chemistry, Biberach an der Riß, Germany
| | - Dietmar Weichert
- Boehringer Ingelheim Pharma GmbH & Co. KG, Global Medicinal Chemistry, Biberach an der Riß, Germany.
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4
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Schopohl B, Kohlhaas M, Nickel AG, Schiuma AF, Maas SL, van der Vorst EPC, Shia YX, Maack C, Steffens S, Puhl SL. Gpr55 deficiency crucially alters cardiomyocyte homeostasis and counteracts angiotensin II induced maladaption in female mice. Br J Pharmacol 2025; 182:670-691. [PMID: 39428581 DOI: 10.1111/bph.17350] [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: 01/18/2024] [Revised: 06/24/2024] [Accepted: 07/20/2024] [Indexed: 10/22/2024] Open
Abstract
BACKGROUND AND PURPOSE Cannabis stimulates several G-protein-coupled-receptors and causes bradycardia and hypotension upon sustained consumption. Moreover, in vitro studies suggest an interference of cannabinoid-signalling with cardiomyocyte contractility and hypertrophy. We aimed at revealing a functional contribution of the cannabinoid-sensitive receptor GPR55 to cardiomyocyte homeostasis and neurohumorally induced hypertrophy in vivo. EXPERIMENTAL APPROACH Gpr55-/- and wild-type (WT) mice were characterized after 28-day angiotensin II (AngII; 1·μg·kg-1 min-1) or vehicle infusion. In isolated adult Gpr55-/- and WT cardiomyocytes, mitochondrial function was assessed under naïve conditions, while cytosolic Ca2+ handling was additionally determined following application of the selective GPR55 antagonist CID16020046. KEY RESULTS Gpr55 deficiency did not affect angiotensin II (AngII) mediated hypertrophic growth, yet, especially in females, it alleviated maladaptive pro-hypertrophic and -inflammatory gene expression and improved inotropy and adrenergic responsiveness compared to WT. In-depth analyses implied increased cytosolic Ca2+ concentrations and transient amplitudes, and accelerated sarcomere contraction kinetics in Gpr55-/- myocytes, which could be mimicked by GPR55 blockade with CID16020046 in female WT cells. Moreover, Gpr55 deficiency up-regulated factors involved in glucose and fatty acid transport independent of the AngII challenge, accelerated basal mitochondrial respiration and reduced basal protein kinase (PK) A, G and C activity and phospholemman (PLM) phosphorylation. CONCLUSIONS AND IMPLICATIONS Our study suggests GPR55 as crucial regulator of cardiomyocyte hypertrophy and homeostasis presumably by regulating PKC/PKA-PLM and PKG signalling, and identifies the receptor as potential target to counteract maladaptation, adrenergic desensitization and metabolic shifts as unfavourable features of the hypertrophied heart in females.
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Affiliation(s)
- Brigitte Schopohl
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany
| | - Michael Kohlhaas
- Comprehensive Heart Failure Center, University Clinic Würzburg, Würzburg, Germany
| | - Alexander G Nickel
- Comprehensive Heart Failure Center, University Clinic Würzburg, Würzburg, Germany
| | | | - Sanne L Maas
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
- Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany
| | - Emiel P C van der Vorst
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany
- Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany
- Interdisciplinary Center for Clinical Research (IZKF), RWTH Aachen University, Aachen, Germany
- Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), RWTH Aachen University, Aachen, Germany
| | - Yi Xuan Shia
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany
| | - Christoph Maack
- Comprehensive Heart Failure Center, University Clinic Würzburg, Würzburg, Germany
- Medical Clinic I, University Clinic Würzburg, Würzburg, Germany
| | - Sabine Steffens
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Munich Heart Alliance, Munich, Germany
| | - Sarah-Lena Puhl
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU) Munich, Munich, Germany
- Comprehensive Heart Failure Center, University Clinic Würzburg, Würzburg, Germany
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He X, Zhao X, Wang H. LPI-GPR55 promotes endothelial cell activation and inhibits autophagy through inducing LINC01235 expression. Ann Med 2024; 56:2407525. [PMID: 39316662 PMCID: PMC11423533 DOI: 10.1080/07853890.2024.2407525] [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: 05/29/2024] [Revised: 08/28/2024] [Accepted: 08/29/2024] [Indexed: 09/26/2024] Open
Abstract
INTRODUCTION Atherosclerosis (AS) is a chronic inflammatory disease characterized by lipid accumulation, inflammation and apoptosis of the arterial wall. This study evaluated the effects of lysophosphatidylinositol (LPI) on endothelial cells activation and autophagy in AS. METHODS qRT-PCR and Western blotting were done to verify the expression of ICAM1, GPR55 and SOD2. RNA-Seq was performed and screened for the different expressions of long noncoding RNAs (lncRNAs), combining bioinformatics analysis to elucidate the mechanism by which lncRNA functions. RESULTS qRT-PCR and Western blotting results showed that LPI increased GPR55 and ICAM1 expression. RNA-Seq analysis and qRT-PCR results showed that LPI increased the expression of LINC01235, LINC00520 and LINC01963; LINC01235 was the most obvious. Mechanistically, bioinformatic analysis demonstrated that LINC01235 inhibited autophagy through sponging miR-224-3p. And miRNA-224-3p targeted RABEP1. CONCLUSIONS LPI promoted endothelial cell activation. LPI induced the expression of LINC01235 and LINC01235 inhibited autophagy through miR-224-3p/RABEP1. Collectively, this study first reveals the function of LINC01235, which may serve as a potential therapeutic target in AS.
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Affiliation(s)
- Xiaoying He
- Shanxi Provincial Key Laboratory of Kidney Disease, Shanxi Provincial People’s Hospital, Taiyuan, China
| | - Xin Zhao
- Shanxi Provincial Key Laboratory of Kidney Disease, Shanxi Provincial People’s Hospital, Taiyuan, China
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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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Liu B, Ruz-Maldonado I, Persaud SJ. Global deletion of G protein-coupled receptor 55 impairs glucose homeostasis during obesity by reducing insulin secretion and β-cell turnover. Diabetes Obes Metab 2024; 26:4591-4601. [PMID: 39113250 DOI: 10.1111/dom.15816] [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: 03/22/2024] [Revised: 06/21/2024] [Accepted: 07/04/2024] [Indexed: 09/19/2024]
Abstract
AIM To investigate the effect of G protein-coupled receptor 55 (GPR55) deletion on glucose homeostasis and islet function following diet-induced obesity. METHODS GPR55-/- and wild-type (WT) mice were fed ad libitum either standard chow (SC) or a high-fat diet (HFD) for 20 weeks. Glucose and insulin tolerance tests were performed at 9/10 and 19/20 weeks of dietary intervention. Insulin secretion in vivo and dynamic insulin secretion following perifusion of isolated islets were also determined, as were islet caspase-3/7 activities and β-cell 5-bromo-20-deoxyuridine (BrdU) incorporation. RESULTS GPR55-/- mice fed a HFD were more susceptible to diet-induced obesity and were more glucose intolerant and insulin resistant than WT mice maintained on a HFD. Islets isolated from HFD-fed GPR55-/- mice showed impaired glucose- and pcacahorbol 12-myristate 13-acetate-stimulated insulin secretion, and they also displayed increased cytokine-induced apoptosis. While there was a 5.6 ± 1.6-fold increase in β-cell BrdU incorporation in the pancreases of WT mice fed a HFD, this compensatory increase in β-cell proliferation in response to the HFD was attenuated in GPR55-/- mice. CONCLUSIONS Under conditions of diet-induced obesity, GPR55-/- mice show impaired glucose handling, which is associated with reduced insulin secretory capacity, increased islet cell apoptosis and insufficient compensatory increases in β-cell proliferation. These observations support that GPR55 plays an important role in positively regulating islet function.
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Affiliation(s)
- Bo Liu
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK
| | - Inmaculada Ruz-Maldonado
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK
- Comparative Medicine & Pathology, Vascular Biology and Therapeutics Program (VBT) Program in Integrative Cell Signaling and Neurobiology of Metabolism (ICSNM), Yale University School of Medicine, New Haven, Connecticut, USA
| | - Shanta J Persaud
- Department of Diabetes, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, London, UK
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8
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Zhou AL, Ward RE. Dietary Milk Phospholipids Increase Body Fat and Modulate Gut Permeability, Systemic Inflammation, and Lipid Metabolism in Mice. J Dairy Sci 2024:S0022-0302(24)01079-8. [PMID: 39154725 DOI: 10.3168/jds.2024-25235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Accepted: 07/22/2024] [Indexed: 08/20/2024]
Abstract
The study aimed at how dietary milk polar lipids affect gut permeability, systemic inflammation, and lipid metabolism during diet-induced obesity (DIO). C57BL/6J mice (n = 6x3) were fed diets with 34% fat as energy for 15 weeks: (1) modified AIN-93G diet (CO); (2) CO with milk gangliosides (GG); (3) CO with milk phospholipids (MPL). Gut permeability was assessed by FITC-dextran and sugar absorption tests. Intestinal tight junction proteins were evaluated by Western blot. Plasma cytokines were measured by immunoassay. Body composition was assessed by magnetic resonance imaging. Tissue lipid profiles were obtained by thin layer chromatography. Hepatic expression of genes associated with lipid metabolism was assessed by RT-qPCR. MPL increased the efficiency of converting food into body fat and facilitated body fat accumulation compared with CO. MPL and GG did not affect fasting glucose or HOMA-IR during DIO. MPL increased while GG decreased plasma TG compared with CO. MPL decreased phospholipids subclasses in the muscle while increased those in the liver compared with CO. GG and MPL had little effect on hepatic expression of genes associated with lipid metabolism. Compared with CO, MPL decreased polar lipids content in colon mucosa. Small intestinal permeability decreased while colon permeability increased and then recovered during the feeding period. High-fat feeding increased plasma endotoxin after DIO but did not affect plasma cytokines. MPL and GG did not affect plasma endotoxin, adipokines and inflammatory cytokines. After the establishment of obesity, MPL increased gut permeability to large molecules but decreased intestinal absorption of small molecules while GG tended to have the opposite effects. MPL and GG decreased mannitol and sucralose excretions, which peaked at d 45 in the CO group. MPL decreased occludin in jejunum mucosa compared with CO. GG and MPL did not affect zonula occludens-1 in gut mucosa. In conclusion, during DIO, milk GG decreased gut permeability, and had little effect on systemic inflammation and lipid metabolism; MPL facilitated body fat accumulation, decreased gut permeability, did not affect systemic inflammation.
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Affiliation(s)
- Albert Lihong Zhou
- Nutrition, Dietetics and Food Sciences, Utah State University, 8700 Old Main Hill, Logan, UT 84322, USA
| | - Robert E Ward
- Nutrition, Dietetics and Food Sciences, Utah State University, 8700 Old Main Hill, Logan, UT 84322, USA.
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9
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Shi Z, Liu X, Wu S, Song N, Tang Q, Li H, Luo S, Chan ASC, Cai X, Liu H, Jiang X. Discovery of Novel Peptide Antagonists Targeting GPR55 for Liver Inflammation and Fibrosis. J Med Chem 2024; 67:12085-12098. [PMID: 38991128 DOI: 10.1021/acs.jmedchem.4c00834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/13/2024]
Abstract
Liver fibrosis is a condition characterized by aberrant proliferation of connective tissue in the liver resulting from diverse etiological factors. G protein-coupled receptor GPR55 has recently been identified as a regulator of liver diseases. Herein, we report the discovery of a cyclic peptide P1-1 that antagonizes GPR55 and suppresses collagen secretion in hepatic stellate cells. The alanine scanning and docking study was carried out to predict the binding mode and allowed for further structural optimization of peptide antagonists for GPR55. The subsequent in vivo study demonstrated that P1-1 ameliorates CCl4-induce and MCD-diet-induce acute liver inflammation and fibrosis. Further study indicates that P1-1 reduces reactive oxygen species (ROS) production, attenuates ER stress, and inhibits mitochondria-associated hepatocyte apoptosis. In this work, we provided the first successful example of antagonizing GPR55 for liver inflammation and fibrosis, which validates GPR55 as a promising target for the treatment of liver fibrosis and affords a high-potent GPR55 antagonist P1-1 as a potential therapeutic candidate.
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Affiliation(s)
- Zihan Shi
- State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Xianyan Liu
- State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Shuohan Wu
- State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Nazi Song
- State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Qinglin Tang
- State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
- Shenzhen Turier Biotech. Co. Ltd, Shenzhen 518000, China
| | - Haonan Li
- State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Suijia Luo
- Shenzhen Turier Biotech. Co. Ltd, Shenzhen 518000, China
| | - Albert S C Chan
- State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Xiaoqing Cai
- State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Han Liu
- State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Xianxing Jiang
- State Key Laboratory of Anti-Infective Drug Discovery and Development, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
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Son SE, Lee YJ, Shin YJ, Kim DH, Im DS. GPR55 Antagonist CID16020046 Attenuates Obesity-Induced Airway Inflammation by Suppressing Chronic Low-Grade Inflammation in the Lungs. Int J Mol Sci 2024; 25:7358. [PMID: 39000464 PMCID: PMC11242637 DOI: 10.3390/ijms25137358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2024] [Revised: 06/27/2024] [Accepted: 07/02/2024] [Indexed: 07/16/2024] Open
Abstract
GPR55 is a receptor for lysophosphatidylinositols (LPIs) in digestive metabolites. Overnutrition leads to obesity, insulin resistance, and increased LPI levels in the plasma. The involvement of LPIs and GPR55 in adiposity, hepatic steatosis, and atherosclerosis has been previously elucidated. However, the therapeutic efficacy of GPR55 antagonists against obesity-induced airway inflammation has not been studied. The present study investigated whether CID16020046, a selective antagonist of GPR55, could modulate obesity-induced airway inflammation caused by a high-fat diet (HFD) in C57BL/6 mice. Administration of CID16020046 (1 mg/kg) inhibits HFD-induced adiposity and glucose intolerance. Analysis of immune cells in BALF showed that CID16020046 inhibited HFD-induced increase in immune cell infiltration. Histological analysis revealed the HFD induced hypersecretion of mucus and extensive fibrosis in the lungs. CID16020046 inhibited these HFD-induced pathological features. qRT-PCR revealed the HFD-induced increase in the expression of Ifn-γ, Tnf-α, Il-6, Il-13, Il-17A, Il-1β, Nlrp3, and Mpo mRNAs in the lungs. CID16020046 inhibited the HFD-induced increases in these genes. The expression levels of adipokines were regulated by the HFD and CID16020046. AdipoQ in the lungs and gonadal white adipose tissue was decreased by the HFD and reversed by CID16020046. In contrast, Lep was increased by the HFD and suppressed by CID16020046. The findings suggest the potential application of the GPR55 antagonist CID16020046 in obesity-induced airway inflammation.
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Affiliation(s)
- So-Eun Son
- Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.-E.S.); (Y.-J.L.); (Y.-J.S.)
| | - Ye-Ji Lee
- Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.-E.S.); (Y.-J.L.); (Y.-J.S.)
| | - Yoon-Jung Shin
- Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.-E.S.); (Y.-J.L.); (Y.-J.S.)
| | - Dong-Hyun Kim
- Department of Fundamental Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea;
| | - Dong-Soon Im
- Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea; (S.-E.S.); (Y.-J.L.); (Y.-J.S.)
- Department of Fundamental Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Republic of Korea;
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11
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Glenn NAK, Finlay DB, Carruthers ER, Mountjoy KG, Walker CS, Grimsey NL. RAMP and MRAP accessory proteins have selective effects on expression and signalling of the CB 1, CB 2, GPR18 and GPR55 cannabinoid receptors. Br J Pharmacol 2024; 181:2212-2231. [PMID: 37085333 DOI: 10.1111/bph.16095] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 03/10/2023] [Accepted: 04/14/2023] [Indexed: 04/23/2023] Open
Abstract
BACKGROUND AND PURPOSE Receptor activity-modifying proteins (RAMPs) and melanocortin receptor accessory proteins (MRAPs) modulate expression and signalling of calcitonin and melanocortin GPCRs. Interactions with other GPCRs have also been reported. The cannabinoid receptors, CB1 and CB2, and two putative cannabinoid receptors, GPR18 and GPR55, exhibit substantial intracellular expression and there are discrepancies in ligand responsiveness between studies. We investigated whether interactions with RAMPs or MRAPs could explain these phenomena. EXPERIMENTAL APPROACH Receptors and accessory proteins were co-expressed in HEK-293 cells. Selected receptors were studied at basal expression levels and also with enhanced expression produced by incorporation of a preprolactin signal sequence/peptide (pplss). Cell surface and total expression of receptors and accessory proteins were quantified using immunocytochemistry. Signalling was measured using cAMP (CAMYEL) and G protein dissociation (TRUPATH Gα13) biosensors. KEY RESULTS MRAP2 enhanced surface and total expression of GPR18. Pplss-GPR18 increased detection of cell surface MRAP2. MRAP1α and MRAP2 reduced GPR55 surface and total expression, correlating with reduced constitutive, but not agonist-induced, signalling. GPR55, pplss-CB1 and CB2 reduced detection of MRAP1α at the cell surface. Pplss-CB1 agonist potency was reduced by MRAP2 in Gα13 but not cAMP assays, consistent with MRAP2 reducing pplss-CB1 expression. Some cannabinoid receptors increased RAMP2 or RAMP3 total expression without influencing surface expression. CONCLUSIONS AND IMPLICATIONS Mutual influences on expression and/or function for specific accessory protein-receptor pairings raises the strong potential for physiological and disease-relevant consequences. Sequestration and/or hetero-oligomerisation of cannabinoid receptors with accessory proteins is a possible novel mechanism for receptor crosstalk. LINKED ARTICLES This article is part of a themed issue Therapeutic Targeting of G Protein-Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc.
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MESH Headings
- Humans
- HEK293 Cells
- Receptors, G-Protein-Coupled/metabolism
- Receptors, G-Protein-Coupled/genetics
- Receptors, Cannabinoid/metabolism
- Signal Transduction
- Receptor, Cannabinoid, CB1/metabolism
- Receptor Activity-Modifying Proteins/metabolism
- Receptor, Cannabinoid, CB2/metabolism
- Receptor, Cannabinoid, CB2/agonists
- Receptor, Cannabinoid, CB2/genetics
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Affiliation(s)
- Nathaniel A K Glenn
- Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
| | - David B Finlay
- Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
| | - Emma R Carruthers
- Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
| | - Kathleen G Mountjoy
- Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- Department of Molecular Medicine and Pathology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
| | - Christopher S Walker
- Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
- School of Biological Sciences, Faculty of Science, University of Auckland, Auckland, New Zealand
| | - Natasha L Grimsey
- Department of Pharmacology and Clinical Pharmacology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- Centre for Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
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12
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Jin C, Chen H, Xie L, Zhou Y, Liu LL, Wu J. GPCRs involved in metabolic diseases: pharmacotherapeutic development updates. Acta Pharmacol Sin 2024; 45:1321-1336. [PMID: 38326623 PMCID: PMC11192902 DOI: 10.1038/s41401-023-01215-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2023] [Accepted: 12/11/2023] [Indexed: 02/09/2024]
Abstract
G protein-coupled receptors (GPCRs) are expressed in a variety of cell types and tissues, and activation of GPCRs is involved in enormous metabolic pathways, including nutrient synthesis, transportation, storage or insulin sensitivity, etc. This review intends to summarize the regulation of metabolic homeostasis and mechanisms by a series of GPCRs, such as GPR91, GPR55, GPR119, GPR109a, GPR142, GPR40, GPR41, GPR43 and GPR120. With deep understanding of GPCR's structure and signaling pathways, it is attempting to uncover the role of GPCRs in major metabolic diseases, including metabolic syndrome, diabetes, dyslipidemia and nonalcoholic steatohepatitis, for which the global prevalence has risen during last two decades. An extensive list of agonists and antagonists with their chemical structures in a nature of small molecular compounds for above-mentioned GPCRs is provided as pharmacologic candidates, and their preliminary data of preclinical studies are discussed. Moreover, their beneficial effects in correcting abnormalities of metabolic syndrome, diabetes and dyslipidemia are summarized when clinical trials have been undertaken. Thus, accumulating data suggest that these agonists or antagonists might become as new pharmacotherapeutic candidates for the treatment of metabolic diseases.
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Affiliation(s)
- Cheng Jin
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
- College of Clinical Medicine, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Hui Chen
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Li Xie
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Yuan Zhou
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China
| | - Li-Li Liu
- Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai, 200032, China.
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, 200032, China.
| | - Jian Wu
- Department of Medical Microbiology & Parasitology, MOE/NHC/CAMS Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University Shanghai Medical College, Shanghai, 200032, China.
- Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai, 200032, China.
- Shanghai Institute of Liver Diseases, Fudan University Shanghai Medical College, Shanghai, 200032, China.
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Mao TH, Huang HQ, Zhang CH. Clinical characteristics and treatment compounds of obesity-related kidney injury. World J Diabetes 2024; 15:1091-1110. [PMID: 38983811 PMCID: PMC11229974 DOI: 10.4239/wjd.v15.i6.1091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 12/22/2023] [Accepted: 04/08/2024] [Indexed: 06/11/2024] Open
Abstract
Disorders in energy homeostasis can lead to various metabolic diseases, particularly obesity. The obesity epidemic has led to an increased incidence of obesity-related nephropathy (ORN), a distinct entity characterized by proteinuria, glomerulomegaly, progressive glomerulosclerosis, and renal function decline. Obesity and its associated renal damage are common in clinical practice, and their incidence is increasing and attracting great attention. There is a great need to identify safe and effective therapeutic modalities, and therapeutics using chemical compounds and natural products are receiving increasing attention. However, the summary is lacking about the specific effects and mechanisms of action of compounds in the treatment of ORN. In this review, we summarize the important clinical features and compound treatment strategies for obesity and obesity-induced kidney injury. We also summarize the pathologic and clinical features of ORN as well as its pathogenesis and potential therapeutics targeting renal inflammation, oxidative stress, insulin resistance, fibrosis, kidney lipid accumulation, and dysregulated autophagy. In addition, detailed information on natural and synthetic compounds used for the treatment of obesity-related kidney disease is summarized. The synthesis of detailed information aims to contribute to a deeper understanding of the clinical treatment modalities for obesity-related kidney diseases, fostering the anticipation of novel insights in this domain.
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Affiliation(s)
- Tuo-Hua Mao
- Department of Endocrinology, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China
| | - Han-Qi Huang
- Department of Endocrinology, Hubei No. 3 People’s Hospital of Jianghan University, Wuhan 430033, Hubei Province, China
| | - Chuan-Hai Zhang
- Department of Physiology, UT Southwestern Medical Center, Dallas, TX 75390, United States
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14
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Almousa AS, Subash-Babu P, Alanazi IO, Alshatwi AA, Alkhalaf H, Bahattab E, Alsiyah A, Alzahrani M. Hemp Seed Oil Inhibits the Adipogenicity of the Differentiation-Induced Human Mesenchymal Stem Cells through Suppressing the Cannabinoid Type 1 (CB1). Molecules 2024; 29:1568. [PMID: 38611847 PMCID: PMC11013118 DOI: 10.3390/molecules29071568] [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: 02/15/2024] [Revised: 03/28/2024] [Accepted: 03/28/2024] [Indexed: 04/14/2024] Open
Abstract
Central and peripheral mechanisms of the endocannabinoid system (ECS) favor energy intake and storage. The ECS, especially cannabidiol (CBD) receptors, controls adipocyte differentiation (hyperplasia) and lipid accumulation (hypertrophy) in adipose tissue. In white adipose tissue, cannabidiol receptor 1 (CB1) stimulation increases lipogenesis and inhibits lipolysis; in brown adipose tissue, it decreases mitochondrial thermogenesis and biogenesis. This study compared the availability of phytocannabinoids [CBD and Δ9-tetrahydrocannabinol (THC)] and polyunsaturated fatty acids [omega 3 (ω3) and omega 6 (ω6)] in different hemp seed oils (HSO). The study also examined the effect of HSO on adipocyte lipid accumulation by suppressing cannabinoid receptors in adipogenesis-stimulated human mesenchymal stem cells (hMSCs). Most importantly, Oil-Red-O' and Nile red tests showed that HSO induced adipogenic hMSC differentiation without differentiation agents. Additionally, HSO-treated cells showed increased peroxisome proliferator-activated receptor gamma (PPARγ) mRNA expression compared to controls (hMSC). HSO reduced PPARγ mRNA expression after differentiation media (DM) treatment. After treatment with HSO, DM-hMSCs had significantly lower CB1 mRNA and protein expressions than normal hMSCs. HSO treatment also decreased transient receptor potential vanilloid 1 (TRPV1), fatty acid amide hydrolase (FAAH), and monoacylglycerol lipase (MGL) mRNAs in hMSC and DM-hMSCs. HSO treatment significantly decreased CB1, CB2, TRPV1, and G-protein-coupled receptor 55 (GPCR55) protein levels in DM-hMSC compared to hMSC in western blot analysis. In this study, HSO initiated adipogenic differentiation in hMSC without DM, but it suppressed CB1 gene and protein expression, potentially decreasing adipocyte lipid accumulation and lipogenic enzymes.
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Affiliation(s)
- Albatul S. Almousa
- Department of Food Science and Nutrition, College of Food Science and Agriculture, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia;
- Department of Human Nutrition, College of Home Economics, King Khalid University, P.O. Box 3236, Abha 10001, Saudi Arabia
| | - Pandurangan Subash-Babu
- Department of Food Science and Nutrition, College of Food Science and Agriculture, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia;
| | - Ibrahim O. Alanazi
- The Healthy Aging Research Institute, King Abdulaziz City for Science and Technology, P.O. Box 6086, Riyadh 11442, Saudi Arabia; (I.O.A.); (H.A.); (E.B.)
- Genome Research Unit, Department of Biochemistry, College of Science, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia
| | - Ali A. Alshatwi
- Department of Food Science and Nutrition, College of Food Science and Agriculture, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia;
| | - Huda Alkhalaf
- The Healthy Aging Research Institute, King Abdulaziz City for Science and Technology, P.O. Box 6086, Riyadh 11442, Saudi Arabia; (I.O.A.); (H.A.); (E.B.)
| | - Eman Bahattab
- The Healthy Aging Research Institute, King Abdulaziz City for Science and Technology, P.O. Box 6086, Riyadh 11442, Saudi Arabia; (I.O.A.); (H.A.); (E.B.)
| | - Atheer Alsiyah
- The Applied Genomics Research Institute, King Abdulaziz City for Science and Technology, P.O. Box 6086, Riyadh 11442, Saudi Arabia;
| | - Mohammad Alzahrani
- Institute of Advanced Agricultural and Food Technologies, King Abdulaziz City for Science and Technology, P.O. Box 6086, Riyadh 11442, Saudi Arabia;
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15
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Chen S, Kim JK. The Role of Cannabidiol in Liver Disease: A Systemic Review. Int J Mol Sci 2024; 25:2370. [PMID: 38397045 PMCID: PMC10888697 DOI: 10.3390/ijms25042370] [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: 01/22/2024] [Revised: 02/14/2024] [Accepted: 02/15/2024] [Indexed: 02/25/2024] Open
Abstract
Cannabidiol (CBD), a non-psychoactive phytocannabinoid abundant in Cannabis sativa, has gained considerable attention for its anti-inflammatory, antioxidant, analgesic, and neuroprotective properties. It exhibits the potential to prevent or slow the progression of various diseases, ranging from malignant tumors and viral infections to neurodegenerative disorders and ischemic diseases. Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, and viral hepatitis stand as prominent causes of morbidity and mortality in chronic liver diseases globally. The literature has substantiated CBD's potential therapeutic effects across diverse liver diseases in in vivo and in vitro models. However, the precise mechanism of action remains elusive, and an absence of evidence hinders its translation into clinical practice. This comprehensive review emphasizes the wealth of data linking CBD to liver diseases. Importantly, we delve into a detailed discussion of the receptors through which CBD might exert its effects, including cannabinoid receptors, CB1 and CB2, peroxisome proliferator-activated receptors (PPARs), G protein-coupled receptor 55 (GPR55), transient receptor potential channels (TRPs), and their intricate connections with liver diseases. In conclusion, we address new questions that warrant further investigation in this evolving field.
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Affiliation(s)
- Si Chen
- Department of Biochemistry and Molecular Biology, Jeonbuk National University Medical School, Jeonju 54896, Republic of Korea;
| | - Jeon-Kyung Kim
- Institute of New Drug Development, School of Pharmacy, Jeonbuk National University, Jeonju 54896, Jeonbuk, Republic of Korea
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16
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Ruhl T, Nuptybayeva A, Kim BS, Beier JP. GPR55 inhibits the pro-adipogenic activity of anandamide in human adipose stromal cells. Exp Cell Res 2024; 435:113908. [PMID: 38163565 DOI: 10.1016/j.yexcr.2023.113908] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 12/22/2023] [Accepted: 12/30/2023] [Indexed: 01/03/2024]
Abstract
The endocannabinoid anandamide (AEA) stimulates adipogenesis via the cannabinoid receptor CB1 in adipose stromal cells (ASCs). However, AEA interacts also with nonclassical cannabinoid receptors, including transient receptor potential cation channel (TRPV)1 and G protein-coupled receptor (GPR)55. Their roles in AEA mediated adipogenesis of human ASCs have not been investigated. We examined the receptor-expressions by immunostaining on human ASCs and tested their functionality by measuring the expression of immediate early genes (IEGs) related to the transcription factor-complex AP-1 upon exposition to receptor agonists. Cells were stimulated with increasing concentrations of specific ligands to investigate the effects on ASC viability (proliferation and metabolic activity), secretory activity, and AEA mediated differentiation. ASCs expressed both receptors, and their activation suppressed IEG expression. TRPV1 did not affect viability or cytokine secretion. GPR55 decreased proliferation, and it inhibited the release of hepatocyte growth factor. Blocking GPR55 increased the pro-adipogenic activity of AEA. These data suggest that GPR55 functions as negative regulator of cannabinoid mediated pro-adipogenic capacity in ASCs.
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Affiliation(s)
- Tim Ruhl
- Department of Plastic Surgery, Hand Surgery-Burn Center, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.
| | - Aigul Nuptybayeva
- Department of Plastic Surgery, Hand Surgery-Burn Center, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.
| | - Bong-Sung Kim
- Department of Plastic Surgery, Hand Surgery-Burn Center, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany; Department of Plastic and Hand Surgery, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland.
| | - Justus P Beier
- Department of Plastic Surgery, Hand Surgery-Burn Center, University Hospital RWTH Aachen, Pauwelsstraße 30, 52074, Aachen, Germany.
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17
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Jiménez-Sánchez C, Sinturel F, Mezza T, Loizides-Mangold U, Montoya JP, Li L, Di Giuseppe G, Quero G, Guessous I, Jornayvaz F, Schrauwen P, Stenvers DJ, Alfieri S, Giaccari A, Berishvili E, Compagnon P, Bosco D, Riezman H, Dibner C, Maechler P. Lysophosphatidylinositols Are Upregulated After Human β-Cell Loss and Potentiate Insulin Release. Diabetes 2024; 73:93-107. [PMID: 37862465 DOI: 10.2337/db23-0205] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 10/16/2023] [Indexed: 10/22/2023]
Abstract
In this study, we identified new lipid species associated with the loss of pancreatic β-cells triggering diabetes. We performed lipidomics measurements on serum from prediabetic mice lacking β-cell prohibitin-2 (a model of monogenic diabetes) patients without previous history of diabetes but scheduled for pancreaticoduodenectomy resulting in the acute reduction of their β-cell mass (∼50%), and patients with type 2 diabetes (T2D). We found lysophosphatidylinositols (lysoPIs) were the main circulating lipid species altered in prediabetic mice. The changes were confirmed in the patients with acute reduction of their β-cell mass and in those with T2D. Increased lysoPIs significantly correlated with HbA1c (reflecting glycemic control), fasting glycemia, and disposition index, and did not correlate with insulin resistance or obesity in human patients with T2D. INS-1E β-cells as well as pancreatic islets isolated from nondiabetic mice and human donors exposed to exogenous lysoPIs showed potentiated glucose-stimulated and basal insulin secretion. Finally, addition of exogenous lysoPIs partially rescued impaired glucose-stimulated insulin secretion in islets from mice and humans in the diabetic state. Overall, lysoPIs appear to be lipid species upregulated in the prediabetic stage associated with the loss of β-cells and that support the secretory function of the remaining β-cells. ARTICLE HIGHLIGHTS Circulating lysophosphatidylinositols (lysoPIs) are increased in situations associated with β-cell loss in mice and humans such as (pre-)diabetes, and hemipancreatectomy. Pancreatic islets isolated from nondiabetic mice and human donors, as well as INS-1E β-cells, exposed to exogenous lysoPIs exhibited potentiated glucose-stimulated and basal insulin secretion. Addition of exogenous lysoPIs partially rescued impaired glucose-stimulated insulin secretion in islets from mice and humans in the diabetic state. LysoPIs appear as lipid species being upregulated already in the prediabetic stage associated with the loss of β-cells and supporting the function of the remaining β-cells.
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Affiliation(s)
- Cecilia Jiménez-Sánchez
- Department of Cell Physiology and Metabolism, University of Geneva Medical Center, Geneva, Switzerland
- Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland
- Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
| | - Flore Sinturel
- Department of Cell Physiology and Metabolism, University of Geneva Medical Center, Geneva, Switzerland
- Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland
- Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
| | - Teresa Mezza
- Pancreas Unit, Centro Malattie dell'Apparato Digerente, Medicina Interna e Gastroenterologia, Fondazione Policlinico Universitario Gemelli, Institute of Hospitalization and Scientific Care (IRCCS), Rome, Italy
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Ursula Loizides-Mangold
- Department of Cell Physiology and Metabolism, University of Geneva Medical Center, Geneva, Switzerland
- Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland
- Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
| | - Jonathan Paz Montoya
- Proteomics Core Facility, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Lingzi Li
- Department of Cell Physiology and Metabolism, University of Geneva Medical Center, Geneva, Switzerland
- Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland
| | - Gianfranco Di Giuseppe
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Giuseppe Quero
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
- Chirurgia Digestiva, Fondazione Policlinico Universitario Gemelli IRCSS Università Cattolica del Sacro Cuore, Rome, Italy
| | - Idris Guessous
- Department of Primary Care Medicine, Geneva University Hospitals, Geneva, Switzerland
| | - François Jornayvaz
- Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland
- Division of Endocrinology, Diabetes, Nutrition and Patient Education, Department of Medicine, University Hospital of Geneva, Geneva, Switzerland
| | - Patrick Schrauwen
- Department of Nutrition and Movement Sciences, Maastricht University Medical Center, Maastricht, the Netherlands
| | - Dirk Jan Stenvers
- Department of Endocrinology and Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
- Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam, the Netherlands
| | - Sergio Alfieri
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Chirurgia Digestiva, Fondazione Policlinico Universitario Gemelli IRCSS Università Cattolica del Sacro Cuore, Rome, Italy
| | - Andrea Giaccari
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Endocrinologia e Diabetologia, Fondazione Policlinico Universitario Gemelli IRCCS, Rome, Italy
| | - Ekaterine Berishvili
- Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland
- Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
- Cell isolation and Transplantation Center, Geneva University Hospitals, Geneva, Switzerland
| | - Philippe Compagnon
- Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
- Cell isolation and Transplantation Center, Geneva University Hospitals, Geneva, Switzerland
| | - Domenico Bosco
- Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland
- Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
- Cell isolation and Transplantation Center, Geneva University Hospitals, Geneva, Switzerland
| | - Howard Riezman
- Department of Biochemistry, Faculty of Science, National Centre of Competence in Research Chemical Biology, University of Geneva, Geneva, Switzerland
| | - Charna Dibner
- Department of Cell Physiology and Metabolism, University of Geneva Medical Center, Geneva, Switzerland
- Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland
- Department of Surgery, Geneva University Hospitals, Geneva, Switzerland
| | - Pierre Maechler
- Department of Cell Physiology and Metabolism, University of Geneva Medical Center, Geneva, Switzerland
- Faculty Diabetes Center, University of Geneva Medical Center, Geneva, Switzerland
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Iannone V, Babu AF, Lok J, Gómez-Gallego C, D'Auria G, Vazquez-Uribe R, Vaaben TH, Bongers M, Mikkonen S, Vaittinen M, Tikkanen I, Kettunen M, Klåvus A, Sehgal R, Kaminska D, Pihlajamaki J, Hanhineva K, El-Nezami H, Sommer MOA, Kolehmainen M. Changes in liver metabolic pathways demonstrate efficacy of the combined dietary and microbial therapeutic intervention in MASLD mouse model. Mol Metab 2023; 78:101823. [PMID: 37839774 PMCID: PMC10618820 DOI: 10.1016/j.molmet.2023.101823] [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: 08/25/2023] [Revised: 10/09/2023] [Accepted: 10/09/2023] [Indexed: 10/17/2023] Open
Abstract
OBJECTIVE Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is the most prevalent liver disease globally, yet no therapies are approved. The effects of Escherichia coli Nissle 1917 expressing aldafermin, an engineered analog of the intestinal hormone FGF19, in combination with dietary change were investigated as a potential treatment for MASLD. METHODS MASLD was induced in C57BL/6J male mice by American lifestyle-induced obesity syndrome diet and then switched to a standard chow diet for seven weeks. In addition to the dietary change, the intervention group received genetically engineered E. coli Nissle expressing aldafermin, while control groups received either E. coli Nissle vehicle or no treatment. MASLD-related plasma biomarkers were measured using an automated clinical chemistry analyzer. The liver steatosis was assessed by histology and bioimaging analysis using Fiji (ImageJ) software. The effects of the intervention in the liver were also evaluated by RNA sequencing and liquid-chromatography-based non-targeted metabolomics analysis. Pathway enrichment studies were conducted by integrating the differentially expressed genes from the transcriptomics findings with the metabolites from the metabolomics results using Ingenuity pathway analysis. RESULTS After the intervention, E. coli Nissle expressing aldafermin along with dietary changes reduced body weight, liver steatosis, plasma aspartate aminotransferase, and plasma cholesterol levels compared to the two control groups. The integration of transcriptomics with non-targeted metabolomics analysis revealed the downregulation of amino acid metabolism and related receptor signaling pathways potentially implicated in the reduction of hepatic steatosis and insulin resistance. Moreover, the downregulation of pathways linked to lipid metabolism and changes in amino acid-related pathways suggested an overall reduction of oxidative stress in the liver. CONCLUSIONS These data support the potential for using engineered microbial therapeutics in combination with dietary changes for managing MASLD.
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Affiliation(s)
- Valeria Iannone
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland
| | - Ambrin Farizah Babu
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland; Afekta Technologies Ltd., Microkatu 1, 70210 Kuopio, Finland
| | - Johnson Lok
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland
| | - Carlos Gómez-Gallego
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland.
| | - Giuseppe D'Auria
- Sequencing and Bioinformatics Service, Foundation for the Promotion of Health and Biomedical Research of Valencia Region, FISABIO, 46020 Valencia, Spain; CIBER in Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, 28029, Madrid, Spain
| | - Ruben Vazquez-Uribe
- Technical University of Denmark, The Novo Nordisk Foundation Center for Biosustainability, 2800 Kongens Lyngby, Denmark
| | - Troels Holger Vaaben
- Technical University of Denmark, The Novo Nordisk Foundation Center for Biosustainability, 2800 Kongens Lyngby, Denmark
| | - Mareike Bongers
- Technical University of Denmark, The Novo Nordisk Foundation Center for Biosustainability, 2800 Kongens Lyngby, Denmark
| | - Santtu Mikkonen
- University Department of Technical Physics, University of Eastern Finland, 70211 Kuopio, Finland
| | - Maija Vaittinen
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland
| | - Ida Tikkanen
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland
| | - Mikko Kettunen
- Biomedical Imaging Unit, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211, Kuopio, Finland
| | - Anton Klåvus
- Afekta Technologies Ltd., Microkatu 1, 70210 Kuopio, Finland
| | - Ratika Sehgal
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland
| | - Dorota Kaminska
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland; Department of Medicine, Division of Cardiology, University of California, Los Angeles, CA 90095, USA
| | - Jussi Pihlajamaki
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland; Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, 70210 Kuopio, Finland
| | - Kati Hanhineva
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland; Afekta Technologies Ltd., Microkatu 1, 70210 Kuopio, Finland; Department of Life Technologies, Food Sciences Unit, University of Turku, 20014 Turku, Finland
| | - Hani El-Nezami
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland; University of Hong Kong, Hong Kong SAR, Molecular and Cell Biology Research Area, School of Biological Sciences, Hong Kong, Hong Kong, China
| | - Morten Otto Alexander Sommer
- Technical University of Denmark, The Novo Nordisk Foundation Center for Biosustainability, 2800 Kongens Lyngby, Denmark.
| | - Marjukka Kolehmainen
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, 70200 Kuopio, Finland
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Shibata K, Hayasaka T, Sakamoto S, Hashimoto S, Kawamura N, Fujiyoshi M, Kimura T, Shimamura T, Fukai M, Taketomi A. Warm Ischemia Induces Spatiotemporal Changes in Lysophosphatidylinositol That Affect Post-Reperfusion Injury in Normal and Steatotic Rat Livers. J Clin Med 2023; 12:jcm12093163. [PMID: 37176603 PMCID: PMC10179083 DOI: 10.3390/jcm12093163] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 04/24/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Warm ischemia-reperfusion injury is a prognostic factor for hepatectomy and liver transplantation. However, its underlying molecular mechanisms are unknown. This study aimed to elucidate these mechanisms and identify the predictive markers of post-reperfusion injury. Rats with normal livers were subjected to 70% hepatic warm ischemia for 15, 30, or 90 min, while those with steatotic livers were subjected to 70% hepatic warm ischemia for only 30 min. The liver and blood were sampled at the end of ischemia and 1, 6, and 24 h after reperfusion. The serum alanine aminotransferase (ALT) activity, Suzuki injury scores, and lipid peroxidation (LPO) products were evaluated. The ALT activity and Suzuki scores increased with ischemic duration and peaked at 1 and 6 h after reperfusion, respectively. Steatotic livers subjected to 30 min ischemia and normal livers subjected to 90 min ischemia showed comparable injury. A similar trend was observed for LPO products. Imaging mass spectrometry of normal livers revealed an increase in lysophosphatidylinositol (LPI (18:0)) and a concomitant decrease in phosphatidylinositol (PI (18:0/20:4)) in Zone 1 (central venous region) with increasing ischemic duration; they returned to their basal values after reperfusion. Similar changes were observed in steatotic livers. Hepatic warm ischemia time-dependent acceleration of PI (18:0/20:4) to LPI (18:0) conversion occurs initially in Zone 1 and is more pronounced in fatty livers. Thus, the LPI (18:0)/PI (18:0/20:4) ratio is a potential predictor of post-reperfusion injury.
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Affiliation(s)
- Kengo Shibata
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Takahiro Hayasaka
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Sodai Sakamoto
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Satsuki Hashimoto
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Norio Kawamura
- Department of Transplant Surgery, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Masato Fujiyoshi
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Taichi Kimura
- Department of Cancer Pathology, Faculty of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Tsuyoshi Shimamura
- Division of Organ Transplantation, Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Moto Fukai
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
- Department of Transplant Surgery, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
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20
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Babayeva M, Loewy ZG. Cannabis Pharmacogenomics: A Path to Personalized Medicine. Curr Issues Mol Biol 2023; 45:3479-3514. [PMID: 37185752 PMCID: PMC10137111 DOI: 10.3390/cimb45040228] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/05/2023] [Accepted: 04/12/2023] [Indexed: 05/17/2023] Open
Abstract
Cannabis and related compounds have created significant research interest as a promising therapy in many disorders. However, the individual therapeutic effects of cannabinoids and the incidence of side effects are still difficult to determine. Pharmacogenomics may provide the answers to many questions and concerns regarding the cannabis/cannabinoid treatment and help us to understand the variability in individual responses and associated risks. Pharmacogenomics research has made meaningful progress in identifying genetic variations that play a critical role in interpatient variability in response to cannabis. This review classifies the current knowledge of pharmacogenomics associated with medical marijuana and related compounds and can assist in improving the outcomes of cannabinoid therapy and to minimize the adverse effects of cannabis use. Specific examples of pharmacogenomics informing pharmacotherapy as a path to personalized medicine are discussed.
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Affiliation(s)
- Mariana Babayeva
- Department of Biomedical and Pharmaceutical Sciences, Touro College of Pharmacy, New York, NY 10027, USA
| | - Zvi G Loewy
- Department of Biomedical and Pharmaceutical Sciences, Touro College of Pharmacy, New York, NY 10027, USA
- Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY 10595, USA
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21
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Wang G, Wang X, Song J, Wang H, Ruan C, Zhang W, Guo Z, Li W, Guo W. Cotton peroxisome-localized lysophospholipase counteracts the toxic effects of Verticillium dahliae NLP1 and confers wilt resistance. THE PLANT JOURNAL : FOR CELL AND MOLECULAR BIOLOGY 2023. [PMID: 37026387 DOI: 10.1111/tpj.16236] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Accepted: 03/28/2023] [Indexed: 06/19/2023]
Abstract
Plasma membrane represents a critical battleground between plants and attacking microbes. Necrosis-and-ethylene-inducing peptide 1 (Nep1)-like proteins (NLPs), cytolytic toxins produced by some bacterial, fungal and oomycete species, are able to target on lipid membranes by binding eudicot plant-specific sphingolipids (glycosylinositol phosphorylceramide) and form transient small pores, causing membrane leakage and subsequent cell death. NLP-producing phytopathogens are a big threat to agriculture worldwide. However, whether there are R proteins/enzymes that counteract the toxicity of NLPs in plants remains largely unknown. Here we show that cotton produces a peroxisome-localized enzyme lysophospholipase, GhLPL2. Upon Verticillium dahliae attack, GhLPL2 accumulates on the membrane and binds to V. dahliae secreted NLP, VdNLP1, to block its contribution to virulence. A higher level of lysophospholipase in cells is required to neutralize VdNLP1 toxicity and induce immunity-related genes expression, meanwhile maintaining normal growth of cotton plants, revealing the role of GhLPL2 protein in balancing resistance to V. dahliae and growth. Intriguingly, GhLPL2 silencing cotton plants also display high resistance to V. dahliae, but show severe dwarfing phenotype and developmental defects, suggesting GhLPL2 is an essential gene in cotton. GhLPL2 silencing results in lysophosphatidylinositol over-accumulation and decreased glycometabolism, leading to a lack of carbon sources required for plants and pathogens to survive. Furthermore, lysophospholipases from several other crops also interact with VdNLP1, implying that blocking NLP virulence by lysophospholipase may be a common strategy in plants. Our work demonstrates that overexpressing lysophospholipase encoding genes have great potential for breeding crops with high resistance against NLP-producing microbial pathogens.
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Affiliation(s)
- Guilin Wang
- State Key Laboratory of Crop Genetics & Germplasm Enhancement and Utilization, Nanjing Agricultural University, Nanjing, 210095, China
- Engineering Research Center of Ministry of Education for Cotton Germplasm Enhancement and Application, Nanjing Agricultural University, Nanjing, 210095, China
| | - Xinyu Wang
- Engineering Research Center of Ministry of Education for Cotton Germplasm Enhancement and Application, Nanjing Agricultural University, Nanjing, 210095, China
- College of Life Sciences, Nanjing Agricultural University, Nanjing, 210095, China
| | - Jian Song
- State Key Laboratory of Crop Genetics & Germplasm Enhancement and Utilization, Nanjing Agricultural University, Nanjing, 210095, China
- Engineering Research Center of Ministry of Education for Cotton Germplasm Enhancement and Application, Nanjing Agricultural University, Nanjing, 210095, China
| | - Haitang Wang
- State Key Laboratory of Crop Genetics & Germplasm Enhancement and Utilization, Nanjing Agricultural University, Nanjing, 210095, China
- Engineering Research Center of Ministry of Education for Cotton Germplasm Enhancement and Application, Nanjing Agricultural University, Nanjing, 210095, China
| | - Chaofeng Ruan
- State Key Laboratory of Crop Genetics & Germplasm Enhancement and Utilization, Nanjing Agricultural University, Nanjing, 210095, China
- Engineering Research Center of Ministry of Education for Cotton Germplasm Enhancement and Application, Nanjing Agricultural University, Nanjing, 210095, China
| | - Wenshu Zhang
- State Key Laboratory of Crop Genetics & Germplasm Enhancement and Utilization, Nanjing Agricultural University, Nanjing, 210095, China
- Engineering Research Center of Ministry of Education for Cotton Germplasm Enhancement and Application, Nanjing Agricultural University, Nanjing, 210095, China
| | - Zhan Guo
- State Key Laboratory of Crop Genetics & Germplasm Enhancement and Utilization, Nanjing Agricultural University, Nanjing, 210095, China
- Engineering Research Center of Ministry of Education for Cotton Germplasm Enhancement and Application, Nanjing Agricultural University, Nanjing, 210095, China
| | - Weixi Li
- State Key Laboratory of Crop Genetics & Germplasm Enhancement and Utilization, Nanjing Agricultural University, Nanjing, 210095, China
- Engineering Research Center of Ministry of Education for Cotton Germplasm Enhancement and Application, Nanjing Agricultural University, Nanjing, 210095, China
| | - Wangzhen Guo
- State Key Laboratory of Crop Genetics & Germplasm Enhancement and Utilization, Nanjing Agricultural University, Nanjing, 210095, China
- Engineering Research Center of Ministry of Education for Cotton Germplasm Enhancement and Application, Nanjing Agricultural University, Nanjing, 210095, China
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22
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Aragón-Herrera A, Moraña-Fernández S, Otero-Santiago M, Anido-Varela L, Campos-Toimil M, García-Seara J, Román A, Seijas J, García-Caballero L, Rodríguez J, Tarazón E, Roselló-Lletí E, Portolés M, Lage R, Gualillo O, González-Juanatey JR, Feijóo-Bandín S, Lago F. The lipidomic and inflammatory profiles of visceral and subcutaneous adipose tissues are distinctly regulated by the SGLT2 inhibitor empagliflozin in Zucker diabetic fatty rats. Biomed Pharmacother 2023; 161:114535. [PMID: 36931025 DOI: 10.1016/j.biopha.2023.114535] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Revised: 03/02/2023] [Accepted: 03/13/2023] [Indexed: 03/17/2023] Open
Abstract
The pharmacological inhibition of sodium-glucose cotransporter 2 (SGLT2) has emerged as a treatment for patients with type 2 diabetes mellitus (T2DM), cardiovascular disease and/or other metabolic disturbances, although some of the mechanisms implicated in their beneficial effects are unknown. The SGLT2 inhibitor (SGLT2i) empagliflozin has been suggested as a regulator of adiposity, energy metabolism, and systemic inflammation in adipose tissue. The aim of our study was to evaluate the impact of a 6-week-empagliflozin treatment on the lipidome of visceral (VAT) and subcutaneous adipose tissue (SAT) from diabetic obese Zucker Diabetic Fatty (ZDF) rats using an untargeted metabolomics approach. We found that empagliflozin increases the content of diglycerides and oxidized fatty acids (FA) in VAT, while in SAT, it decreases the levels of several lysophospholipids and increases 2 phosphatidylcholines. Empagliflozin also reduces the expression of the cytokines interleukin-1 beta (IL-1β), IL-6, tumor necrosis factor-alpha (TNFα), monocyte-chemotactic protein-1 (MCP-1) and IL-10, and of Cd86 and Cd163 M1 and M2 macrophage markers in VAT, with no changes in SAT, except for a decrease in IL-1β. Empagliflozin treatment also shows an effect on lipolysis increasing the expression of hormone-sensitive lipase (HSL) in SAT and VAT and of adipose triglyceride lipase (ATGL) in VAT, together with a decrease in the adipose content of the FA transporter cluster of differentiation 36 (CD36). In conclusion, our data highlighted differences in the VAT and SAT lipidomes, inflammatory profiles and lipolytic function, which suggest a distinct metabolism of these two white adipose tissue depots after the empagliflozin treatment.
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Affiliation(s)
- Alana Aragón-Herrera
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain
| | - Sandra Moraña-Fernández
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain; Cardiology Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS) and Institute of Biomedical Research of Santiago de Compostela (IDIS-SERGAS). Av. Barcelona, Campus Vida, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Manuel Otero-Santiago
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain
| | - Laura Anido-Varela
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain
| | - Manuel Campos-Toimil
- Group of Pharmacology of Chronic Diseases (CD Pharma), Department of Pharmacology, Pharmacy and Pharmaceutical Technology, University of Santiago de Compostela, Spain
| | - Javier García-Seara
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain; Arrhytmia Unit, Clinical University Hospital of Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - Ana Román
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain; Cardiology Department, Clinical University Hospital of Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - José Seijas
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain; Cardiology Department, Clinical University Hospital of Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - Lucía García-Caballero
- Department of Morphological Sciences, School of Medicine and Dentistry, University of Santiago de Compostela, Santiago de Compostela, Spain
| | - Javier Rodríguez
- Clinical Biochemistry Laboratory, Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain
| | - Estefanía Tarazón
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain; Clinical and Translational Research in Cardiology Unit, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain
| | - Esther Roselló-Lletí
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain; Clinical and Translational Research in Cardiology Unit, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain
| | - Manuel Portolés
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain; Clinical and Translational Research in Cardiology Unit, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain
| | - Ricardo Lage
- Cardiology Group, Center for Research in Molecular Medicine and Chronic Diseases (CIMUS) and Institute of Biomedical Research of Santiago de Compostela (IDIS-SERGAS). Av. Barcelona, Campus Vida, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Oreste Gualillo
- Laboratory of Neuroendocrine Interactions in Rheumatology and Inflammatory Diseases, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain
| | - José Ramón González-Juanatey
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain; Cardiology Department, Clinical University Hospital of Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain
| | - Sandra Feijóo-Bandín
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain.
| | - Francisca Lago
- Cellular and Molecular Cardiology Research Unit, Institute of Biomedical Research and Xerencia de Xestión Integrada de Santiago (XXIS/SERGAS), Santiago de Compostela, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Institute of Health Carlos III, Madrid, Spain
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23
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Iannone V, Lok J, Babu AF, Gómez-Gallego C, Willman RM, Koistinen VM, Klåvus A, Kettunen MI, Kårlund A, Schwab U, Hanhineva K, Kolehmainen M, El-Nezami H. Associations of altered hepatic gene expression in American lifestyle-induced obesity syndrome diet-fed mice with metabolic changes during NAFLD development and progression. J Nutr Biochem 2023; 115:109307. [PMID: 36868506 DOI: 10.1016/j.jnutbio.2023.109307] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 01/20/2023] [Accepted: 02/24/2023] [Indexed: 03/05/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) pathogenesis remains poorly understood due to the complex metabolic and inflammatory changes in the liver. This study aimed to elucidate hepatic events related to inflammation and lipid metabolism and their linkage with metabolic alterations during NAFLD in American lifestyle-induced obesity syndrome (ALIOS) diet-fed mice. Forty-eight C57BL/6J male mice were fed with ALIOS diet (n=24) or control chow diet (n=24) for 8, 12, and 16 weeks. At the end of each timepoint, eight mice were sacrificed where plasma and liver were collected. Hepatic fat accumulation was followed using magnetic resonance imaging and confirmed with histology. Further, targeted gene expression and non-targeted metabolomics analysis were conducted. Our results showed higher hepatic steatosis, body weight, energy consumption, and liver mass in ALIOS diet-fed mice compared to control mice. ALIOS diet altered expression of genes related to inflammation (Tnfa and IL-6) and lipid metabolism (Cd36, Fasn, Scd1, Cpt1a, and Ppara). Metabolomics analysis indicated decrease of lipids containing polyunsaturated fatty acids such as LPE(20:5) and LPC(20:5) with increase of other lipid species such as LPI(16:0) and LPC(16:2) and peptides such as alanyl-phenylalanine and glutamyl-arginine. We further observed novel correlations between different metabolites including sphingolipid, lysophospholipids, peptides, and bile acid with inflammation, lipid uptake and synthesis. Together with the reduction of antioxidant metabolites and gut microbiota-derived metabolites contribute to NAFLD development and progression. The combination of non-targeted metabolomics with gene expression in future studies can further identify key metabolic routes during NAFLD which could be the targets of potential novel therapeutics.
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Affiliation(s)
- Valeria Iannone
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Johnson Lok
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Ambrin Farizah Babu
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Afekta Technologies Ltd., Kuopio, Finland
| | - Carlos Gómez-Gallego
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Roosa Maria Willman
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Department of Medicine, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
| | - Ville Mikael Koistinen
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Afekta Technologies Ltd., Kuopio, Finland; Department of Life technologies, Food Sciences Unit, University of Turku, Turku, Finland
| | | | - Mikko I Kettunen
- Kuopio Biomedical Imaging Unit, A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Anna Kårlund
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Ursula Schwab
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland
| | - Kati Hanhineva
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Afekta Technologies Ltd., Kuopio, Finland; Department of Life technologies, Food Sciences Unit, University of Turku, Turku, Finland.
| | - Marjukka Kolehmainen
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
| | - Hani El-Nezami
- School of Medicine, Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Molecular and Cell Biology Division, School of Biological Sciences, University of Hong Kong, Hong Kong China
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GPCR in Adipose Tissue Function-Focus on Lipolysis. Biomedicines 2023; 11:biomedicines11020588. [PMID: 36831123 PMCID: PMC9953751 DOI: 10.3390/biomedicines11020588] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 02/06/2023] [Accepted: 02/10/2023] [Indexed: 02/18/2023] Open
Abstract
Adipose tissue can be divided anatomically, histologically, and functionally into two major entities white and brown adipose tissues (WAT and BAT, respectively). WAT is the primary energy depot, storing most of the bioavailable triacylglycerol molecules of the body, whereas BAT is designed for dissipating energy in the form of heat, a process also known as non-shivering thermogenesis as a defense against a cold environment. Importantly, BAT-dependent energy dissipation directly correlates with cardiometabolic health and has been postulated as an intriguing target for anti-obesity therapies. In general, adipose tissue (AT) lipid content is defined by lipid uptake and lipogenesis on one side, and, on the other side, it is defined by the breakdown of lipids and the release of fatty acids by lipolysis. The equilibrium between lipogenesis and lipolysis is important for adipocyte and general metabolic homeostasis. Overloading adipocytes with lipids causes cell stress, leading to the recruitment of immune cells and adipose tissue inflammation, which can affect the whole organism (metaflammation). The most important consequence of energy and lipid overload is obesity and associated pathophysiologies, including insulin resistance, type 2 diabetes, and cardiovascular disease. The fate of lipolysis products (fatty acids and glycerol) largely differs between AT: WAT releases fatty acids into the blood to deliver energy to other tissues (e.g., muscle). Activation of BAT, instead, liberates fatty acids that are used within brown adipocyte mitochondria for thermogenesis. The enzymes involved in lipolysis are tightly regulated by the second messenger cyclic adenosine monophosphate (cAMP), which is activated or inhibited by G protein-coupled receptors (GPCRs) that interact with heterotrimeric G proteins (G proteins). Thus, GPCRs are the upstream regulators of the equilibrium between lipogenesis and lipolysis. Moreover, GPCRs are of special pharmacological interest because about one third of the approved drugs target GPCRs. Here, we will discuss the effects of some of most studied as well as "novel" GPCRs and their ligands. We will review different facets of in vitro, ex vivo, and in vivo studies, obtained with both pharmacological and genetic approaches. Finally, we will report some possible therapeutic strategies to treat obesity employing GPCRs as primary target.
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McCloskey AG, Miskelly MG, Lafferty RA, Flatt PR, McKillop AM. Antidiabetic actions of GPR55 agonist Abn-CBD and sitagliptin in obese-diabetic high fat fed mice. Biochem Pharmacol 2023; 208:115398. [PMID: 36581052 DOI: 10.1016/j.bcp.2022.115398] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 12/19/2022] [Accepted: 12/20/2022] [Indexed: 12/27/2022]
Abstract
GPR55 has been recognized as a novel anti-diabetic target exerting positive effects on beta cell function and mass. This study evaluated the metabolic actions and therapeutic efficacy of GPR55 agonist abnormal cannabidiol (Abn-CBD) administered alone and in combination with sitagliptin in diet-induced obese-diabetic mice. Chronic effects of 21-day oral administration of Abn-CBD (0.1 µmol/kg BW) monotherapy and in combination with sitagliptin (50 mg/kg BW) were assessed in obese-diabetic HFF mice (n = 8). Assessments of plasma glucose, circulating insulin, DPP-IV activity, CRP, amylase, lipids, body weight and food intake were undertaken. Glucose tolerance, insulin sensitivity, DEXA scanning and islet morphology analysis were performed at 21-days. Sitagliptin, Abn-CBD alone and in combination with sitagliptin attenuated plasma glucose by 37-53 % (p < 0.01 - p < 0.001) and enhanced circulating insulin concentrations by 23-31 % (p < 0.001). Abn-CBD alone and with sitagliptin reduced bodyweight by 9-10 % (p < 0.05). After 21-days, Abn-CBD in combination with sitagliptin (44 %; p < 0.01) improved glucose tolerance, whilst enhancing insulin sensitivity by 79 % (p < 0.01). Abn-CBD increased islet area (86 %; p < 0.05), beta cell mass (p < 0.05) and beta cell proliferation (164 %; p < 0.001), whilst in combination with sitagliptin islet area was decreased (50 %; p < 0.01). Abn-CBD alone, in combination with sitagliptin or sitagliptin alone decreased triglycerides by 34-65 % (p < 0.001) and total cholesterol concentrations by 15-25 % (p < 0.001). In addition, Abn-CBD in combination with sitagliptin reduced fat mass by 19 % (p < 0.05) and reduced CRP concentrations (39 %; p < 0.05). These findings advocate Abn-CBD monotherapy and in combination with sitagliptin as a novel and effective approach for bodyweight control and the treatment of glucose intolerance and dyslipidaemia in type-2-diabetes.
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Affiliation(s)
- Andrew G McCloskey
- School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, U.K; Health and Biomedical Research Centre (HEAL), Atlantic Technological University, ATU Sligo, Ash Lane, Sligo, F91 YW50, Ireland
| | - Michael G Miskelly
- School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, U.K
| | - Ryan A Lafferty
- School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, U.K
| | - Peter R Flatt
- School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, U.K
| | - Aine M McKillop
- School of Biomedical Sciences, Ulster University, Cromore Road, Coleraine, BT52 1SA, Northern Ireland, U.K.
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Cao X, van Putten JPM, Wösten MMSM. Biological functions of bacterial lysophospholipids. Adv Microb Physiol 2023; 82:129-154. [PMID: 36948653 DOI: 10.1016/bs.ampbs.2022.10.001] [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: 11/13/2022]
Abstract
Lysophospholipids (LPLs) are lipid-derived metabolic intermediates in the cell membrane. The biological functions of LPLs are distinct from their corresponding phospholipids. In eukaryotic cells LPLs are important bioactive signaling molecules that regulate many important biological processes, but in bacteria the function of LPLs is still not fully defined. Bacterial LPLs are usually present in cells in very small amounts, but can strongly increase under certain environmental conditions. In addition to their basic function as precursors in membrane lipid metabolism, the formation of distinct LPLs contributes to the proliferation of bacteria under harsh circumstances or may act as signaling molecules in bacterial pathogenesis. This review provides an overview of the current knowledge of the biological functions of bacterial LPLs including lysoPE, lysoPA, lysoPC, lysoPG, lysoPS and lysoPI in bacterial adaptation, survival, and host-microbe interactions.
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Affiliation(s)
- Xuefeng Cao
- Department Biomolecular Health Sciences, Utrecht University, Utrecht, The Netherlands
| | - Jos P M van Putten
- Department Biomolecular Health Sciences, Utrecht University, Utrecht, The Netherlands
| | - Marc M S M Wösten
- Department Biomolecular Health Sciences, Utrecht University, Utrecht, The Netherlands.
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Salsinha AS, Socodato R, Relvas JB, Pintado M. The pro- and antiinflammatory activity of fatty acids. BIOACTIVE LIPIDS 2023:51-75. [DOI: 10.1016/b978-0-12-824043-4.00002-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Lysolecithin Improves Broiler Growth Performance through Upregulating Growth-Related Genes and Nutrient Transporter Genes Expression Independent of Experimental Diet Nutrition Level. Animals (Basel) 2022; 12:ani12233365. [PMID: 36496888 PMCID: PMC9739769 DOI: 10.3390/ani12233365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 11/21/2022] [Accepted: 11/24/2022] [Indexed: 12/05/2022] Open
Abstract
We investigated the effect and interaction of lysolecithin (LPL) and nutrition level on growth performance, nutrient ileal digestibility, expression of growth-related genes and nutrient transporter genes in broilers. A total of 1280 one day old Ross 308 mixed sex chicks with an average body weight 42.23 ± 2.4 g were randomly allotted into 2 × 2 factorial arrangement (20 replicates per treatment and 16 chickens per replicate) with two types of diet (Normal nutrition treatments starter, grower and finisher diets with ME of 3000 kcal/kg, 3100 kcal/kg and 3200 kcal/kg, respectively, and CP level of 22%, 21%, and 20%, respectively; high nutrition treatments diets with 50 kcal/kg ME and 0.5% CP higher than normal nutrition treatment at each stage). Two levels of LPL supplementation (0 and 500 mg/kg) were also employed. From day 21 to day 35 and full stage of the experiment, the birds fed a high nutrition (HN) diet had a greater body weight gain (BWG) and lower feed conversion ratio (FCR) than those fed a normal nutrition (NN) diet (p < 0.05). Besides, lysolecithin increased BWG significantly (p < 0.05). The birds fed a diet with LPL revealed increasing fat digestibility compared to birds fed the basal diet (p < 0.05). LPL significantly increased the ileal digestibility of amino acids, including Ile, Thr, Phe, His, Arg, Tyr, Glu, Pro, Gly, Ala (p < 0.05). No interaction was found between LPL and nutrition level in BWG, FCR and nutrient digestibility. In HN diet, the genes expression of myogenic differentiation 1 (MYOD1), myogenin (MYOG), cluster of differentiation 36 (CD36), fatty acid-binding protein (FABP1), cationic amino acid transporter 1 (CAT1) and Y + L amino acid transporter 1 (y+, LAT1) were significantly elevated via LPL supplementation (p < 0.05). In NN diet, LPL significantly increased the genes expression of growth hormone (GH), insulin-like growth factor 1 (IGF1), MYOD1 and y+, LAT1 (p < 0.05). In conclusion, upregulating the nutrients transporter gene and growth-related gene expression of the host, independent of nutrition level changes, may be the action mechanism of lysolecithin on growth promotion in animals.
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Lysophosphatidylinositol Induced Morphological Changes and Stress Fiber Formation through the GPR55-RhoA-ROCK Pathway. Int J Mol Sci 2022; 23:ijms231810932. [PMID: 36142844 PMCID: PMC9504244 DOI: 10.3390/ijms231810932] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/14/2022] [Accepted: 09/15/2022] [Indexed: 11/30/2022] Open
Abstract
We previously reported that lysophosphatidylinositol (LPI) functions as an endogenous agonist of GPR55, a novel cannabinoid receptor. However, the physiological roles of LPI-GPR55 have not yet been elucidated in detail. In the present study, we found that LPI induced morphological changes in GPR55-expressing HEK293 cells. LPI induced the cell rounding of GPR55-expressing HEK293 cells but not of empty-vector-transfected cells. LPI also induced the activation of small GTP-binding protein RhoA and increased stress fiber formation in GPR55-expressing HEK293 cells. The inhibition of RhoA and Rho kinase ROCK by the C3 exoenzyme and the ROCK inhibitor reduced LPI-induced cell rounding and stress fiber formation. These results clearly indicated that the LPI-induced morphological changes and the assembly of the cytoskeletons were mediated through the GPR55-RhoA-ROCK pathway.
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Orphan GPR26 Counteracts Early Phases of Hyperglycemia-Mediated Monocyte Activation and Is Suppressed in Diabetic Patients. Biomedicines 2022; 10:biomedicines10071736. [PMID: 35885041 PMCID: PMC9312814 DOI: 10.3390/biomedicines10071736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 07/07/2022] [Accepted: 07/13/2022] [Indexed: 11/17/2022] Open
Abstract
Diabetes is the ninth leading cause of death, with an estimated 1.5 million deaths worldwide. Type 2 diabetes (T2D) results from the body’s ineffective use of insulin and is largely the result of excess body weight and physical inactivity. T2D increases the risk of cardiovascular diseases, retinopathy, and kidney failure by two-to three-fold. Hyperglycemia, as a hallmark of diabetes, acts as a potent stimulator of inflammatory condition by activating endothelial cells and by dysregulating monocyte activation. G-protein couple receptors (GPCRs) can both exacerbate and promote inflammatory resolution. Genome-wide association studies (GWAS) indicate that GPCRs are differentially regulated in inflammatory and vessel cells from diabetic patients. However, most of these GPCRs are orphan receptors, for which the mechanism of action in diabetes is unknown. Our data indicated that orphan GPCR26 is downregulated in the PBMC isolated from T2D patients. In contrast, GPR26 was initially upregulated in human monocytes and PBMC treated with high glucose (HG) levels and then decreased upon chronic and prolonged HG exposure. GPR26 levels were decreased in T2D patients treated with insulin compared to non-insulin treated patients. Moreover, GPR26 inversely correlated with the BMI and the HbA1c of diabetic compared to non-diabetic patients. Knockdown of GPR26 enhanced monocyte ROS production, MAPK signaling, pro-inflammatory activation, monocyte adhesion to ECs, and enhanced the activity of Caspase 3, a pro-apoptotic molecule. The same mechanisms were activated by HG and exacerbated when GPR26 was knocked down. Hence, our data indicated that GPR26 is initially activated to protect monocytes from HG and is inhibited under chronic hyperglycemic conditions.
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Varadharajan V, Massey WJ, Brown JM. Membrane-bound O-acyltransferase 7 (MBOAT7)-driven phosphatidylinositol remodeling in advanced liver disease. J Lipid Res 2022; 63:100234. [PMID: 35636492 PMCID: PMC9240865 DOI: 10.1016/j.jlr.2022.100234] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Revised: 05/12/2022] [Accepted: 05/16/2022] [Indexed: 01/21/2023] Open
Abstract
Advanced liver diseases account for approximately 2 million deaths annually worldwide. Roughly, half of liver disease-associated deaths arise from complications of cirrhosis and the other half driven by viral hepatitis and hepatocellular carcinoma. Unfortunately, the development of therapeutic strategies to treat subjects with advanced liver disease has been hampered by a lack of mechanistic understanding of liver disease progression and a lack of human-relevant animal models. An important advance has been made within the past several years, as several genome-wide association studies have discovered that an SNP near the gene encoding membrane-bound O-acyltransferase 7 (MBOAT7) is associated with severe liver diseases. This common MBOAT7 variant (rs641738, C>T), which reduces MBOAT7 expression, confers increased susceptibility to nonalcoholic fatty liver disease, alcohol-associated liver disease, and liver fibrosis in patients chronically infected with viral hepatitis. Recent studies in mice also show that Mboat7 loss of function can promote hepatic steatosis, inflammation, and fibrosis, causally linking this phosphatidylinositol remodeling enzyme to liver health in both rodents and humans. Herein, we review recent insights into the mechanisms by which MBOAT7-driven phosphatidylinositol remodeling influences liver disease progression and discuss how rapid progress in this area could inform drug discovery moving forward.
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Affiliation(s)
- Venkateshwari Varadharajan
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - William J Massey
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - J Mark Brown
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute Cleveland Clinic, Cleveland, OH, USA; Center for Microbiome and Human Health, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
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Functional Selectivity of Coumarin Derivates Acting via GPR55 in Neuroinflammation. Int J Mol Sci 2022; 23:ijms23020959. [PMID: 35055142 PMCID: PMC8779649 DOI: 10.3390/ijms23020959] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 01/09/2022] [Accepted: 01/13/2022] [Indexed: 12/22/2022] Open
Abstract
Anti-neuroinflammatory treatment has gained importance in the search for pharmacological treatments of different neurological and psychiatric diseases, such as depression, schizophrenia, Parkinson’s disease, and Alzheimer’s disease. Clinical studies demonstrate a reduction of the mentioned diseases’ symptoms after the administration of anti-inflammatory drugs. Novel coumarin derivates have been shown to elicit anti-neuroinflammatory effects via G-protein coupled receptor GPR55, with possibly reduced side-effects compared to the known anti-inflammatory drugs. In this study, we, therefore, evaluated the anti-inflammatory capacities of the two novel coumarin-based compounds, KIT C and KIT H, in human neuroblastoma cells and primary murine microglia. Both compounds reduced PGE2-concentrations likely via the inhibition of COX-2 synthesis in SK-N-SH cells but only KIT C decreased PGE2-levels in primary microglia. The examination of other pro- and anti-inflammatory parameters showed varying effects of both compounds. Therefore, the differences in the effects of KIT C and KIT H might be explained by functional selectivity as well as tissue- or cell-dependent expression and signal pathways coupled to GPR55. Understanding the role of chemical residues in functional selectivity and specific cell- and tissue-targeting might open new therapeutic options in pharmacological drug development and might improve the treatment of the mentioned diseases by intervening in an early step of their pathogenesis.
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Khan RN, Maner-Smith K, A. Owens J, Barbian ME, Jones RM, R. Naudin C. At the heart of microbial conversations: endocannabinoids and the microbiome in cardiometabolic risk. Gut Microbes 2022; 13:1-21. [PMID: 33896380 PMCID: PMC8078674 DOI: 10.1080/19490976.2021.1911572] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Cardiometabolic syndrome encompasses intertwined risk factors such as hypertension, dyslipidemia, elevated triglycerides, abdominal obesity, and other maladaptive metabolic and inflammatory aberrations. As the molecular mechanisms linking cardiovascular disease and metabolic disorders are investigated, endocannabinoids have emerged as molecules of interest. The endocannabinoid system (ECS) of biologically active lipids has been implicated in several conditions, including chronic liver disease, osteoporosis, and more recently in cardiovascular diseases. The gut microbiome is a major regulator of inflammatory and metabolic signaling in the host, and if disrupted, has the potential to drive metabolic and cardiovascular diseases. Extensive studies have unraveled the impact of the gut microbiome on host physiology, with recent reports showing that gut microbes exquisitely control the ECS, with significant influences on host metabolic and cardiac health. In this review, we outline how modulation of the gut microbiome affects host metabolism and cardiovascular health via the ECS, and how these findings could be exploited as novel therapeutic targets for various metabolic and cardiac diseases.
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Affiliation(s)
- Ramsha Nabihah Khan
- Division of Gastroenterology and Hepatology, Department of Pediatrics, Children’s Healthcare of Atlanta and Emory University, Atlanta, Georgia, USA
| | - Kristal Maner-Smith
- Emory Integrated Metabolomics and Lipidomics Core, Emory University, Atlanta, Georgia, USA
| | - Joshua A. Owens
- Division of Gastroenterology and Hepatology, Department of Pediatrics, Children’s Healthcare of Atlanta and Emory University, Atlanta, Georgia, USA
| | - Maria Estefania Barbian
- Division of Neonatology, Department of Pediatrics, Children’s Healthcare of Atlanta and Emory University, Atlanta, Georgia, USA
| | - Rheinallt M. Jones
- Division of Gastroenterology and Hepatology, Department of Pediatrics, Children’s Healthcare of Atlanta and Emory University, Atlanta, Georgia, USA
| | - Crystal R. Naudin
- Division of Gastroenterology and Hepatology, Department of Pediatrics, Children’s Healthcare of Atlanta and Emory University, Atlanta, Georgia, USA,CONTACT Crystal R. Naudin Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA30322, United States of America
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Lian J, Casari I, Falasca M. Modulatory role of the endocannabinoidome in the pathophysiology of the gastrointestinal tract. Pharmacol Res 2021; 175:106025. [PMID: 34883211 DOI: 10.1016/j.phrs.2021.106025] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 11/29/2021] [Accepted: 12/05/2021] [Indexed: 12/13/2022]
Abstract
Originating from Eastern Asia, the plant Cannabis sativa has been used for centuries as a medicinal treatment. The unwanted psychotropic effects of one of its major components, Δ9-tetrahydrocannabinol, discouraged its therapeutic employment until, recently, the discovery of cannabinoids receptors and their endogenous ligands endocannabinoids reignited the interest. The endocannabinoid system has lately been found to play an important role in the maintenance of human health, both centrally and peripherally. However, the initial idea of the endocannabinoid system structure has been quickly understood to be too simplistic and, as new receptors, mediators, and enzymes have been discovered to participate in a complex relationship, the new, more comprehensive term "expanded endocannabinoid system" or "endocannabinoidome", has taken over. The discovery of other endocannabinoid-like receptors, such as the G protein-coupled receptor 119 and G protein-coupled receptor 55, has opened the way to the development of potential therapeutic targets for the treatment of various metabolic disorders. In addition, recent findings have also provided evidence suggesting the potential therapeutic link between the endocannabinoidome and various inflammatory-based gut diseases, such as inflammatory bowel disease and cancer. This review will provide an introduction to the endocannabinoidome, focusing on its modulatory role in the gastrointestinal tract and on the interest generated by the link between gut microbiota, the endocannabinoid system and metabolic diseases such as inflammatory bowel disease, type-2 diabetes and obesity. In addition, we will look at the potential novel aspects and benefits of drugs targeting the endocannabinoid system.
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Affiliation(s)
- Jerome Lian
- Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia
| | - Ilaria Casari
- Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia
| | - Marco Falasca
- Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia.
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Lee SJ, Im DS. GPR55 Antagonist CID16020046 Protects against Atherosclerosis Development in Mice by Inhibiting Monocyte Adhesion and Mac-1 Expression. Int J Mol Sci 2021; 22:ijms222313084. [PMID: 34884889 PMCID: PMC8658038 DOI: 10.3390/ijms222313084] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/02/2021] [Accepted: 12/02/2021] [Indexed: 12/30/2022] Open
Abstract
GPR55 recognizes several lipid molecules such as lysophosphatidylinositol. GPR55 expression was reported in human monocytes. However, its role in monocyte adhesion and atherosclerosis development has not been studied. The role of GPR55 in monocyte adhesion and atherosclerosis development was investigated in human THP-1 monocytes and ApoE-/- mice using O-1602 (a potent agonist of GPR55) and CID16020046 (a specific GPR55 antagonist). O-1602 treatment significantly increased monocyte adhesion to human umbilical vein endothelial cells, and the O-1602-induced adhesion was inhibited by treatment with CID16020046. O-1602 induced the expression of Mac-1 adhesion molecules, whereas CID16020046 inhibited this induction. Analysis of the promoter region of Mac-1 elucidated the binding sites of AP-1 and NF-κB between nucleotides -750 and -503 as GPR55 responsive elements. O-1602 induction of Mac-1 was found to be dependent on the signaling components of GPR55, that is, Gq protein, Ca2+, CaMKK, and PI3K. In Apo-/- mice, administration of CID16020046 ameliorated high-fat diet-induced atherosclerosis development. These results suggest that high-fat diet-induced GPR55 activation leads to the adhesion of monocytes to endothelial cells via induction of Mac-1, and CID16020046 blockage of GPR55 could suppress monocyte adhesion to vascular endothelial cells through suppression of Mac-1 expression, leading to protection against the development of atherosclerosis.
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Affiliation(s)
- Seung-Jin Lee
- Department of Pharmacy, College of Pharmacy, Pusan National University, Busan 46241, Korea;
| | - Dong-Soon Im
- East West Pharmaceutical Research Center, Department of Biomedical and Pharmaceutical Sciences, Graduate School, Kyung Hee University, Seoul 02447, Korea
- Correspondence: ; Tel.: +82-2-961-7399; Fax: +82-2-961-9580
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Soti M, Ranjbar H, Kohlmeier KA, Shabani M. Parkinson's disease related alterations in cannabinoid transmission. Brain Res Bull 2021; 178:82-96. [PMID: 34808322 DOI: 10.1016/j.brainresbull.2021.11.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/29/2021] [Accepted: 11/15/2021] [Indexed: 02/07/2023]
Abstract
Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic (DAergic) neurons of the substantia nigra pars compacta (SNc) by neurodegeneration. Recent findings in animal models of PD propose tonic inhibition of the remaining DA neurons through GABA release from reactive glial cells. Movement dysfunctions could be ameliorated by promotion of activity in dormant DA cells. The endocannabinoid system (ECS) is extensively present in basal ganglia (BG) and is known as an indirect modulator of DAergic neurotransmission, thus drugs designed to target this system have shown promising therapeutic potential in PD patients. Interestingly, down/up-regulation of cannabinoid receptors (CBRs) varies across the different stages of PD, suggesting that some of the motor/ non-motor deficits may be related to changes in CBRs. Determination of the profile of changes of these receptors across the different stages of PD as well as their neural distribution within the BG could improve understanding of PD and identify pathways important in disease pathobiology. In this review, we focus on temporal and spatial alterations of CBRs during PD in the BG. At present, as inconclusive, but suggestive results have been obtained, future investigations should be conducted to extend preclinical studies examining CBRs changes within each stage in controlled clinical trials in order to determine the potential of targeting CBRs in management of PD.
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Affiliation(s)
- Monavareh Soti
- Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran
| | - Hoda Ranjbar
- Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran
| | - Kristi A Kohlmeier
- Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Mohammad Shabani
- Neuroscience Research Center, Neuropharmacology Institute, Kerman University of Medical Sciences, Kerman, Iran.
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Nilsson Å, Duan RD, Ohlsson L. Digestion and Absorption of Milk Phospholipids in Newborns and Adults. Front Nutr 2021; 8:724006. [PMID: 34490332 PMCID: PMC8417471 DOI: 10.3389/fnut.2021.724006] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 07/19/2021] [Indexed: 12/25/2022] Open
Abstract
Milk polar lipids provide choline, ethanolamine, and polyunsaturated fatty acids, which are needed for the growth and plasticity of the tissues in a suckling child. They may also inhibit cholesterol absorption by interacting with cholesterol during micelle formation. They may also have beneficial luminal, mucosal, and metabolic effects in both the neonate and the adult. The milk fat globule membrane contains large proportions of sphingomyelin (SM), phosphatidylcholine (PC), and phosphatidylethanolamine (PE), and some phosphatidylserine (PS), phosphatidylinositol (PI), and glycosphingolipids. Large-scale technical procedures are available for the enrichment of milk fat globule membrane (MFGM) in milk replacement formulations and food additives. Pancreatic phospholipase A2 (PLA2) and mucosal phospholipase B digest glycero-phospholipids in the adult. In the neonate, where these enzymes may be poorly expressed, pancreatic lipase-related protein 2 probably has a more important role. Mucosal alkaline SM-ase and ceramidase catalyze the digestion of SM in both the neonate and the adult. In the mucosa, the sphingosine is converted into sphingosine-1-phosphate, which is both an intermediate in the conversion to palmitic acid and a signaling molecule. This reaction sequence also generates ethanolamine. Here, we summarize the pathways by which digestion and absorption may be linked to the biological effects of milk polar lipids. In addition to the inhibition of cholesterol absorption and the generation of lipid signals in the gut, the utilization of absorbed choline and ethanolamine for mucosal and hepatic phospholipid synthesis and the acylation of absorbed lyso-PC with polyunsaturated fatty acids to chylomicron and mucosal phospholipids are important.
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Affiliation(s)
- Åke Nilsson
- Division of Medicine, Gastroenterology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden
| | - Rui-Dong Duan
- Gastroenterology and Nutrition Laboratory, Division of Medicine, Department of Clinical Science, Lund University, Lund, Sweden
| | - Lena Ohlsson
- Division of Medicine, Experimental Vascular Medicine, Department of Clinical Science, Lund University, Lund, Sweden
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Ayakannu T, Taylor AH, Konje JC. Expression of the putative cannabinoid receptor GPR55 is increased in endometrial carcinoma. Histochem Cell Biol 2021; 156:449-460. [PMID: 34324032 PMCID: PMC8604869 DOI: 10.1007/s00418-021-02018-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/15/2021] [Indexed: 12/24/2022]
Abstract
Although the expression of the putative cannabinoid receptor GPR55 has been shown to be involved in the growth of various tumours and is increased in a number of cancers, its expression has not been examined in patients with endometrial cancer (EC). Quantitative RT-PCR (for mRNA levels) and immunohistochemistry (for protein levels) were used to measure GPR55 expression in patients with Type 1 and Type 2 EC and correlated against cannabinoid receptor (CB1 and CB2) protein levels using non-cancerous endometrium as the control tissue. The data indicated that GPR55 transcript and GPR55 protein levels were significantly (p < 0.002 and p < 0.0001, respectively) higher in EC tissues than in control tissues. The levels of immunoreactive GPR55 protein were correlated with GPR55 transcript levels, but not with the expression of CB1 receptor protein, and were inversely correlated with CB2 protein expression, which was significantly decreased. It can be concluded that GPR55 expression is elevated in women with EC, and thus could provide a potential novel biomarker and therapeutic target for this disease.
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Affiliation(s)
- Thangesweran Ayakannu
- Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK.,Department of Obstetrics and Gynaecology, Gynaecology Oncology Centre, Liverpool Women's Hospital, Liverpool Women's NHS Foundation Trust, Liverpool, UK.,Endocannabinoid Research Group, Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, UK
| | - Anthony H Taylor
- Endocannabinoid Research Group, Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, UK. .,Department of Molecular and Cell Biology, University of Leicester, George Davies Centre for Medicine, University Road, Leicester, LE2 7RH, Leicestershire, UK.
| | - Justin C Konje
- Endocannabinoid Research Group, Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, University of Leicester, Leicester, UK.,Department of Health Sciences, University of Leicester, Leicester, UK
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39
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Kurano M, Kobayashi T, Sakai E, Tsukamoto K, Yatomi Y. Lysophosphatidylinositol, especially albumin-bound form, induces inflammatory cytokines in macrophages. FASEB J 2021; 35:e21673. [PMID: 34042213 DOI: 10.1096/fj.202100245r] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 04/23/2021] [Accepted: 05/03/2021] [Indexed: 12/12/2022]
Abstract
Lysophosphatidylinositol (LPI) is a glycero-lysophospholipid and a natural agonist against GPR55. The roles of the LPI/GPR55 axis in the pathogenesis of inflammation have been controversial. In the present study, we attempted to elucidate the roles of the LPI/GPR55 axis in inflammation, especially the secretion of inflammatory cytokines, IL-6 and TNF-α from macrophages. We treated RAW264.7 cells and mouse peritoneal macrophages (MPMs) with LPI and observed that LPI induced the secretion of IL-6 and TNF-α from these cells, as well as the phosphorylation of p38. These responses were inhibited by treatment with CID16020046 (CID), an antagonist against GPR55, or SB202190, an inhibitor of p38 cascade or knockdown of GPR55 with siRNA. Treatment with CID or ML-193, another antagonist against GPR55, attenuated the elevation of inflammatory cytokines in the plasma or tissue of db/db mice and in a septic mouse model induced using lipopolysaccharide, suggesting contributions to the improvement of insulin resistance and protection against organ injuries by treatment with CID or ML-193, respectively. In human subjects, although the serum LPI levels were not different, the levels of LPI in the lipoprotein fractions were lower and the levels in the lipoprotein-depleted fractions were higher in subjects with diabetes. LPI bound to albumin induced the secretion of IL-6 and TNF-α from RAW264.7 cells to a greater degree than LPI bound to LDL or HDL. These results suggest that LPI, especially the albumin-bound form, induced inflammatory cytokines depending on the GPR55/p38 pathway, which might contribute to the pathogenesis of obesity-induced inflammation and acute inflammation.
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Affiliation(s)
- Makoto Kurano
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan
| | - Tamaki Kobayashi
- Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan
| | - Eri Sakai
- Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan
| | - Kazuhisa Tsukamoto
- Department of Internal Medicine, Teikyo University School of Medicine, Tokyo, Japan
| | - Yutaka Yatomi
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan
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40
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Puhl SL, Hilby M, Kohlhaas M, Keidel LM, Jansen Y, Hristov M, Schindler J, Maack C, Steffens S. Haematopoietic and cardiac GPR55 synchronize post-myocardial infarction remodelling. Sci Rep 2021; 11:14385. [PMID: 34257332 PMCID: PMC8277802 DOI: 10.1038/s41598-021-93755-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 06/28/2021] [Indexed: 12/15/2022] Open
Abstract
While classical cannabinoid receptors are known to crucially impact on myocardial infarction (MI) repair, a function of the cannabinoid-sensitive receptor GPR55 herein is poorly understood. We investigated the role of GPR55 in cardiac physiology and post-MI inflammation and remodelling. Global GPR55-/- and wildtype (WT) mice were basally characterized or assigned to 1, 3 or 28 days permanent MI and subsequently analysed via pro-inflammatory and pro-hypertrophic parameters. GPR55-/- deficiency was basally associated with bradycardia, increased diastolic LV volume and sarcomere length and a subtle inflammatory phenotype. While infarct size and myeloid cell infiltration were unaffected by GPR55 depletion, acute cardiac chemokine production was prolonged post-MI. Concurrently, GPR55-/- hearts exhibited a premature expansion of pro-reparative and phagocytic macrophages paralleled by early up-regulation of extracellular matrix (ECM) factors 3 days post-MI, which could be mimicked by sole haematopoietic GPR55 depletion. Moreover, global GPR55 deficiency mitigated MI-induced foetal gene re-programming and cardiomyocyte hypertrophy, culminating in aggravated LV dilatation and infarct expansion. GPR55 regulates cardiac homeostasis and ischaemia responses by maintaining adequate LV filling and modulating three crucial processes post-MI: wound healing kinetics, cardiomyocyte hypertrophy and maladaptive remodelling.
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Affiliation(s)
- Sarah-Lena Puhl
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU) Munich, Pettenkoferstr. 9, 80336, Munich, Germany
| | - Michael Hilby
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU) Munich, Pettenkoferstr. 9, 80336, Munich, Germany
| | - Michael Kohlhaas
- Comprehensive Heart Failure Center, University Clinic Würzburg, Würzburg, Germany
| | - Linus M Keidel
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU) Munich, Pettenkoferstr. 9, 80336, Munich, Germany
| | - Yvonne Jansen
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU) Munich, Pettenkoferstr. 9, 80336, Munich, Germany
| | - Michael Hristov
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU) Munich, Pettenkoferstr. 9, 80336, Munich, Germany
| | - Jakob Schindler
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU) Munich, Pettenkoferstr. 9, 80336, Munich, Germany
| | - Christoph Maack
- Comprehensive Heart Failure Center, University Clinic Würzburg, Würzburg, Germany
- Medical Clinic I, University Clinic Würzburg, Würzburg, Germany
| | - Sabine Steffens
- Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-Universität (LMU) Munich, Pettenkoferstr. 9, 80336, Munich, Germany.
- German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
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41
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Hannich JT, Loizides‐Mangold U, Sinturel F, Harayama T, Vandereycken B, Saini C, Gosselin P, Brulhart‐Meynet M, Robert M, Chanon S, Durand C, Paz Montoya J, David FPA, Guessous I, Pataky Z, Golay A, Jornayvaz FR, Philippe J, Dermitzakis ET, Brown SA, Lefai E, Riezman H, Dibner C. Ether lipids, sphingolipids and toxic 1-deoxyceramides as hallmarks for lean and obese type 2 diabetic patients. Acta Physiol (Oxf) 2021; 232:e13610. [PMID: 33351229 DOI: 10.1111/apha.13610] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 12/08/2020] [Accepted: 12/21/2020] [Indexed: 12/12/2022]
Abstract
AIM The worldwide increase in obesity and type 2 diabetes (T2D) represents a major health challenge. Chronically altered lipids induced by obesity further promote the development of T2D, and the accumulation of toxic lipid metabolites in serum and peripheral organs may contribute to the diabetic phenotype. METHODS To better understand the complex metabolic pattern of lean and obese T2D and non-T2D individuals, we analysed the lipid profile of human serum, skeletal muscle and visceral adipose tissue of two cohorts by systematic mass spectrometry-based lipid analysis. RESULTS Lipid homeostasis was strongly altered in a disease- and tissue-specific manner, allowing us to define T2D signatures associated with obesity from those that were obesity independent. Lipid changes encompassed lyso-, diacyl- and ether-phospholipids. Moreover, strong changes in sphingolipids included cytotoxic 1-deoxyceramide accumulation in a disease-specific manner in serum and visceral adipose tissue. The high amounts of non-canonical 1-deoxyceramide present in human adipose tissue most likely come from cell-autonomous synthesis because 1-deoxyceramide production increased upon differentiation to adipocytes in mouse cell culture experiments. CONCLUSION Taken together, the observed lipidome changes in obesity and T2D will facilitate the identification of T2D patient subgroups and represent an important step towards personalized medicine in diabetes.
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Affiliation(s)
- J. Thomas Hannich
- Department of Biochemistry Faculty of Science NCCR Chemical Biology University of Geneva Geneva Switzerland
| | - Ursula Loizides‐Mangold
- Division of Endocrinology Diabetes, Nutrition and Patient Education Department of Medicine University Hospital of Geneva Geneva Switzerland
- Department of Cell Physiology and Metabolism Faculty of Medicine University of Geneva Geneva Switzerland
- Diabetes Center Faculty of Medicine University of Geneva Geneva Switzerland
- Institute of Genetics and Genomics in Geneva (iGE3) University of Geneva Geneva Switzerland
| | - Flore Sinturel
- Division of Endocrinology Diabetes, Nutrition and Patient Education Department of Medicine University Hospital of Geneva Geneva Switzerland
- Department of Cell Physiology and Metabolism Faculty of Medicine University of Geneva Geneva Switzerland
- Diabetes Center Faculty of Medicine University of Geneva Geneva Switzerland
- Institute of Genetics and Genomics in Geneva (iGE3) University of Geneva Geneva Switzerland
| | - Takeshi Harayama
- Department of Biochemistry Faculty of Science NCCR Chemical Biology University of Geneva Geneva Switzerland
| | | | - Camille Saini
- Department and Division of Primary Care Medicine University Hospital of Geneva Geneva Switzerland
| | - Pauline Gosselin
- Division of Endocrinology Diabetes, Nutrition and Patient Education Department of Medicine University Hospital of Geneva Geneva Switzerland
- Department of Cell Physiology and Metabolism Faculty of Medicine University of Geneva Geneva Switzerland
- Diabetes Center Faculty of Medicine University of Geneva Geneva Switzerland
- Institute of Genetics and Genomics in Geneva (iGE3) University of Geneva Geneva Switzerland
- Department and Division of Primary Care Medicine University Hospital of Geneva Geneva Switzerland
| | - Marie‐Claude Brulhart‐Meynet
- Division of Endocrinology Diabetes, Nutrition and Patient Education Department of Medicine University Hospital of Geneva Geneva Switzerland
| | - Maud Robert
- Department of Digestive and Bariatric Surgery Edouard Herriot University HospitalUniversity Lyon France
| | - Stephanie Chanon
- CarMeN Laboratory INSERM U1060 INRA 1397 University Lyon 1 Oullins France
| | - Christine Durand
- CarMeN Laboratory INSERM U1060 INRA 1397 University Lyon 1 Oullins France
| | - Jonathan Paz Montoya
- Proteomics Core Facility Ecole Polytechnique Fédérale de Lausanne Lausanne Switzerland
| | - Fabrice P. A. David
- Gene Expression Core Facility Ecole Polytechnique Fédérale de Lausanne Lausanne Switzerland
| | - Idris Guessous
- Department and Division of Primary Care Medicine University Hospital of Geneva Geneva Switzerland
| | - Zoltan Pataky
- Division of Endocrinology Diabetes, Nutrition and Patient Education Department of Medicine WHO Collaborating Centre University Hospital of GenevaUniversity of Geneva Geneva Switzerland
| | - Alain Golay
- Division of Endocrinology Diabetes, Nutrition and Patient Education Department of Medicine WHO Collaborating Centre University Hospital of GenevaUniversity of Geneva Geneva Switzerland
| | - François R. Jornayvaz
- Division of Endocrinology Diabetes, Nutrition and Patient Education Department of Medicine University Hospital of Geneva Geneva Switzerland
- Diabetes Center Faculty of Medicine University of Geneva Geneva Switzerland
| | - Jacques Philippe
- Division of Endocrinology Diabetes, Nutrition and Patient Education Department of Medicine University Hospital of Geneva Geneva Switzerland
- Diabetes Center Faculty of Medicine University of Geneva Geneva Switzerland
| | - Emmanouil T. Dermitzakis
- Diabetes Center Faculty of Medicine University of Geneva Geneva Switzerland
- Institute of Genetics and Genomics in Geneva (iGE3) University of Geneva Geneva Switzerland
- Department of Genetic Medicine and Development Faculty of Medicine University of Geneva Geneva Switzerland
| | - Steven A. Brown
- Institute of Pharmacology and Toxicology University of Zurich Zurich Switzerland
| | - Etienne Lefai
- INRA Unité de Nutrition Humaine Université Clermont Auvergne Paris France
| | - Howard Riezman
- Department of Biochemistry Faculty of Science NCCR Chemical Biology University of Geneva Geneva Switzerland
| | - Charna Dibner
- Division of Endocrinology Diabetes, Nutrition and Patient Education Department of Medicine University Hospital of Geneva Geneva Switzerland
- Department of Cell Physiology and Metabolism Faculty of Medicine University of Geneva Geneva Switzerland
- Diabetes Center Faculty of Medicine University of Geneva Geneva Switzerland
- Institute of Genetics and Genomics in Geneva (iGE3) University of Geneva Geneva Switzerland
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Kang S, Lee AY, Park SY, Liu KH, Im DS. O-1602 Promotes Hepatic Steatosis through GPR55 and PI3 Kinase/Akt/SREBP-1c Signaling in Mice. Int J Mol Sci 2021; 22:3091. [PMID: 33803038 PMCID: PMC8003045 DOI: 10.3390/ijms22063091] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 03/15/2021] [Accepted: 03/15/2021] [Indexed: 11/30/2022] Open
Abstract
Non-alcoholic fatty liver disease is recognized as the leading cause of chronic liver disease. Overnutrition and obesity are associated with hepatic steatosis. G protein-coupled receptor 55 (GPR55) has not been extensively studied in hepatic steatosis, although its endogenous ligands have been implicated in liver disease progression. Therefore, the functions of GPR55 were investigated in Hep3B human hepatoma cells and mice fed high-fat diets. O-1602, the most potent agonist of GPR55, induced lipid accumulation in hepatocytes, which was reversed by treatment with CID16020046, an antagonist of GPR55. O-1602 also induced intracellular calcium rise in Hep3B cells in a GPR55-independent manner. O-1602-induced lipid accumulation was dependent on the PI3 kinase/Akt/SREBP-1c signaling cascade. Furthermore, we found increased levels of lysophosphatidylinositol species of 16:0, 18:0, 18:1, 18:2, 20:1, and 20:2 in the livers of mice fed a high-fat diet for 4 weeks. One-week treatment with CID16020046 suppressed high-fat diet-induced lipid accumulation and O-1602-induced increase of serum triglyceride levels in vivo. Therefore, the present data suggest the pro-steatotic function of GPR55 signaling in hepatocytes and provide a potential therapeutic target for non-alcoholic fatty liver disease.
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Affiliation(s)
- Saeromi Kang
- College of Pharmacy, Pusan National University, Busan 46241, Korea; (S.K.); (A.-Y.L.)
| | - Ae-Yeon Lee
- College of Pharmacy, Pusan National University, Busan 46241, Korea; (S.K.); (A.-Y.L.)
| | - So-Young Park
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea; (S.-Y.P.); (K.-H.L.)
| | - Kwang-Hyeon Liu
- BK21 FOUR KNU Community-Based Intelligent Novel Drug Discovery Education Unit, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu 41566, Korea; (S.-Y.P.); (K.-H.L.)
| | - Dong-Soon Im
- College of Pharmacy, Pusan National University, Busan 46241, Korea; (S.K.); (A.-Y.L.)
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, Graduate School, Kyung Hee University, Seoul 02447, Korea
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43
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Kurtz R, Anderman MF, Shepard BD. GPCRs get fatty: the role of G protein-coupled receptor signaling in the development and progression of nonalcoholic fatty liver disease. Am J Physiol Gastrointest Liver Physiol 2021; 320:G304-G318. [PMID: 33205999 PMCID: PMC8202238 DOI: 10.1152/ajpgi.00275.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD), characterized by the abnormal deposition of lipids within the liver not due to alcohol consumption, is a growing epidemic affecting over 30% of the United States population. Both simple fatty liver and its more severe counterpart, nonalcoholic steatohepatitis, represent one of the most common forms of liver disease. Recently, several G protein-coupled receptors have emerged as targets for therapeutic intervention for these disorders. These include those with known hepatic function as well as those involved in global metabolic regulation. In this review, we highlight these emerging therapeutic targets, focusing on several common themes including their activation by microbial metabolites, stimulatory effect on insulin and incretin secretion, and contribution to glucose tolerance. The overlap in ligands, localization, and downstream effects of activation indicate the interdependent nature of these receptors and highlight the importance of this signaling family in the development and prevention of NAFLD.
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Affiliation(s)
- Ryan Kurtz
- Department of Human Science, Georgetown University, Washington, District of Columbia
| | - Meghan F. Anderman
- Department of Human Science, Georgetown University, Washington, District of Columbia
| | - Blythe D. Shepard
- Department of Human Science, Georgetown University, Washington, District of Columbia
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44
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Yang M, Zhang CY. G protein-coupled receptors as potential targets for nonalcoholic fatty liver disease treatment. World J Gastroenterol 2021; 27:677-691. [PMID: 33716447 PMCID: PMC7934005 DOI: 10.3748/wjg.v27.i8.677] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/24/2020] [Accepted: 01/21/2021] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a broad-spectrum disease, ranging from simple hepatic steatosis to nonalcoholic steatohepatitis, which can progress to cirrhosis and liver cancer. Abnormal hepatic lipid accumulation is the major manifestation of this disease, and lipotoxicity promotes NAFLD progression. In addition, intermediate metabolites such as succinate can stimulate the activation of hepatic stellate cells to produce extracellular matrix proteins, resulting in progression of NAFLD to fibrosis and even cirrhosis. G protein-coupled receptors (GPCRs) have been shown to play essential roles in metabolic disorders, such as NAFLD and obesity, through their function as receptors for bile acids and free fatty acids. In addition, GPCRs link gut microbiota-mediated connections in a variety of diseases, such as intestinal diseases, hepatic steatosis, diabetes, and cardiovascular diseases. The latest findings show that gut microbiota-derived acetate contributes to liver lipogenesis by converting dietary fructose into hepatic acetyl-CoA and fatty acids. GPCR agonists, including peptides and natural products like docosahexaenoic acid, have been applied to investigate their role in liver diseases. Therapies such as probiotics and GPCR agonists may be applied to modulate GPCR function to ameliorate liver metabolism syndrome. This review summarizes the current findings regarding the role of GPCRs in the development and progression of NAFLD and describes some preclinical and clinical studies of GPCR-mediated treatment. Overall, understanding GPCR-mediated signaling in liver disease may provide new therapeutic options for NAFLD.
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Affiliation(s)
- Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65212, United States
| | - Chun-Ye Zhang
- Department of Veterinary Pathobiology, University of Missouri, Columbia, MO 65212, United States
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45
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Fondevila MF, Fernandez U, Gonzalez-Rellan MJ, Da Silva Lima N, Buque X, Gonzalez-Rodriguez A, Alonso C, Iruarrizaga-Lejarreta M, Delgado TC, Varela-Rey M, Senra A, Garcia-Outeiral V, Novoa E, Iglesias C, Porteiro B, Beiroa D, Folgueira C, Tojo M, Torres JL, Hernández-Cosido L, Blanco Ó, Arab JP, Barrera F, Guallar D, Fidalgo M, López M, Dieguez C, Marcos M, Martinez-Chantar ML, Arrese M, Garcia-Monzon C, Mato JM, Aspichueta P, Nogueiras R. The L-α-Lysophosphatidylinositol/G Protein-Coupled Receptor 55 System Induces the Development of Nonalcoholic Steatosis and Steatohepatitis. Hepatology 2021; 73:606-624. [PMID: 32329085 PMCID: PMC7894478 DOI: 10.1002/hep.31290] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 03/24/2020] [Accepted: 04/05/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS G protein-coupled receptor (GPR) 55 is a putative cannabinoid receptor, and l-α-lysophosphatidylinositol (LPI) is its only known endogenous ligand. Although GPR55 has been linked to energy homeostasis in different organs, its specific role in lipid metabolism in the liver and its contribution to the pathophysiology of nonalcoholic fatty liver disease (NAFLD) remains unknown. APPROACH AND RESULTS We measured (1) GPR55 expression in the liver of patients with NAFLD compared with individuals without obesity and without liver disease, as well as animal models with steatosis and nonalcoholic steatohepatitis (NASH), and (2) the effects of LPI and genetic disruption of GPR55 in mice, human hepatocytes, and human hepatic stellate cells. Notably, we found that circulating LPI and liver expression of GPR55 were up-regulated in patients with NASH. LPI induced adenosine monophosphate-activated protein kinase activation of acetyl-coenzyme A carboxylase (ACC) and increased lipid content in human hepatocytes and in the liver of treated mice by inducing de novo lipogenesis and decreasing β-oxidation. The inhibition of GPR55 and ACCα blocked the effects of LPI, and the in vivo knockdown of GPR55 was sufficient to improve liver damage in mice fed a high-fat diet and in mice fed a methionine-choline-deficient diet. Finally, LPI promoted the initiation of hepatic stellate cell activation by stimulating GPR55 and activation of ACC. CONCLUSIONS The LPI/GPR55 system plays a role in the development of NAFLD and NASH by activating ACC.
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Affiliation(s)
- Marcos F Fondevila
- Department of PhysiologyResearch Centre of Molecular Medicine and Chronic DiseasesUniversity of Santiago de Compostela-Instituto de Investigación SanitariaSantiago de CompostelaSpain.,Centro de Fisiopatología de la Obesidad y NutriciónCentro de Investigación Biomédica en RedSantiago de CompostelaSpain
| | - Uxia Fernandez
- Department of PhysiologyResearch Centre of Molecular Medicine and Chronic DiseasesUniversity of Santiago de Compostela-Instituto de Investigación SanitariaSantiago de CompostelaSpain
| | - Maria J Gonzalez-Rellan
- Department of PhysiologyResearch Centre of Molecular Medicine and Chronic DiseasesUniversity of Santiago de Compostela-Instituto de Investigación SanitariaSantiago de CompostelaSpain
| | - Natalia Da Silva Lima
- Department of PhysiologyResearch Centre of Molecular Medicine and Chronic DiseasesUniversity of Santiago de Compostela-Instituto de Investigación SanitariaSantiago de CompostelaSpain
| | - Xabier Buque
- Department of PhysiologyUniversity of the Basque Country UPV/EHULeioaSpain.,Biocruces Bizkaia Health Research InstituteBarakaldoSpain
| | - Agueda Gonzalez-Rodriguez
- Liver Research UnitSanta Cristina University HospitalInstituto de Investigación Sanitaria PrincesaMadridSpain
| | | | | | - Teresa C Delgado
- Liver Disease LaboratoryCenter for Cooperative Research in BiosciencesBasque Research and Technology Alliance-Centro de Enfermedades Hepáticas y DigestivasCentro de Investigación Biomédica en RedDerioSpain
| | - Marta Varela-Rey
- Liver Disease LaboratoryCenter for Cooperative Research in BiosciencesBasque Research and Technology Alliance-Centro de Enfermedades Hepáticas y DigestivasCentro de Investigación Biomédica en RedDerioSpain
| | - Ana Senra
- Department of PhysiologyResearch Centre of Molecular Medicine and Chronic DiseasesUniversity of Santiago de Compostela-Instituto de Investigación SanitariaSantiago de CompostelaSpain
| | - Vera Garcia-Outeiral
- Department of PhysiologyResearch Centre of Molecular Medicine and Chronic DiseasesUniversity of Santiago de Compostela-Instituto de Investigación SanitariaSantiago de CompostelaSpain
| | - Eva Novoa
- Department of PhysiologyResearch Centre of Molecular Medicine and Chronic DiseasesUniversity of Santiago de Compostela-Instituto de Investigación SanitariaSantiago de CompostelaSpain
| | - Cristina Iglesias
- Department of PhysiologyResearch Centre of Molecular Medicine and Chronic DiseasesUniversity of Santiago de Compostela-Instituto de Investigación SanitariaSantiago de CompostelaSpain
| | - Begoña Porteiro
- Department of PhysiologyResearch Centre of Molecular Medicine and Chronic DiseasesUniversity of Santiago de Compostela-Instituto de Investigación SanitariaSantiago de CompostelaSpain.,Centro de Fisiopatología de la Obesidad y NutriciónCentro de Investigación Biomédica en RedSantiago de CompostelaSpain
| | - Daniel Beiroa
- Department of PhysiologyResearch Centre of Molecular Medicine and Chronic DiseasesUniversity of Santiago de Compostela-Instituto de Investigación SanitariaSantiago de CompostelaSpain.,Centro de Fisiopatología de la Obesidad y NutriciónCentro de Investigación Biomédica en RedSantiago de CompostelaSpain
| | - Cintia Folgueira
- Department of PhysiologyResearch Centre of Molecular Medicine and Chronic DiseasesUniversity of Santiago de Compostela-Instituto de Investigación SanitariaSantiago de CompostelaSpain
| | - Marta Tojo
- Department of PhysiologyResearch Centre of Molecular Medicine and Chronic DiseasesUniversity of Santiago de Compostela-Instituto de Investigación SanitariaSantiago de CompostelaSpain
| | - Jorge L Torres
- Department of Internal MedicineUniversity Hospital of Salamanca-Institute of Biomedical Research of SalamancaUniversity of SalamancaSalamancaSpain
| | - Lourdes Hernández-Cosido
- Department of General and Gastrointestinal SurgeryUniversity Hospital of Salamanca-Institute of Biomedical Research of SalamancaUniversity of SalamancaSalamancaSpain
| | - Óscar Blanco
- Department of PathologyUniversity Hospital of Salamanca-Institute of Biomedical Research of SalamancaUniversity of SalamancaSalamancaSpain
| | - Juan Pablo Arab
- Departament of GastroenterologyEscuela de MedicinaPontificia Universidad Católica de Chile, Santiago, ChileChile and Centro de Envejecimiento y Regeneración (CARE) Facultad de Ciencias Biológicaspontificia Universidad Católica de ChileSantiagoChile
| | - Francisco Barrera
- Departament of GastroenterologyEscuela de MedicinaPontificia Universidad Católica de Chile, Santiago, ChileChile and Centro de Envejecimiento y Regeneración (CARE) Facultad de Ciencias Biológicaspontificia Universidad Católica de ChileSantiagoChile
| | - Diana Guallar
- Department of PhysiologyResearch Centre of Molecular Medicine and Chronic DiseasesUniversity of Santiago de Compostela-Instituto de Investigación SanitariaSantiago de CompostelaSpain
| | - Miguel Fidalgo
- Department of PhysiologyResearch Centre of Molecular Medicine and Chronic DiseasesUniversity of Santiago de Compostela-Instituto de Investigación SanitariaSantiago de CompostelaSpain
| | - Miguel López
- Department of PhysiologyResearch Centre of Molecular Medicine and Chronic DiseasesUniversity of Santiago de Compostela-Instituto de Investigación SanitariaSantiago de CompostelaSpain.,Centro de Fisiopatología de la Obesidad y NutriciónCentro de Investigación Biomédica en RedSantiago de CompostelaSpain
| | - Carlos Dieguez
- Department of PhysiologyResearch Centre of Molecular Medicine and Chronic DiseasesUniversity of Santiago de Compostela-Instituto de Investigación SanitariaSantiago de CompostelaSpain.,Centro de Fisiopatología de la Obesidad y NutriciónCentro de Investigación Biomédica en RedSantiago de CompostelaSpain
| | - Miguel Marcos
- Department of Internal MedicineUniversity Hospital of Salamanca-Institute of Biomedical Research of SalamancaUniversity of SalamancaSalamancaSpain
| | - Maria L Martinez-Chantar
- Liver Disease LaboratoryCenter for Cooperative Research in BiosciencesBasque Research and Technology Alliance-Centro de Enfermedades Hepáticas y DigestivasCentro de Investigación Biomédica en RedDerioSpain
| | - Marco Arrese
- Departament of GastroenterologyEscuela de MedicinaPontificia Universidad Católica de Chile, Santiago, ChileChile and Centro de Envejecimiento y Regeneración (CARE) Facultad de Ciencias Biológicaspontificia Universidad Católica de ChileSantiagoChile
| | - Carmelo Garcia-Monzon
- Liver Research UnitSanta Cristina University HospitalInstituto de Investigación Sanitaria PrincesaMadridSpain
| | - Jose M Mato
- Liver Disease LaboratoryCenter for Cooperative Research in BiosciencesBasque Research and Technology Alliance-Centro de Enfermedades Hepáticas y DigestivasCentro de Investigación Biomédica en RedDerioSpain.,Liver Metabolism LaboratoryCenter for Cooperative Research in Biosciences, Basque Research and Technology Alliance-Centro de Enfermedades Hepáticas y DigestivasCentro de Investigación Biomédica en RedDerioSpain
| | - Patricia Aspichueta
- Department of PhysiologyUniversity of the Basque Country UPV/EHULeioaSpain.,Biocruces Bizkaia Health Research InstituteBarakaldoSpain
| | - Ruben Nogueiras
- Department of PhysiologyResearch Centre of Molecular Medicine and Chronic DiseasesUniversity of Santiago de Compostela-Instituto de Investigación SanitariaSantiago de CompostelaSpain.,Centro de Fisiopatología de la Obesidad y NutriciónCentro de Investigación Biomédica en RedSantiago de CompostelaSpain.,Galician Agency of Innovation (GAIN)Xunta de GaliciaSantiago de CompostelaSpain
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Arranz MJ, Gallego-Fabrega C, Martín-Blanco A, Soler J, Elices M, Dominguez-Clavé E, Salazar J, Vega D, Briones-Buixassa L, Pascual JC. A genome-wide methylation study reveals X chromosome and childhood trauma methylation alterations associated with borderline personality disorder. Transl Psychiatry 2021; 11:5. [PMID: 33414392 PMCID: PMC7791113 DOI: 10.1038/s41398-020-01139-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 12/02/2020] [Accepted: 12/07/2020] [Indexed: 02/06/2023] Open
Abstract
Borderline personality disorder (BPD) is a severe and highly prevalent psychiatric disorder, more common in females than in males and with notable differences in presentation between genders. Recent studies have shown that epigenetic modifications such as DNA methylation may modulate gene × environment interactions and impact on neurodevelopment. We conducted an epigenome wide study (Illumina Infinium HumanMethylation450k beadchip) in a group of BPD patients with (N = 49) and without (N = 47) childhood traumas and in a control group (N = 44). Results were confirmed in a replication cohort (N = 293 BPD patients and N = 114 controls) using EpiTYPER assays. Differentially methylated CpG sites were observed in several genes and intragenic regions in the X chromosome (PQBP1, ZNF41, RPL10, cg07810091 and cg24395855) and in chromosome 6 (TAP2). BPD patients showed significantly lower methylation levels in these CpG sites than healthy controls. These differences seemed to be increased by the existence of childhood trauma. Comparisons between BPD patients with childhood trauma and patients and controls without revealed significant differences in four genes (POU5F1, GGT6, TNFRSF13C and FAM113B), none of them in the X chromosome. Gene set enrichment analyses revealed that epigenetic alterations were more frequently found in genes controlling oestrogen regulation, neurogenesis and cell differentiation. These results suggest that epigenetic alterations in the X chromosome and oestrogen-regulation genes may contribute to the development of BPD and explain the differences in presentation between genders. Furthermore, childhood trauma events may modulate the magnitude of the epigenetic alterations contributing to BPD.
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Affiliation(s)
- María J. Arranz
- grid.414875.b0000 0004 1794 4956Fundació Docència i Recerca Mutua Terrassa, Terrassa, Spain ,grid.7722.00000 0001 1811 6966Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Institut de Recerca Biomèdica Sant Pau (IIB-Sant Pau), Barcelona, Spain
| | - Cristina Gallego-Fabrega
- grid.414875.b0000 0004 1794 4956Fundació Docència i Recerca Mutua Terrassa, Terrassa, Spain ,grid.7722.00000 0001 1811 6966Stroke Pharmacogenomics and Genetics Group, Institut de Recerca Biomèdica Sant Pau (IIB-Sant Pau), Barcelona, Spain
| | - Ana Martín-Blanco
- grid.7722.00000 0001 1811 6966Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Institut de Recerca Biomèdica Sant Pau (IIB-Sant Pau), Barcelona, Spain ,grid.413396.a0000 0004 1768 8905Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain ,grid.7080.fDepartment of Psychiatry and Forensic Medicine & Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Joaquim Soler
- grid.7722.00000 0001 1811 6966Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Institut de Recerca Biomèdica Sant Pau (IIB-Sant Pau), Barcelona, Spain ,grid.413396.a0000 0004 1768 8905Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain ,grid.7080.fDepartment of Psychiatry and Forensic Medicine & Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Matilde Elices
- grid.7722.00000 0001 1811 6966Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Institut de Recerca Biomèdica Sant Pau (IIB-Sant Pau), Barcelona, Spain ,grid.413396.a0000 0004 1768 8905Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain ,grid.7080.fDepartment of Psychiatry and Forensic Medicine & Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, Spain
| | - Elisabet Dominguez-Clavé
- grid.413396.a0000 0004 1768 8905Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Juliana Salazar
- grid.7722.00000 0001 1811 6966Translational Medical Oncology Laboratory, Institut de Recerca Biomèdica Sant Pau (IIB-Sant Pau), Bellaterra, Spain
| | - Daniel Vega
- grid.7080.fDepartment of Psychiatry and Forensic Medicine & Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, Spain ,Psychiatry and Mental Health Department, Hospital of Igualada, Consorci Sanitari de l’Anoia & Fundació Sanitària d’Igualada, Igualada, Spain
| | - Laia Briones-Buixassa
- Psychiatry and Mental Health Department, Hospital of Igualada, Consorci Sanitari de l’Anoia & Fundació Sanitària d’Igualada, Igualada, Spain
| | - Juan Carlos Pascual
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Institut de Recerca Biomèdica Sant Pau (IIB-Sant Pau), Barcelona, Spain. .,Department of Psychiatry, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. .,Department of Psychiatry and Forensic Medicine & Institute of Neurosciences, Universitat Autònoma de Barcelona, Bellaterra, Spain.
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Abe J, Guy AT, Ding F, Greimel P, Hirabayashi Y, Kamiguchi H, Ito Y. Systematic synthesis of novel phosphoglycolipid analogues as potential agonists of GPR55. Org Biomol Chem 2020; 18:8467-8473. [PMID: 33063071 DOI: 10.1039/d0ob01756f] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Rhodopsin-like G protein-coupled receptor (GPCR) GPR55 is attracting attention as a pharmaceutical target, because of its relationship with various physiological and pathological events. Although GPR55 was initially deorphanized as a cannabinoid receptor, lysophosphatidylinositol (LPI) is now widely perceived to be an endogenous ligand of GPR55. Recently, lysophosphatidyl-β-d-glucoside (LPGlc) has been found to act on GPR55 to repel dorsal root ganglion (DRG) neurons. In this study, we designed and synthesized various LPGlc analogues having the squaryldiamide group as potential agonists of GPR55. By the axon turning assay, several analogues exhibited similar activities to that of LPGlc. These results will provide valuable information for understanding the mode of action of LPGlc and its analogues and for the discovery of potent and selective antagonists or agonists of GPR55.
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Affiliation(s)
- Junpei Abe
- Graduate School of Science, Osaka University, Toyonaka, 560-0043, Japan
| | - Adam T Guy
- RIKEN Center for Brain Research, Wako, Saitama, 351-0198, Japan
| | - Feiqing Ding
- School of Pharmaceutical Sciences (Shenzhen), SunYat-sen University, Guangzhou 510275, China
| | - Peter Greimel
- RIKEN Center for Brain Research, Wako, Saitama, 351-0198, Japan
| | | | | | - Yukishige Ito
- Graduate School of Science, Osaka University, Toyonaka, 560-0043, Japan and RIKEN Cluster for Pioneering Research, Wako, Saitama, 351-0198, Japan.
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48
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Emerging roles of lysophospholipids in health and disease. Prog Lipid Res 2020; 80:101068. [PMID: 33068601 DOI: 10.1016/j.plipres.2020.101068] [Citation(s) in RCA: 191] [Impact Index Per Article: 38.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 10/09/2020] [Accepted: 10/11/2020] [Indexed: 12/22/2022]
Abstract
Lipids are abundant and play essential roles in human health and disease. The main functions of lipids are building blocks for membrane biogenesis. However, lipids are also metabolized to produce signaling molecules. Here, we discuss the emerging roles of circulating lysophospholipids. These lysophospholipids consist of lysoglycerophospholipids and lysosphingolipids. They are both present in cells at low concentration, but their concentrations in extracellular fluids are significantly higher. The biological functions of some of these lysophospholipids have been recently revealed. Remarkably, some of the lysophospholipids play pivotal signaling roles as well as being precursors for membrane biogenesis. Revealing how circulating lysophospholipids are produced, released, transported, and utilized in multi-organ systems is critical to understand their functions. The discovery of enzymes, carriers, transporters, and membrane receptors for these lysophospholipids has shed light on their physiological significance. In this review, we summarize the biological roles of these lysophospholipids via discussing about the proteins regulating their functions. We also discuss about their potential impacts to human health and diseases.
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Wargent ET, Kepczynska M, Zaibi MS, Hislop DC, Arch JR, Stocker CJ. High fat-fed GPR55 null mice display impaired glucose tolerance without concomitant changes in energy balance or insulin sensitivity but are less responsive to the effects of the cannabinoids rimonabant or Δ(9)-tetrahydrocannabivarin on weight gain. PeerJ 2020; 8:e9811. [PMID: 32904155 PMCID: PMC7451014 DOI: 10.7717/peerj.9811] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 08/04/2020] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The insulin-sensitizing phytocannabinoid, Δ(9)-tetrahydrocannabivarin (THCV) can signal partly via G-protein coupled receptor-55 (GPR55 behaving as either an agonist or an antagonist depending on the assay). The cannabinoid receptor type 1 (CB1R) inverse agonist rimonabant is also a GPR55 agonist under some conditions. Previous studies have shown varied effects of deletion of GPR55 on energy balance and glucose homeostasis in mice. The contribution of signalling via GPR55 to the metabolic effects of THCV and rimonabant has been little studied. METHODS In a preliminary experiment, energy balance and glucose homeostasis were studied in GPR55 knockout and wild-type mice fed on both standard chow (to 20 weeks of age) and high fat diets (from 6 to 15 weeks of age). In the main experiment, all mice were fed on the high fat diet (from 6 to 14 weeks of age). In addition to replicating the preliminary experiment, the effects of once daily administration of THCV (15 mg kg-1 po) and rimonabant (10 mg kg-1 po) were compared in the two genotypes. RESULTS There was no effect of genotype on absolute body weight or weight gain, body composition measured by either dual-energy X-ray absorptiometry or Nuclear Magnetic Resonance (NMR), fat pad weights, food intake, energy expenditure, locomotor activity, glucose tolerance or insulin tolerance in mice fed on chow. When the mice were fed a high fat diet, there was again no effect of genotype on these various aspects of energy balance. However, in both experiments, glucose tolerance was worse in the knockout than the wild-type mice. Genotype did not affect insulin tolerance in either experiment. Weight loss in rimonabant- and THCV-treated mice was lower in knockout than in wild-type mice, but surprisingly there was no detectable effect of genotype on the effects of the drugs on any aspect of glucose homeostasis after taking into account the effect of genotype in vehicle-treated mice. CONCLUSIONS Our two experiments differ from those reported by others in finding impaired glucose tolerance in GPR55 knockout mice in the absence of any effect on body weight, body composition, locomotor activity or energy expenditure. Nor could we detect any effect of genotype on insulin tolerance, so the possibility that GPR55 regulates glucose-stimulated insulin secretion merits further investigation. By contrast with the genotype effect in untreated mice, we found that THCV and rimonabant reduced weight gain, and this effect was in part mediated by GPR55.
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Affiliation(s)
- Edward T. Wargent
- Institute of Translational Medicine, University of Buckingham, Buckingham, United Kingdom
| | | | - Mohamed Sghaier Zaibi
- Institute of Translational Medicine, University of Buckingham, Buckingham, United Kingdom
| | - David C. Hislop
- Medical School, University of Buckingham, Buckingham, United Kingdom
| | - Jonathan R.S. Arch
- Institute of Translational Medicine, University of Buckingham, Buckingham, United Kingdom
| | - Claire J. Stocker
- Medical School, University of Buckingham, Buckingham, United Kingdom
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50
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The Role of Atypical Cannabinoid Ligands O-1602 and O-1918 on Skeletal Muscle Homeostasis with a Focus on Obesity. Int J Mol Sci 2020; 21:ijms21165922. [PMID: 32824681 PMCID: PMC7460607 DOI: 10.3390/ijms21165922] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/28/2020] [Accepted: 08/13/2020] [Indexed: 11/17/2022] Open
Abstract
O-1602 and O-1918 are atypical cannabinoid ligands for GPR55 and GPR18, which may be novel pharmaceuticals for the treatment of obesity by targeting energy homeostasis regulation in skeletal muscle. This study aimed to determine the effect of O-1602 or O-1918 on markers of oxidative capacity and fatty acid metabolism in the skeletal muscle. Diet-induced obese (DIO) male Sprague Dawley rats were administered a daily intraperitoneal injection of O-1602, O-1918 or vehicle for 6 weeks. C2C12 myotubes were treated with O-1602 or O-1918 and human primary myotubes were treated with O-1918. GPR18 mRNA was expressed in the skeletal muscle of DIO rats and was up-regulated in red gastrocnemius when compared with white gastrocnemius. O-1602 had no effect on mRNA expression on selected markers for oxidative capacity, fatty acid metabolism or adiponectin signalling in gastrocnemius from DIO rats or in C2C12 myotubes, while APPL2 mRNA was up-regulated in white gastrocnemius in DIO rats treated with O-1918. In C2C12 myotubes treated with O-1918, PGC1α, NFATc1 and PDK4 mRNA were up-regulated. There were no effects of O-1918 on mRNA expression in human primary myotubes derived from obese and obese T2DM individuals. In conclusion, O-1602 does not alter mRNA expression of key pathways important for skeletal muscle energy homeostasis in obesity. In contrast, O-1918 appears to alter markers of oxidative capacity and fatty acid metabolism in C2C12 myotubes only. GPR18 is expressed in DIO rat skeletal muscle and future work could focus on selectively modulating GPR18 in a tissue-specific manner, which may be beneficial for obesity-targeted therapies.
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