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Downie CG, Highland HM, Alotaibi M, Welch BM, Howard AG, Cheng S, Miller N, Jain M, Kaplan RC, Lilly AG, Long T, Sofer T, Thyagarajan B, Yu B, North KE, Avery CL. Genome-wide association study reveals shared and distinct genetic architecture of fatty acids and oxylipins in the Hispanic Community Health Study/Study of Latinos. HGG ADVANCES 2025; 6:100390. [PMID: 39644095 PMCID: PMC11751521 DOI: 10.1016/j.xhgg.2024.100390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 12/02/2024] [Accepted: 12/02/2024] [Indexed: 12/09/2024] Open
Abstract
Bioactive fatty acid-derived oxylipin molecules play key roles mediating inflammation and oxidative stress. Circulating levels of fatty acids and oxylipins are influenced by environmental and genetic factors; characterizing the genetic architecture of bioactive lipids could yield new insights into underlying biology. We performed a genome-wide association study (GWAS) of 81 fatty acids and oxylipins in 11,584 Hispanic Community Health Study/Study of Latinos (HCHS/SOL) participants with genetic and lipidomic data measured at study baseline (58.6% female, mean age = 46.1 years (standard deviation 13.8)). Additionally, given the effects of central obesity on inflammation, we examined interactions with waist circumference using two-degree-of-freedom joint tests. Thirty-three of the 81 oxylipins and fatty acids were significantly heritable (heritability range: 0-32.7%). Forty (49.4%) oxylipins and fatty acids had at least one genome-wide significant (p < 6.94E-11) variant resulting in 19 independent genetic loci. Six loci (lead variant minor allele frequency [MAF] range: 0.08-0.50), including desaturase-encoding FADS and OATP1B1 transporter protein-encoding SLCO1B1, exhibited associations with two or more fatty acids and oxylipins. At several of these loci, there was evidence of colocalization of the top variant across fatty acids and oxylipins. The remaining loci were only associated with one oxylipin or fatty acid and included several CYP loci. We also identified an additional rare variant (MAF = 0.002) near CARS2 in two-degree-of-freedom tests. Our analyses revealed shared and distinct genetic architecture underlying fatty acids and oxylipins, providing insights into genetic factors and motivating work to characterize these compounds and elucidate their roles in disease.
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Affiliation(s)
- Carolina G Downie
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Heather M Highland
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Mona Alotaibi
- Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, San Diego, CA, USA
| | - Barrett M Welch
- School of Public Health, University of Nevada, Reno, Reno, NV, USA
| | - Annie Green Howard
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Susan Cheng
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | | | - Mohit Jain
- Sapient Bioanalytics, San Diego, CA, USA; Departments of Medicine and Pharmacology, University of California, San Diego, San Diego, CA, USA
| | - Robert C Kaplan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA; Public Health Sciences Division, Fred Hutchison Cancer Center, Seattle, WA, USA
| | - Adam G Lilly
- Department of Sociology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Tao Long
- Sapient Bioanalytics, San Diego, CA, USA
| | - Tamar Sofer
- CardioVascular Institute (CVI), Beth Israel Deaconess Medical Center, Boston, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Bharat Thyagarajan
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical Center, Minneapolis, MN, USA
| | - Bing Yu
- Department of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas Health Science Center at Houston, School of Public Health, Houston, TX, USA
| | - Kari E North
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Christy L Avery
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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Revol-Cavalier J, Quaranta A, Newman JW, Brash AR, Hamberg M, Wheelock CE. The Octadecanoids: Synthesis and Bioactivity of 18-Carbon Oxygenated Fatty Acids in Mammals, Bacteria, and Fungi. Chem Rev 2025; 125:1-90. [PMID: 39680864 PMCID: PMC11719350 DOI: 10.1021/acs.chemrev.3c00520] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 11/06/2024] [Accepted: 11/15/2024] [Indexed: 12/18/2024]
Abstract
The octadecanoids are a broad class of lipids consisting of the oxygenated products of 18-carbon fatty acids. Originally referring to production of the phytohormone jasmonic acid, the octadecanoid pathway has been expanded to include products of all 18-carbon fatty acids. Octadecanoids are formed biosynthetically in mammals via cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP) activity, as well as nonenzymatically by photo- and autoxidation mechanisms. While octadecanoids are well-known mediators in plants, their role in the regulation of mammalian biological processes has been generally neglected. However, there have been significant advancements in recognizing the importance of these compounds in mammals and their involvement in the mediation of inflammation, nociception, and cell proliferation, as well as in immuno- and tissue modulation, coagulation processes, hormone regulation, and skin barrier formation. More recently, the gut microbiome has been shown to be a significant source of octadecanoid biosynthesis, providing additional biosynthetic routes including hydratase activity (e.g., CLA-HY, FA-HY1, FA-HY2). In this review, we summarize the current field of octadecanoids, propose standardized nomenclature, provide details of octadecanoid preparation and measurement, summarize the phase-I metabolic pathway of octadecanoid formation in mammals, bacteria, and fungi, and describe their biological activity in relation to mammalian pathophysiology as well as their potential use as biomarkers of health and disease.
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Affiliation(s)
- Johanna Revol-Cavalier
- Unit
of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm SE-171 77, Sweden
- Larodan
Research Laboratory, Karolinska Institutet, Stockholm SE-171 77, Sweden
| | - Alessandro Quaranta
- Unit
of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm SE-171 77, Sweden
| | - John W. Newman
- Western
Human Nutrition Research Center, Agricultural
Research Service, USDA, Davis, California 95616, United States
- Department
of Nutrition, University of California, Davis, Davis, California 95616, United States
- West
Coast Metabolomics Center, Genome Center, University of California, Davis, Davis, California 95616, United States
| | - Alan R. Brash
- Department
of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232, United States
| | - Mats Hamberg
- Unit
of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm SE-171 77, Sweden
- Larodan
Research Laboratory, Karolinska Institutet, Stockholm SE-171 77, Sweden
| | - Craig E. Wheelock
- Unit
of Integrative Metabolomics, Institute of Environmental Medicine, Karolinska Institutet, Stockholm SE-171 77, Sweden
- Department
of Respiratory Medicine and Allergy, Karolinska
University Hospital, Stockholm SE-141-86, Sweden
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Wang Y, Wang J, Ma X, Li H, Sun X, Kang M, Zhang H, Xue Y, Fang Y. CD312 Promotes Paediatric Acute Lymphoblastic Leukaemia Through GNA15-Mediated Non-Classical GPCR Signalling Pathway. J Cell Mol Med 2024; 28:e70283. [PMID: 39656442 PMCID: PMC11629795 DOI: 10.1111/jcmm.70283] [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: 08/29/2024] [Revised: 11/06/2024] [Accepted: 11/11/2024] [Indexed: 12/12/2024] Open
Abstract
The bone marrow-infiltrated immune microenvironment plays a crucial role in blood system diseases, such as leukaemia. In this study, we aimed to investigate the critical role of the immune microenvironment in the onset and progression of childhood acute lymphoblastic leukaemia (ALL). Through high-throughput detection and screening of the GPCR database in the childhood ALL immune microenvironment, we identified CD312 as a candidate target. CD312 is associated with the distribution of Treg and CTL cells within the bone marrow immune microenvironment of ALL children. After CD312 knockdown, the proportion of the Treg subgroup in immune cells was significantly reduced, whereas the proportion of CTL subgroup cells was increased. CD312 exhibited good affinity with GNA15 in the transmembrane intracellular segment, and it could interact with GNA15. The BrdU staining assay revealed that the proliferation of leukaemia cells was enhanced in the CD312-overexpressed CD3+ T cells group via the phosphorylation of ERK, JNK and p38, whereas it was decreased by GNA15 knockdown in the co-culture system. In conclusion, our study suggests that CD312 fosters a suppressive immune microenvironment in the onset and progression of paediatric ALL through a GNA15-mediated non-classical GPCR signalling pathway.
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Affiliation(s)
- Yaping Wang
- Department of Hematology and Oncology, Children's Hospital of Nanjing Medical UniversityNanjing Medical UniversityNanjingChina
| | - Jiali Wang
- Department of Hematology and Oncology, Children's Hospital of Nanjing Medical UniversityNanjing Medical UniversityNanjingChina
| | - Xiaopeng Ma
- Department of Hematology and Oncology, Children's Hospital of Nanjing Medical UniversityNanjing Medical UniversityNanjingChina
| | - Huimin Li
- Department of Hematology and Oncology, Children's Hospital of Nanjing Medical UniversityNanjing Medical UniversityNanjingChina
| | - Xiaoyan Sun
- Department of Hematology and Oncology, Children's Hospital of Nanjing Medical UniversityNanjing Medical UniversityNanjingChina
| | - Meiyun Kang
- Department of Hematology and Oncology, Children's Hospital of Nanjing Medical UniversityNanjing Medical UniversityNanjingChina
| | - Heng Zhang
- Department of Hematology and Oncology, Children's Hospital of Nanjing Medical UniversityNanjing Medical UniversityNanjingChina
| | - Yao Xue
- Department of Hematology and Oncology, Children's Hospital of Nanjing Medical UniversityNanjing Medical UniversityNanjingChina
| | - Yongjun Fang
- Department of Hematology and Oncology, Children's Hospital of Nanjing Medical UniversityNanjing Medical UniversityNanjingChina
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Hu Y, Li W, Cheng X, Yang H, She ZG, Cai J, Li H, Zhang XJ. Emerging Roles and Therapeutic Applications of Arachidonic Acid Pathways in Cardiometabolic Diseases. Circ Res 2024; 135:222-260. [PMID: 38900855 DOI: 10.1161/circresaha.124.324383] [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] [Indexed: 06/22/2024]
Abstract
Cardiometabolic disease has become a major health burden worldwide, with sharply increasing prevalence but highly limited therapeutic interventions. Emerging evidence has revealed that arachidonic acid derivatives and pathway factors link metabolic disorders to cardiovascular risks and intimately participate in the progression and severity of cardiometabolic diseases. In this review, we systemically summarized and updated the biological functions of arachidonic acid pathways in cardiometabolic diseases, mainly focusing on heart failure, hypertension, atherosclerosis, nonalcoholic fatty liver disease, obesity, and diabetes. We further discussed the cellular and molecular mechanisms of arachidonic acid pathway-mediated regulation of cardiometabolic diseases and highlighted the emerging clinical advances to improve these pathological conditions by targeting arachidonic acid metabolites and pathway factors.
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Affiliation(s)
- Yufeng Hu
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China (Y.H., X.C., H.Y., Z.-G.S., J.C., H.L., X.-J.Z.)
- Key Laboratory of Cardiovascular Disease Prevention and Control, Ministry of Education, First Affiliated Hospital of Gannan Medical University, Ganzhou, China (Y.H., X.C., H.Y.)
| | - Wei Li
- Department of Cardiology, Renmin Hospital of Wuhan University, China (W.L., Z.-G.S., H.L.)
| | - Xu Cheng
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China (Y.H., X.C., H.Y., Z.-G.S., J.C., H.L., X.-J.Z.)
- Key Laboratory of Cardiovascular Disease Prevention and Control, Ministry of Education, First Affiliated Hospital of Gannan Medical University, Ganzhou, China (Y.H., X.C., H.Y.)
| | - Hailong Yang
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China (Y.H., X.C., H.Y., Z.-G.S., J.C., H.L., X.-J.Z.)
- Key Laboratory of Cardiovascular Disease Prevention and Control, Ministry of Education, First Affiliated Hospital of Gannan Medical University, Ganzhou, China (Y.H., X.C., H.Y.)
| | - Zhi-Gang She
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China (Y.H., X.C., H.Y., Z.-G.S., J.C., H.L., X.-J.Z.)
- Department of Cardiology, Renmin Hospital of Wuhan University, China (W.L., Z.-G.S., H.L.)
| | - Jingjing Cai
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China (Y.H., X.C., H.Y., Z.-G.S., J.C., H.L., X.-J.Z.)
- Department of Cardiology, The Third Xiangya Hospital, Central South University, Changsha, China (J.C.)
| | - Hongliang Li
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China (Y.H., X.C., H.Y., Z.-G.S., J.C., H.L., X.-J.Z.)
- Department of Cardiology, Renmin Hospital of Wuhan University, China (W.L., Z.-G.S., H.L.)
- Medical Science Research Center, Zhongnan Hospital of Wuhan University, Wuhan 430071, China (H.L.)
| | - Xiao-Jing Zhang
- State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Gannan Innovation and Translational Medicine Research Institute, Gannan Medical University, Ganzhou, China (Y.H., X.C., H.Y., Z.-G.S., J.C., H.L., X.-J.Z.)
- School of Basic Medical Sciences, Wuhan University, China (X.-J.Z.)
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5
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Downie CG, Highland HM, Alotaibi M, Welch BM, Howard AG, Cheng S, Miller N, Jain M, Kaplan RC, Lilly AG, Long T, Sofer T, Thyagarajan B, Yu B, North KE, Avery CL. Genome-wide association study reveals shared and distinct genetic architecture underlying fatty acid and bioactive oxylipin metabolites in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.05.21.24307719. [PMID: 38826448 PMCID: PMC11142272 DOI: 10.1101/2024.05.21.24307719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/04/2024]
Abstract
Bioactive fatty acid-derived oxylipin molecules play key roles in mediating inflammation and oxidative stress, which underlie many chronic diseases. Circulating levels of fatty acids and oxylipins are influenced by both environmental and genetic factors; characterizing the genetic architecture of bioactive lipids could yield new insights into underlying biological pathways. Thus, we performed a genome wide association study (GWAS) of n=81 fatty acids and oxylipins in n=11,584 Hispanic Community Health Study/Study of Latinos (HCHS/SOL) participants with genetic and lipidomic data measured at study baseline (58.6% female, mean age = 46.1 years, standard deviation = 13.8 years). Additionally, given the effects of central obesity on inflammation, we examined interactions with waist circumference using two-degree-of-freedom joint tests. Heritability estimates ranged from 0% to 47.9%, and 48 of the 81oxylipins and fatty acids were significantly heritable. Moreover, 40 (49.4%) of the 81 oxylipins and fatty acids had at least one genome-wide significant (p< 6.94E-11) variant resulting in 19 independent genetic loci involved in fatty acid and oxylipin synthesis, as well as downstream pathways. Four loci (lead variant minor allele frequency [MAF] range: 0.08-0.50), including the desaturase-encoding FADS and the OATP1B1 transporter protein-encoding SLCO1B1, exhibited associations with four or more fatty acids and oxylipins. The majority of the 15 remaining loci (87.5%) (lead variant MAF range = 0.03-0.45, mean = 0.23) were only associated with one oxylipin or fatty acid, demonstrating evidence of distinct genetic effects. Finally, while most loci identified in two-degree-of-freedom tests were previously identified in our main effects analyses, we also identified an additional rare variant (MAF = 0.002) near CARS2, a locus previously implicated in inflammation. Our analyses revealed shared and distinct genetic architecture underlying fatty acids and oxylipins, providing insights into genetic factors and motivating future multi-omics work to characterize these compounds and elucidate their roles in disease pathways.
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Affiliation(s)
- Carolina G Downie
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Heather M Highland
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Mona Alotaibi
- Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, San Diego, CA
| | - Barrett M Welch
- School of Public Health, University of Nevada, Reno, Reno, NV
| | - Annie Green Howard
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Susan Cheng
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA
| | | | - Mohit Jain
- Sapient Bioanalytics, San Diego, CA
- Departments of Medicine and Pharmacology, University of California, San Diego, San Diego, CA
| | - Robert C Kaplan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY; Public Health Sciences Division, Fred Hutchison Cancer Center, Seattle, WA
| | - Adam G Lilly
- Department of Sociology, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Tao Long
- Sapient Bioanalytics, San Diego, CA
| | - Tamar Sofer
- CardioVascular Institute (CVI), Beth Israel Deaconess Medical Center, Boston, MA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA
| | - Bharat Thyagarajan
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical Center, Minneapolis, MN
| | - Bing Yu
- Department of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas Health Science Center at Houston School of Public Health, Houston, TX
| | - Kari E North
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Christy L Avery
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC
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Huang R, Wang B, He J, Zhang Z, Xie R, Li S, Li Q, Tian C, Tuo Y, Zheng R, Chen W, Xiang M. Lian-Qu formula treats metabolic syndrome via reducing fat synthesis, insulin resistance and inflammation. JOURNAL OF ETHNOPHARMACOLOGY 2023; 306:116060. [PMID: 36535333 DOI: 10.1016/j.jep.2022.116060] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 12/08/2022] [Accepted: 12/14/2022] [Indexed: 06/17/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Metabolic syndrome (MetS) is a pathological condition characterized by obesity, hyperglycemia, hypertension and hyperlipidemia that increases the risk of cardiovascular disease, type 2 diabetes and non-alcoholic fatty liver disease. The traditional Chinese medicine Lian-Qu formula (LQF) is modified from Xiaoxianxiong decoction, which has been used for coronary heart disease or metabolic disease in clinical for a long time. However, the pharmacological mechanism of LQF on MetS is unclear. AIM OF THE STUDY Here, we explored the actions of LQF on MetS via network pharmacology and validated the mechanism in the MetS mice. MATERIALS AND METHODS The chemical components of LQF were searched in the traditional Chinese medicine systems pharmacology database and the natural product activity & species source database. The related targets of MetS disease were gathered from genes cluster with literature profiles database. The protein-protein interaction network was constructed to obtain the key target genes. The Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment of the key targets were performed to predict the potential mechanisms of LQF action on MetS. And then, the high-fat diet-induced MetS mice were used to validate its therapeutic effect and molecular targets. Insulin tolerance test and oral glucose tolerance test were used to assess insulin sensitivity. Body weight and visceral fat index were measured to assess obesity. Liver metabolism was detected by H&E section, oil red O staining and untargeted lipid metabolomics experiments. Finally, the key targets of LQF action on MetS were verified by PCR and ELISA kits. RESULTS A total of 466 components in LQF were obtained, among which 71 were active. These components correspond to 74 targets associated with MetS. The predicted targets of LQF worked on MetS were AKT1, INSR, PPARs, FASN, LDLR, TNF, CRP, IL-6, IL-1β and so on. Furthermore, these targets were related to pathways in cellular response to lipid, inflammatory response, glucose transmembrane transport and insulin resistance. Finally, the animal experiments validated that LQF inhibited lipids accumulation by inhibiting the gene expression of FASN and increasing ADPN, and it relieved insulin resistance by increasing GLUT-4 expression. Moreover, LQF alleviated inflammation by reducing IL-6 and CRP levels. CONCLUSION LQF exerted anti-MetS effects through improving insulin sensitivity, ameliorating hyperlipidemia and obesity, reducing liver injury, and inhibiting inflammatory response.
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Affiliation(s)
- Rongrong Huang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Pharmacy, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Baotian Wang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jialuo He
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zijun Zhang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Rui Xie
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Senlin Li
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qing Li
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cheng Tian
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yali Tuo
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Clinical Pharmacy, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ran Zheng
- National Engineering Research Center for Big Data Technology and System Services Computing Technology and System Lab, Cluster and Grid Computing Lab, School of Computer Science and Technology, Huazhong University of Science and Technology, Wuhan, China.
| | - Weihong Chen
- Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Ming Xiang
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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7
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Strassheim D, Sullivan T, Irwin DC, Gerasimovskaya E, Lahm T, Klemm DJ, Dempsey EC, Stenmark KR, Karoor V. Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases. Cells 2021; 10:3347. [PMID: 34943862 PMCID: PMC8699532 DOI: 10.3390/cells10123347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 11/10/2021] [Accepted: 11/18/2021] [Indexed: 12/15/2022] Open
Abstract
G protein-coupled receptors (GPCRs) have originally been described as a family of receptors activated by hormones, neurotransmitters, and other mediators. However, in recent years GPCRs have shown to bind endogenous metabolites, which serve functions other than as signaling mediators. These receptors respond to fatty acids, mono- and disaccharides, amino acids, or various intermediates and products of metabolism, including ketone bodies, lactate, succinate, or bile acids. Given that many of these metabolic processes are dysregulated under pathological conditions, including diabetes, dyslipidemia, and obesity, receptors of endogenous metabolites have also been recognized as potential drug targets to prevent and/or treat metabolic and cardiovascular diseases. This review describes G protein-coupled receptors activated by endogenous metabolites and summarizes their physiological, pathophysiological, and potential pharmacological roles.
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Affiliation(s)
- Derek Strassheim
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
| | - Timothy Sullivan
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
| | - David C. Irwin
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
| | - Evgenia Gerasimovskaya
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
| | - Tim Lahm
- Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health Denver, Denver, CO 80206, USA;
- Rocky Mountain Regional VA Medical Center, Aurora, CO 80045, USA
| | - Dwight J. Klemm
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
- Rocky Mountain Regional VA Medical Center, Aurora, CO 80045, USA
- Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Edward C. Dempsey
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
- Rocky Mountain Regional VA Medical Center, Aurora, CO 80045, USA
- Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Kurt R. Stenmark
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
| | - Vijaya Karoor
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
- Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health Denver, Denver, CO 80206, USA;
- Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
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