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Turza A, Bosca M, Muresan-Pop M, Mare L, Borodi G, Popescu V. Novel Solid Forms of Cardarine/GW501516 and Their Characterization by X-Ray Diffraction, Thermal, Computational, FTIR, and UV Analysis. Pharmaceutics 2025; 17:152. [PMID: 40006519 DOI: 10.3390/pharmaceutics17020152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Revised: 01/17/2025] [Accepted: 01/21/2025] [Indexed: 02/27/2025] Open
Abstract
Cardarine (C21H18F3NO3S2), better known by the popular name of GW501516, is a peroxisome proliferator-activated receptor delta (PPR-δ) agonist that presents potential use in the approach of cardiovascular diseases and metabolic disorders, dyslipidemia, and insulin resistance. The capability of cardarine to exhibit new solid forms by recrystallization from a broad class of solvents was explored. A total of four new solid forms were obtained: a new polymorph of cardarine (C21H18F3NO3S2), the cardarine: 4,4'-bipyridine cocrystal (C21H18F3NO3S2·0.5C10H8N2), the cardarine methanol solvate (C21H18F3NO3S2·CH3OH), and the cardarine dimethylformamide solvate (C21H18F3NO3S2·C3H7NO). Moreover, two derivatives of cardarine were obtained, in the form of the mono-oxidized cardarine structure (C21H18F3NO4S2) and the dioxidized cardarine structure (C21H18F3NO5S2). The formation process was proven by the determination of their crystal structures using single crystal X-ray diffraction and followed by their lattice energies evaluation. Further investigations have been conducted by powder X-ray diffraction, DTA/TGA thermal analysis, and FTIR spectroscopy. The stability and solubility were analyzed as well.
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Affiliation(s)
- Alexandru Turza
- National Institute For R&D of Isotopic and Molecular Technologies, 67-103 Donat, 400293 Cluj-Napoca, Romania
| | - Maria Bosca
- Department of Physics and Chemistry, Technical University of Cluj-Napoca, 400114 Cluj-Napoca, Romania
| | - Marieta Muresan-Pop
- Institute of Interdisciplinary Research in Bio-Nano-Sciences, Babes Bolyai University, 42 Treboniu Laurian, 400271 Cluj-Napoca, Romania
| | - Liviu Mare
- Department of Physics and Chemistry, Technical University of Cluj-Napoca, 400114 Cluj-Napoca, Romania
| | - Gheorghe Borodi
- National Institute For R&D of Isotopic and Molecular Technologies, 67-103 Donat, 400293 Cluj-Napoca, Romania
| | - Violeta Popescu
- Department of Physics and Chemistry, Technical University of Cluj-Napoca, 400114 Cluj-Napoca, Romania
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Sun JL, Kim YJ, Cho W, Lim DS, Gwon HJ, Abd El-Aty AM, Nas MA, Jeong JH, Jung TW. Interleukin 38 improves insulin resistance in hyperlipidemic skeletal muscle cells via PPARδ/SIRT1-mediated suppression of STAT3 signaling and oxidative stress. Biochem Biophys Res Commun 2024; 722:150158. [PMID: 38795455 DOI: 10.1016/j.bbrc.2024.150158] [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: 05/12/2024] [Accepted: 05/21/2024] [Indexed: 05/28/2024]
Abstract
The cytokine interleukin-38 (IL-38), a recently discovered member of the IL-1 family, has been shown to regulate inflammation and improve hepatic endoplasmic reticulum stress and lipid metabolism in individuals with obesity. However, its impact on insulin signaling in skeletal muscle cells and the underlying mechanisms remain unclear. In vitro obesity models were established using palmitate treatment, and Western blot analysis was performed to assess target proteins. Commercial kits were used to measure glucose uptake in cultured myocytes. Our study showed that IL-38 treatment alleviated the impairment of insulin signaling, including IRS-1 and Akt phosphorylation, and increased glucose uptake in palmitate-treated C2C12 myocytes. Increased levels of STAT3-mediated signaling and oxidative stress were observed in these cells following palmitate treatment, and these effects were reversed by IL-38 treatment. In addition, IL-38 treatment upregulated the expression of PPARδ, SIRT1 and antioxidants. Knockdown of PPARδ or SIRT1 using appropriate siRNAs abrogated the effects of IL-38 on insulin signaling, oxidative stress, and the STAT3-dependent pathway. These results suggest that IL-38 alleviates insulin resistance by inhibiting STAT3-mediated signaling and oxidative stress in skeletal muscle cells through PPARδ/SIRT1. This study provides fundamental evidence to support the potential use of IL-38 as a safe therapeutic agent for the treatment of insulin resistance and type 2 diabetes.
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Affiliation(s)
- Jaw Long Sun
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Young Jin Kim
- Department of Surgery, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Wonjun Cho
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Do Su Lim
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Hyeon Ji Gwon
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - A M Abd El-Aty
- Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, 12211-Giza, Egypt; Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, 25240, Turkey.
| | - Mehmet Akif Nas
- Department of Medical Education, Medical Faculty, Ataturk University, Erzurum, 25240, Turkey
| | - Ji Hoon Jeong
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea.
| | - Tae Woo Jung
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea.
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Turza A, Pascuta P, Muresan-Pop M, Mare L, Borodi G, Popescu V. Five Novel Polymorphs of Cardarine/GW501516 and Their Characterization by X-ray Diffraction, Computational Methods, Thermal Analysis and a Pharmaceutical Perspective. Pharmaceutics 2024; 16:623. [PMID: 38794285 PMCID: PMC11125426 DOI: 10.3390/pharmaceutics16050623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 04/30/2024] [Accepted: 05/03/2024] [Indexed: 05/26/2024] Open
Abstract
GW501516, also known by the name of cardarine, is a synthetic peroxisome-proliferator-activated receptor delta (PPR-δ) agonist agent developed for applications in the treatment of metabolic disorders and cardiovascular diseases. A broad polymorph screening in various solvents and mixtures was completed in order to explore its capabilities to grow polymorphs. The crystal structures of four polymorphs were elucidated using single-crystal X-ray diffraction, while one structure was solved via a powder X-ray diffraction method. The solid state features (nature of intermolecular interactions) were investigated by computational methods. The polymorphs were further investigated by thermal DSC analysis and X-ray diffraction on powders. From a pharmaceutical perspective, the stability and solubility of the polymorphs were analyzed as well.
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Affiliation(s)
- Alexandru Turza
- National Institute For R&D of Isotopic and Molecular Technologies, 67-103 Donat, 400293 Cluj-Napoca, Romania;
| | - Petru Pascuta
- Department of Physics and Chemistry, Technical University of Cluj-Napoca, 400114 Cluj-Napoca, Romania; (P.P.); (L.M.); (V.P.)
| | - Marieta Muresan-Pop
- Institute of Interdisciplinary Research in Bio-Nano-Sciences, Babes Bolyai University, 400084 Cluj-Napoca, Romania;
| | - Liviu Mare
- Department of Physics and Chemistry, Technical University of Cluj-Napoca, 400114 Cluj-Napoca, Romania; (P.P.); (L.M.); (V.P.)
| | - Gheorghe Borodi
- National Institute For R&D of Isotopic and Molecular Technologies, 67-103 Donat, 400293 Cluj-Napoca, Romania;
| | - Violeta Popescu
- Department of Physics and Chemistry, Technical University of Cluj-Napoca, 400114 Cluj-Napoca, Romania; (P.P.); (L.M.); (V.P.)
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Rivera CN, Hinkle JS, Watne RM, Macgowan TC, Wommack AJ, Vaughan RA. PPAR β/ δ Agonism with GW501516 Increases Myotube PGC-1 α Content and Reduces BCAA Media Content Independent of Changes in BCAA Catabolic Enzyme Expression. PPAR Res 2023; 2023:4779199. [PMID: 37325367 PMCID: PMC10264138 DOI: 10.1155/2023/4779199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 05/01/2023] [Accepted: 05/17/2023] [Indexed: 06/17/2023] Open
Abstract
Background Type 2 diabetes is characterized by reduced insulin sensitivity, elevated blood metabolites, and reduced mitochondrial metabolism with reduced expression of genes governing metabolism such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). PGC-1α regulates the expression of branched-chain amino acid (BCAA) metabolism, and thus, increased circulating BCAA in diabetics may be partially explained by reduced PGC-1α expression. PGC-1α functions in-part through interactions with peroxisome proliferator-activated receptor β/δ (PPARβ/δ). The present report examined the effects of the PPARβ/δ agonism on cell metabolism and related gene/protein expression of cultured myotubes, with a primary emphasis on determining the effects of GW on BCAA disposal and catabolic enzyme expression. Methods C2C12 myotubes were treated with GW501516 (GW) for up to 24 hours. Mitochondrial and glycolytic metabolism were measured via oxygen consumption and extracellular acidification rate, respectively. Metabolic gene and protein expression were assessed via quantitative real-time polymerase chain reaction (qRT-PCR) and western blot, respectively. Media BCAA content was assessed via liquid chromatography-mass spectrometry (LC/MS). Results GW significantly increased PGC-1α protein expression, mitochondrial content, and mitochondrial function. GW also significantly reduced BCAA content within culture media following 24-hour treatment; however, expression of BCAA catabolic enzymes/transporter was unchanged. Conclusion These data confirm the ability of GW to increase muscle PGC-1α content and decrease BCAA media content without affecting BCAA catabolic enzymes/transporter. These findings suggest heightened BCAA uptake (and possibly metabolism) may occur without substantial changes in the protein levels of related cell machinery.
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Affiliation(s)
- Caroline N. Rivera
- Department of Exercise Science, High Point University, High Point, NC, USA
| | - Jason S. Hinkle
- Department of Exercise Science, High Point University, High Point, NC, USA
| | - Rachel M. Watne
- Department of Chemistry, High Point University, High Point, NC, USA
| | | | | | - Roger A. Vaughan
- Department of Exercise Science, High Point University, High Point, NC, USA
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Paw M, Wnuk D, Madeja Z, Michalik M. PPARδ Agonist GW501516 Suppresses the TGF-β-Induced Profibrotic Response of Human Bronchial Fibroblasts from Asthmatic Patients. Int J Mol Sci 2023; 24:ijms24097721. [PMID: 37175437 PMCID: PMC10178673 DOI: 10.3390/ijms24097721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 03/30/2023] [Accepted: 04/21/2023] [Indexed: 05/15/2023] Open
Abstract
The airway wall remodeling observed in asthma is associated with subepithelial fibrosis and enhanced activation of human bronchial fibroblasts (HBFs) in the fibroblast to myofibroblast transition (FMT), induced mainly by transforming growth factor-β (TGF-β). The relationships between asthma severity, obesity, and hyperlipidemia suggest the involvement of peroxisome proliferator-activated receptors (PPARs) in the remodeling of asthmatic bronchi. In this study, we investigated the effect of PPARδ ligands (GW501516 as an agonist, and GSK0660 as an antagonist) on the FMT potential of HBFs derived from asthmatic patients cultured in vitro. This report shows, for the first time, the inhibitory effect of a PPARδ agonist on the number of myofibroblasts and the expression of myofibroblast-related markers-α-smooth muscle actin, collagen 1, tenascin C, and connexin 43-in asthma-related TGF-β-treated HBF populations. We suggest that actin cytoskeleton reorganization and Smad2 transcriptional activity altered by GW501516 lead to the attenuation of the FMT in HBF populations derived from asthmatics. In conclusion, our data demonstrate that a PPARδ agonist stimulates antifibrotic effects in an in vitro model of bronchial subepithelial fibrosis. This suggests its potential role in the development of a possible novel therapeutic approach for the treatment of subepithelial fibrosis during asthma.
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Affiliation(s)
- Milena Paw
- Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland
| | - Dawid Wnuk
- Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland
| | - Zbigniew Madeja
- Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland
| | - Marta Michalik
- Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Gronostajowa 7, 30-387 Kraków, Poland
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Feng H, Liu T, Yousuf S, Zhang X, Huang W, Li A, Xie L, Miao X. Identification of potential miRNA-mRNA regulatory network and the key miRNAs in intramuscular and subcutaneous adipose. Front Vet Sci 2022; 9:976603. [PMID: 36090166 PMCID: PMC9453844 DOI: 10.3389/fvets.2022.976603] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/01/2022] [Indexed: 11/13/2022] Open
Abstract
Intramuscular fat (IMF) is an important indicator for evaluating meat quality. Breeds with high IMF content are often accompanied by high subcutaneous fat (SCF), severely affecting the meat rate of pigs. Studying the mechanisms of miRNAs related to lipogenesis and lipid metabolism has important implications for pig breeding. We constructed two small RNA libraries from intramuscular and subcutaneous fat to evaluate the patterns of lipogenesis in Laiwu pig, a Chinese breed. A total of 286 differentially expressed miRNAs (DEmiRNAs), including 193 known miRNA and 93 novel miRNAs, were identified from two types of adipose. GO and KEGG enrichment analysis for DEmiRNAs showed that their target genes involved in many adipogenesis and lipid metabolism biological processes and signaling pathways, such as Wnt signaling pathway,MAPK signaling pathway, Hippo signaling pathway, PI3K-Akt signaling pathway, Melanogenesis, Signaling pathways regulating pluripotency of stem cells and so on. Then, we constructed a miRNA-mRNA interaction network to find out which miRNAs were the key miRNAs of regulation in Wnt signaling pathway. In this pathway, miR-331-3p, miR-339-5p, miR-874 and novel346_mature target PPARD, WNT10B, RSPO3, WNT2B. This study provides a theoretical basis for further understanding the post-transcriptional regulation mechanism of meat quality formation and predicting and treating diseases caused by ectopic fat.
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Jung TW, Lee HJ, Pyun DH, Kim TJ, Bang JS, Song JH, Shin YK, Abd El-Aty AM, Jeong JH. Capmatinib improves insulin sensitivity and inflammation in palmitate-treated C2C12 myocytes through the PPARδ/p38-dependent pathway. Mol Cell Endocrinol 2021; 534:111364. [PMID: 34126189 DOI: 10.1016/j.mce.2021.111364] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 06/04/2021] [Accepted: 06/07/2021] [Indexed: 12/17/2022]
Abstract
Capmatinib (CAP) has been used to treat metastatic non-small lung cancer (NSCL) and suppress inflammation. It causes hypoglycemia in NSCL patients. Therefore, it is expected that CAP improves inflammation-mediated insulin resistance due to its anti-inflammatory effect. However, the impacts of CAP on insulin signaling in skeletal muscle cells have not yet been fully elucidated. Herein, we investigated the effect of CAP on insulin resistance in palmitate-treated C2C12 myocytes and explored the related molecular mechanisms. We found that treatment of C2C12 myocytes with CAP reversed palmitate-induced impairment of insulin signaling and glucose uptake. CAP treatment ameliorated phosphorylation of inflammatory markers, including NFκB and IκB, in palmitate-treated C2C12 myocytes. Further, it augmented PPARδ expression and suppressed palmitate-induced p38 phosphorylation in a dose-dependent manner. siRNA-mediated suppression of PPARδ abolished the effects of CAP on palmitate-induced insulin resistance and inflammation as well as p38 phosphorylation. Therefore, it has been shown that CAP treatment ameliorates insulin resistance in palmitate-treated C2C12 myocytes via PPARδ/p38 signaling-mediated suppression of inflammation. These results may represent a novel therapeutic approach that could halt insulin resistance and type 2 diabetes.
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Affiliation(s)
- Tae Woo Jung
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Hyun Jung Lee
- Department of Anatomy and Cell Biology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea
| | - Do Hyeon Pyun
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Tae Jin Kim
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Joon Seok Bang
- College of Pharmacy, Sookmyung Women's University, Seoul, Republic of Korea
| | - Jin-Ho Song
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - Yong Kyoo Shin
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - A M Abd El-Aty
- State Key Laboratory of Biobased Material and Green Papermaking, College of Food Science and Engineering, Qilu University of Technology, Shandong Academy of Science, Jinan 250353, China; Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, 12211, Egypt; Department of Medical Pharmacology, Medical Faculty, Ataturk University, Erzurum, Turkey.
| | - Ji Hoon Jeong
- Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, Republic of Korea; Department of Global Innovative Drugs, Graduate School of Chung-Ang University, Seoul, Republic of Korea.
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Aguilar-Recarte D, Barroso E, Gumà A, Pizarro-Delgado J, Peña L, Ruart M, Palomer X, Wahli W, Vázquez-Carrera M. GDF15 mediates the metabolic effects of PPARβ/δ by activating AMPK. Cell Rep 2021; 36:109501. [PMID: 34380027 DOI: 10.1016/j.celrep.2021.109501] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 03/31/2021] [Accepted: 07/15/2021] [Indexed: 11/20/2022] Open
Abstract
Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) activates AMP-activated protein kinase (AMPK) and plays a crucial role in glucose and lipid metabolism. Here, we examine whether PPARβ/δ activation effects depend on growth differentiation factor 15 (GDF15), a stress response cytokine that regulates energy metabolism. Pharmacological PPARβ/δ activation increases GDF15 levels and ameliorates glucose intolerance, fatty acid oxidation, endoplasmic reticulum stress, and inflammation, and activates AMPK in HFD-fed mice, whereas these effects are abrogated by the injection of a GDF15 neutralizing antibody and in Gdf15-/- mice. The AMPK-p53 pathway is involved in the PPARβ/δ-mediated increase in GDF15, which in turn activates again AMPK. Consistently, Gdf15-/- mice show reduced AMPK activation in skeletal muscle, whereas GDF15 administration results in AMPK activation in this organ. Collectively, these data reveal a mechanism by which PPARβ/δ activation increases GDF15 levels via AMPK and p53, which in turn mediates the metabolic effects of PPARβ/δ by sustaining AMPK activation.
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Affiliation(s)
- David Aguilar-Recarte
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
| | - Emma Barroso
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
| | - Anna Gumà
- Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain; Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, 08028 Barcelona, Spain
| | - Javier Pizarro-Delgado
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
| | - Lucía Peña
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
| | - Maria Ruart
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
| | - Xavier Palomer
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
| | - Walter Wahli
- Center for Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland; Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore 308232, Singapore; ToxAlim (Research Center in Food Toxicology), INRAE, UMR1331, 31300 Toulouse Cedex, France
| | - Manuel Vázquez-Carrera
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, 08028 Barcelona, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), University of Barcelona, 08028 Barcelona, Spain; Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain; Pediatric Research Institute-Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain.
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Aguilar-Recarte D, Palomer X, Wahli W, Vázquez-Carrera M. The PPARβ/δ-AMPK Connection in the Treatment of Insulin Resistance. Int J Mol Sci 2021; 22:8555. [PMID: 34445261 PMCID: PMC8395240 DOI: 10.3390/ijms22168555] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 08/03/2021] [Accepted: 08/05/2021] [Indexed: 12/12/2022] Open
Abstract
The current treatment options for type 2 diabetes mellitus do not adequately control the disease in many patients. Consequently, there is a need for new drugs to prevent and treat type 2 diabetes mellitus. Among the new potential pharmacological strategies, activators of peroxisome proliferator-activated receptor (PPAR)β/δ show promise. Remarkably, most of the antidiabetic effects of PPARβ/δ agonists involve AMP-activated protein kinase (AMPK) activation. This review summarizes the recent mechanistic insights into the antidiabetic effects of the PPARβ/δ-AMPK pathway, including the upregulation of glucose uptake, muscle remodeling, enhanced fatty acid oxidation, and autophagy, as well as the inhibition of endoplasmic reticulum stress and inflammation. A better understanding of the mechanisms underlying the effects resulting from the PPARβ/δ-AMPK pathway may provide the basis for the development of new therapies in the prevention and treatment of insulin resistance and type 2 diabetes mellitus.
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Affiliation(s)
- David Aguilar-Recarte
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Institute of Biomedicine of the University of Barcelona (IBUB), Faculty of Pharmacy and Food Sciences, University of Barcelona, Avinguda Joan XXIII 27-31, 08028 Barcelona, Spain; (D.A.-R.); (X.P.)
- Pediatric Research Institute-Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Xavier Palomer
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Institute of Biomedicine of the University of Barcelona (IBUB), Faculty of Pharmacy and Food Sciences, University of Barcelona, Avinguda Joan XXIII 27-31, 08028 Barcelona, Spain; (D.A.-R.); (X.P.)
- Pediatric Research Institute-Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Walter Wahli
- Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland;
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore 308232, Singapore
- ToxAlim (Research Center in Food Toxicology), INRAE, UMR1331, CEDEX, 31300 Toulouse, France
| | - Manuel Vázquez-Carrera
- Department of Pharmacology, Toxicology and Therapeutic Chemistry, Institute of Biomedicine of the University of Barcelona (IBUB), Faculty of Pharmacy and Food Sciences, University of Barcelona, Avinguda Joan XXIII 27-31, 08028 Barcelona, Spain; (D.A.-R.); (X.P.)
- Pediatric Research Institute-Hospital Sant Joan de Déu, 08950 Esplugues de Llobregat, Spain
- Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, 28029 Madrid, Spain
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Shan J, Kimura H, Yokoi S, Kamiyama K, Imamoto T, Takeda I, Kobayashi M, Mikami D, Takahashi N, Kasuno K, Sugaya T, Iwano M. PPAR-δ activation reduces cisplatin-induced apoptosis via inhibiting p53/Bax/caspase-3 pathway without modulating autophagy in murine renal proximal tubular cells. Clin Exp Nephrol 2021; 25:598-607. [PMID: 33646450 DOI: 10.1007/s10157-021-02039-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 02/22/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND Cisplatin-induced injury of renal proximal tubular cells results basically from increased apoptosis via mitochondrial damage, and is mitigated by appropriate enhancement of autophagy. Peroxisome proliferator-activated receptor-delta (PPAR-δ) reportedly protects against not only mitochondrial damages but also enhances autophagy. Thus, PPAR-δ may protect against cisplatin-induced kidney injury. METHODS We examined the protective effects of PPAR-δ activation on cisplatin-induced cellular injury and their detailed mechanisms in a murine renal proximal tubular (mProx) cell line using GW0742, an authentic PPAR-δ activator. Cisplatin-induced cell damages were evaluated by TUNEL assay and immunoblot analyses for p53, 14-3-3, Bax, Bcl2, cytochrome C, and activated caspases. Autophagy status was examined by immunoblot analyses for p62 and LC3. RESULTS GW0742 suppressed cisplatin-induced apoptosis of mProx cells by reducing the activation of caspase-3 via attenuating the phosphorylation of p53 and 14-3-3, mitochondrial Bax accumulation, cytochrome C release from mitochondria to the cytosol and ensuing cytosolic caspase-9 activation. In contrast, GW0742 did not diminish cisplatin-enhanced activation of caspases-8 or -12 as extrinsic or endothelium reticulum apoptotic pathways, respectively. The inhibitory effect of GW0742 on cisplatin-induced caspase-3 activation was significantly diminished by silencing of the PPAR-δ gene expression. GW0742 itself had no influence on starvation-stimulated or cisplatin-induced autophagy in mProx cells, suggesting that the protective effects were not mediated by autophagy modification. CONCLUSION Our results indicate that GW0742 may serve as a candidate agent to mitigate cisplatin nephrotoxicity via inhibiting the mitochondrial apoptotic pathway considerably depending on PPAR-δ, without modulating autophagy.
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Affiliation(s)
- Juanping Shan
- Division of Nephrology, Shaoxing Peoples' Hospital, Shaoxing, China
| | - Hideki Kimura
- Department of Clinical Laboratory, University of Fukui Hospital, 23-3 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida, Fukui, 910-1193, Japan.
| | - Seiji Yokoi
- Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Kazuko Kamiyama
- Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Toru Imamoto
- Department of Clinical Laboratory, University of Fukui Hospital, 23-3 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida, Fukui, 910-1193, Japan
| | - Izumi Takeda
- Department of Clinical Laboratory, University of Fukui Hospital, 23-3 Matsuoka-shimoaizuki, Eiheiji-cho, Yoshida, Fukui, 910-1193, Japan
| | - Mamiko Kobayashi
- Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Daisuke Mikami
- Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Naoki Takahashi
- Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | - Kenji Kasuno
- Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
| | | | - Masayuki Iwano
- Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan
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11
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Chung KW, Ha S, Kim SM, Kim DH, An HJ, Lee EK, Moon HR, Chung HY. PPARα/β Activation Alleviates Age-Associated Renal Fibrosis in Sprague Dawley Rats. J Gerontol A Biol Sci Med Sci 2020; 75:452-458. [PMID: 31112599 DOI: 10.1093/gerona/glz083] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Indexed: 12/17/2022] Open
Abstract
Age-associated renal fibrosis is commonly observed, with a decline in renal function during aging. Although peroxisome proliferator-activated receptors α/β (PPARα/β) activation has been shown to exert beneficial effects on age-associated renal changes, its effects on age-associated renal fibrosis have not been investigated yet. Here, we show that the PPARα/β activator, MHY2013, can significantly alter lipid metabolism in renal tubule epithelial cells and attenuate renal fibrosis in aged Sprague Dawley (SD) rats. We found that MHY2013 significantly increased nuclear translocation and activity of PPARα/β in NRK52E renal epithelial cells. Moreover, the enhanced PPARα/β activity increased the expression of fatty acid oxidation-associated PPARα/β target genes. In addition, transforming growth factor-β (TGF-β)- and oleic acid-induced lipid accumulation and fibrosis-associated gene expression were decreased in NRK52E cells by MHY2013 pretreatment. To evaluate the effects of MHY2013 on age-associated renal fibrosis, aged SD rates were orally administered MHY2013 (1 and 5 mg/kg) daily for 1 month. MHY2013 efficiently increased PPARα/β activation and reduced renal lipid accumulation in aged SD rat kidneys. Furthermore, renal fibrosis was significantly decreased by MHY2013, indicating the importance of renal lipid metabolism in age-associated renal fibrosis. Taken together, our results suggest that activation of PPARα/β signaling during aging prevents age-associated renal fibrosis.
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Affiliation(s)
- Ki Wung Chung
- Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, Republic of Korea.,College of Pharmacy, Kyungsung University, Busan, Republic of Korea
| | - Sugyeong Ha
- Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Seong Min Kim
- Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Dae Hyun Kim
- Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Hye Jin An
- Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Eun Kyeong Lee
- Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Hyung Ryong Moon
- Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, Republic of Korea
| | - Hae Young Chung
- Department of Pharmacy, College of Pharmacy, Pusan National University, Busan, Republic of Korea
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12
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da Cruz BO, Cardozo LFMDF, Magliano DC, Stockler-Pinto MB. Nutritional strategies to modulate inflammation pathways via regulation of peroxisome proliferator-activated receptor β/δ. Nutr Rev 2020; 78:207-214. [PMID: 31584650 DOI: 10.1093/nutrit/nuz058] [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: 11/14/2022] Open
Abstract
The peroxisome proliferator-activated receptor (PPAR) β/δ has an important role in multiple inflammatory conditions, including obesity, hypertension, cancer, cardiovascular disease, diabetes mellitus, and autoimmune diseases. PPARβ/δ forms a heterodimer with the retinoic acid receptor and binds to peroxisome proliferator response elements to initiate transcription of its target genes. PPARβ/δ is also able to suppress the activities of several transcription factors, including nuclear factor κB, and activator protein 1, thus regulating anti-inflammatory cellular responses and playing a protective role in several diseases. Recent studies have shown that nutritional compounds, including nutrients and bioactive compounds, can regulate PPARβ/δ expression. This review discusses key nutritional compounds that are known to modulate PPARβ/δ and are likely to affect human health.
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Affiliation(s)
- Beatriz O da Cruz
- B.O. da Cruz, L.F.M. de F. Cardozo, D.C. Magliano, and M.B. Stockler-Pinto are with the Graduate Program in Cardiovascular Sciences, Fluminense Federal University (UFF), Niterói-RJ, Brazil
| | - Ludmila F M de França Cardozo
- B.O. da Cruz, L.F.M. de F. Cardozo, D.C. Magliano, and M.B. Stockler-Pinto are with the Graduate Program in Cardiovascular Sciences, Fluminense Federal University (UFF), Niterói-RJ, Brazil
| | - D'Angelo C Magliano
- B.O. da Cruz, L.F.M. de F. Cardozo, D.C. Magliano, and M.B. Stockler-Pinto are with the Graduate Program in Cardiovascular Sciences, Fluminense Federal University (UFF), Niterói-RJ, Brazil.,D.C. Magliano is with Laboratory of Morphological and Metabolic Analyses, Fluminense Federal University (UFF), Niterói-RJ, Brazil
| | - Milena B Stockler-Pinto
- B.O. da Cruz, L.F.M. de F. Cardozo, D.C. Magliano, and M.B. Stockler-Pinto are with the Graduate Program in Cardiovascular Sciences, Fluminense Federal University (UFF), Niterói-RJ, Brazil.,M.B. Stockler-Pinto is with the Graduate Program in Nutrition Sciences, Fluminense Federal University (UFF), Niterói-RJ, Brazil
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13
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Nisr RB, Shah DS, Ganley IG, Hundal HS. Proinflammatory NFkB signalling promotes mitochondrial dysfunction in skeletal muscle in response to cellular fuel overloading. Cell Mol Life Sci 2019; 76:4887-4904. [PMID: 31101940 PMCID: PMC6881256 DOI: 10.1007/s00018-019-03148-8] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 05/08/2019] [Accepted: 05/13/2019] [Indexed: 11/29/2022]
Abstract
Sustained nutrient (fuel) excess, as occurs during obesity and diabetes, has been linked to increased inflammation, impaired mitochondrial homeostasis, lipotoxicity, and insulin resistance in skeletal muscle. Precisely how mitochondrial dysfunction is initiated and whether it contributes to insulin resistance in this tissue remains a poorly resolved issue. Herein, we examine the contribution that an increase in proinflammatory NFkB signalling makes towards regulation of mitochondrial bioenergetics, morphology, and dynamics and its impact upon insulin action in skeletal muscle cells subject to chronic fuel (glucose and palmitate) overloading. We show sustained nutrient excess of L6 myotubes promotes activation of the IKKβ-NFkB pathway (as judged by a six-fold increase in IL-6 mRNA expression; an NFkB target gene) and that this was associated with a marked reduction in mitochondrial respiratory capacity (>50%), a three-fold increase in mitochondrial fragmentation and 2.5-fold increase in mitophagy. Under these circumstances, we also noted a reduction in the mRNA and protein abundance of PGC1α and that of key mitochondrial components (SDHA, ANT-1, UCP3, and MFN2) as well as an increase in cellular ROS and impaired insulin action in myotubes. Strikingly, pharmacological or genetic repression of NFkB activity ameliorated disturbances in mitochondrial respiratory function/morphology, attenuated loss of SDHA, ANT-1, UCP3, and MFN2 and mitigated the increase in ROS and the associated reduction in myotube insulin sensitivity. Our findings indicate that sustained oversupply of metabolic fuel to skeletal muscle cells induces heightened NFkB signalling and that this serves as a critical driver for disturbances in mitochondrial function and morphology, redox status, and insulin signalling.
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Affiliation(s)
- Raid B Nisr
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK
| | - Dinesh S Shah
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK
| | - Ian G Ganley
- MRC Protein Phosphorylation and Ubiquitylation Unit, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK
| | - Harinder S Hundal
- Division of Cell Signalling and Immunology, Sir James Black Centre, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
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14
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Wu X, Ma Y, Chen H, Hao Z, Su N, Li X, Shen J, Wang H. Lysophosphatidic acid induces interleukin-6 and CXCL15 secretion from MLO-Y4 cells through activation of the LPA 1 receptor and PKCθ signaling pathway. Int Immunopharmacol 2019; 74:105664. [PMID: 31233937 DOI: 10.1016/j.intimp.2019.05.049] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2019] [Revised: 05/23/2019] [Accepted: 05/25/2019] [Indexed: 02/05/2023]
Abstract
Lysophosphatidic acid (LPA) is a multifunctional phospholipid. Osteocytes are the most abundant cells in bone and can orchestrate bone formation and resorption, in part by producing cytokines that regulate osteoblast and osteoclast differentiation and activity. Interleukin (IL)-6 and IL-8 are two important cytokines that have potent effects on bone fracture healing. Previous studies suggest that platelet-derived LPA may influence fracture healing by inducing osteocyte dendrite outgrowth. However, the biological mechanism through which LPA induces cytokine production in osteocytes is poorly understood. In this study, we report that LPA markedly enhanced IL-6 and CXCL15 (mouse homologue of human IL-8) production in MLO-Y4 cells and that this enhancement was suppressed by the LPA1/3-selective antagonist Ki16425, the Gi/o protein inhibitor PTX or the protein kinase C (PKC) inhibitor sotrastaurin. We also observed that of all the PKC isoform targets of sotrastaurin, only PKCθ was activated by LPA in MLO-Y4 cells and that this activation was blocked by sotrastaurin, Ki16425 or PTX. Taken together, the results of the present study demonstrate that LPA may be a potent inducer of IL-6 and CXCL15 production in MLO-Y4 cells and that this induction is associated with the activation of LPA1, Gi/o protein and the PKCθ pathway. These findings may help us better understand the mechanism of fracture healing and contribute to the treatment of bone damage.
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Affiliation(s)
- Xiangnan Wu
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Yuanyuan Ma
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
| | - Helin Chen
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Zhichao Hao
- Guanghua School of Stomatology, Hospital of Stomatology, Sun Yat-sen University, Guangdong Provincial Key Laboratory of Stomatology, Guangzhou 510055, China
| | - Naichuan Su
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Xiaoyu Li
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Jiefei Shen
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
| | - Hang Wang
- State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Prosthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
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15
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Shen J, Liu M, Xu J, Sun B, Xu H, Zhang W. ARL15 overexpression attenuates high glucose-induced impairment of insulin signaling and oxidative stress in human umbilical vein endothelial cells. Life Sci 2019; 220:127-135. [DOI: 10.1016/j.lfs.2019.01.030] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 01/10/2019] [Accepted: 01/18/2019] [Indexed: 02/07/2023]
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16
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Supplementation comprising dietary fish oil with all-trans retinoic acid decreased blood lipids and fat accumulation in C57BL/6J mice. J Funct Foods 2019. [DOI: 10.1016/j.jff.2018.11.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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17
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Jana BA, Chintamaneni PK, Krishnamurthy PT, Wadhwani A, Mohankumar SK. Cytosolic lipid excess-induced mitochondrial dysfunction is the cause or effect of high fat diet-induced skeletal muscle insulin resistance: a molecular insight. Mol Biol Rep 2018; 46:957-963. [DOI: 10.1007/s11033-018-4551-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Accepted: 11/30/2018] [Indexed: 12/30/2022]
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18
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Ardiansyah, Inagawa Y, Koseki T, Agista AZ, Ikeda I, Goto T, Komai M, Shirakawa H. Adenosine and adenosine-5'-monophosphate ingestion ameliorates abnormal glucose metabolism in mice fed a high-fat diet. BMC COMPLEMENTARY AND ALTERNATIVE MEDICINE 2018; 18:304. [PMID: 30428888 PMCID: PMC6236947 DOI: 10.1186/s12906-018-2367-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/25/2018] [Accepted: 10/30/2018] [Indexed: 12/21/2022]
Abstract
Background We have previously reported that ingestion of adenosine (ADN) and adenosine-5′-monophosphate (AMP) improves abnormal glucose metabolism in the stroke-prone spontaneously hypertensive rat model of non-obesity-associated insulin resistance. In this study, we investigated the effect of ADN and AMP ingestion on glucose metabolism in mice with high-fat diet-induced obesity. Methods Seven-week-old C57BL/6 J mice were administered distilled water (as a control), 10 mg/L ADN, or 13 mg/L AMP via their drinking water for 14 or 25 weeks, during which they were fed a high-fat diet. Oral glucose tolerance test (OGTT) was conducted on 21-week-old mice fasted for 16 h. Insulin tolerance test (ITT) was performed on 22-week-old mice fasted for 3 h. Blood and muscle were collected for further analysis of serum parameters, gene and protein expression levels, respectively. Results Glucose metabolism in the ADN and AMP groups was significantly improved compared with the control. OGTT and ITT showed that ADN and AMP groups lower than control group. Furthermore, phosphorylation of AMP-activated protein kinase (AMPK) and mRNA levels of genes involved in lipid oxidation were enhanced in the skeletal muscle of ADN- and AMP-treated mice. Conclusion These results indicate that ingestion of ADN or AMP induces activation of AMPK in skeletal muscle and mitigates insulin resistance in mice with high-fat diet-induced diabetes. Electronic supplementary material The online version of this article (10.1186/s12906-018-2367-6) contains supplementary material, which is available to authorized users.
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19
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PPARβ/δ: A Key Therapeutic Target in Metabolic Disorders. Int J Mol Sci 2018; 19:ijms19030913. [PMID: 29558390 PMCID: PMC5877774 DOI: 10.3390/ijms19030913] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 03/09/2018] [Accepted: 03/17/2018] [Indexed: 12/11/2022] Open
Abstract
Research in recent years on peroxisome proliferator-activated receptor (PPAR)β/δ indicates that it plays a key role in the maintenance of energy homeostasis, both at the cellular level and within the organism as a whole. PPARβ/δ activation might help prevent the development of metabolic disorders, including obesity, dyslipidaemia, type 2 diabetes mellitus and non-alcoholic fatty liver disease. This review highlights research findings on the PPARβ/δ regulation of energy metabolism and the development of diseases related to altered cellular and body metabolism. It also describes the potential of the pharmacological activation of PPARβ/δ as a treatment for human metabolic disorders.
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20
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Musutova M, Elkalaf M, Klubickova N, Koc M, Povysil S, Rambousek J, Volckaert B, Duska F, Trinh MD, Kalous M, Trnka J, Balusikova K, Kovar J, Polak J. The Effect of Hypoxia and Metformin on Fatty Acid Uptake, Storage, and Oxidation in L6 Differentiated Myotubes. Front Endocrinol (Lausanne) 2018; 9:616. [PMID: 30386299 PMCID: PMC6199370 DOI: 10.3389/fendo.2018.00616] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 09/27/2018] [Indexed: 12/25/2022] Open
Abstract
Metabolic impairments associated with obstructive sleep apnea syndrome (OSA) are linked to tissue hypoxia, however, the explanatory molecular and endocrine mechanisms remain unknown. Using gas-permeable cultureware, we studied the chronic effects of mild and severe hypoxia on free fatty acid (FFA) uptake, storage, and oxidation in L6 myotubes under 20, 4, or 1% O2. Additionally, the impact of metformin and the peroxisome proliferator-activated receptor (PPAR) β/δ agonist, called GW501516, were investigated. Exposure to mild and severe hypoxia reduced FFA uptake by 37 and 32%, respectively, while metformin treatment increased FFA uptake by 39% under mild hypoxia. GW501516 reduced FFA uptake under all conditions. Protein expressions of CD36 (cluster of differentiation 36) and SCL27A4 (solute carrier family 27 fatty acid transporter, member 4) were reduced by 17 and 23% under severe hypoxia. Gene expression of UCP2 (uncoupling protein 2) was reduced by severe hypoxia by 81%. Metformin increased CD36 protein levels by 28% under control conditions and SCL27A4 levels by 56% under mild hypoxia. Intracellular lipids were reduced by mild hypoxia by 18%, while in controls only, metformin administration further reduced intracellular lipids (20% O2) by 36%. Finally, palmitate oxidation was reduced by severe hypoxia, while metformin treatment reduced non-mitochondrial O2 consumption, palmitate oxidation, and proton leak at all O2 levels. Hypoxia directly reduced FFA uptake and intracellular lipids uptake in myotubes, at least partially, due to the reduction in CD36 transporters. Metformin, but not GW501516, can increase FFA uptake and SCL27A4 expression under mild hypoxia. Described effects might contribute to elevated plasma FFA levels and metabolic derangements in OSA.
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Affiliation(s)
- Martina Musutova
- Department for the Study of Obesity and Diabetes, Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Moustafa Elkalaf
- Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Natalie Klubickova
- Department for the Study of Obesity and Diabetes, Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Michal Koc
- Department for the Study of Obesity and Diabetes, Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Stanislav Povysil
- Department for the Study of Obesity and Diabetes, Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Jan Rambousek
- Department for the Study of Obesity and Diabetes, Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Beatriz Volckaert
- Department for the Study of Obesity and Diabetes, Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Frantisek Duska
- Department of Anesthesiology and Intensive Care, Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Minh Duc Trinh
- Department for the Study of Obesity and Diabetes, Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Martin Kalous
- Department of Cell Biology, Faculty of Science, Charles University, Prague, Czechia
| | - Jan Trnka
- Department of Biochemistry, Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czechia
| | - Kamila Balusikova
- Division of Cell and Molecular Biology, Third Faculty of Medicine, Department of Biochemistry, Cell and Molecular Biology & Center for Research of Diabetes, Metabolism and Nutrition, Charles University, Prague, Czechia
| | - Jan Kovar
- Division of Cell and Molecular Biology, Third Faculty of Medicine, Department of Biochemistry, Cell and Molecular Biology & Center for Research of Diabetes, Metabolism and Nutrition, Charles University, Prague, Czechia
| | - Jan Polak
- Department for the Study of Obesity and Diabetes, Third Faculty of Medicine, Charles University, Prague, Czechia
- *Correspondence: Jan Polak
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21
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Geraets IME, Chanda D, van Tienen FHJ, van den Wijngaard A, Kamps R, Neumann D, Liu Y, Glatz JFC, Luiken JJFP, Nabben M. Human embryonic stem cell-derived cardiomyocytes as an in vitro model to study cardiac insulin resistance. Biochim Biophys Acta Mol Basis Dis 2017; 1864:1960-1967. [PMID: 29277329 DOI: 10.1016/j.bbadis.2017.12.025] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Revised: 12/12/2017] [Accepted: 12/14/2017] [Indexed: 12/25/2022]
Abstract
Patients with type 2 diabetes (T2D) and/or insulin resistance (IR) have an increased risk for the development of heart failure (HF). Evidence indicates that this increased risk is linked to an altered cardiac substrate preference of the insulin resistant heart, which shifts from a balanced utilization of glucose and long-chain fatty acids (FAs) towards an almost complete reliance on FAs as main fuel source. This shift leads to a loss of endosomal proton pump activity and increased cardiac fat accumulation, which eventually triggers cardiac dysfunction. In this review, we describe the advantages and disadvantages of currently used in vitro models to study the underlying mechanism of IR-induced HF and provide insight into a human in vitro model: human embryonic stem cell-derived cardiomyocytes (hESC-CMs). Using functional metabolic assays we demonstrate that, similar to rodent studies, hESC-CMs subjected to 16h of high palmitate (HP) treatment develop the main features of IR, i.e., decreased insulin-stimulated glucose and FA uptake, as well as loss of endosomal acidification and insulin signaling. Taken together, these data propose that HP-treated hESC-CMs are a promising in vitro model of lipid overload-induced IR for further research into the underlying mechanism of cardiac IR and for identifying new pharmacological agents and therapeutic strategies. This article is part of a Special issue entitled Cardiac adaptations to obesity, diabetes and insulin resistance, edited by Professors Jan F.C. Glatz, Jason R.B. Dyck and Christine Des Rosiers.
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Affiliation(s)
- Ilvy M E Geraets
- Department of Genetics and Cell Biology, School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, The Netherlands
| | - Dipanjan Chanda
- Department of Genetics and Cell Biology, School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, The Netherlands
| | - Florence H J van Tienen
- Department of Clinical Genetics, Maastricht University Medical Centre(+) (MUMC(+)), Maastricht, The Netherlands
| | - Arthur van den Wijngaard
- Department of Clinical Genetics, Maastricht University Medical Centre(+) (MUMC(+)), Maastricht, The Netherlands
| | - Rick Kamps
- Department of Clinical Genetics, Maastricht University Medical Centre(+) (MUMC(+)), Maastricht, The Netherlands
| | - Dietbert Neumann
- Department of Genetics and Cell Biology, School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, The Netherlands
| | - Yilin Liu
- Department of Genetics and Cell Biology, School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, The Netherlands
| | - Jan F C Glatz
- Department of Genetics and Cell Biology, School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, The Netherlands
| | - Joost J F P Luiken
- Department of Genetics and Cell Biology, School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, The Netherlands
| | - Miranda Nabben
- Department of Genetics and Cell Biology, School for Cardiovascular Diseases (CARIM), Maastricht University, Maastricht, The Netherlands.
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Ajith TA, Jayakumar TG. Peroxisome proliferator-activated receptors in cardiac energy metabolism and cardiovascular disease. Clin Exp Pharmacol Physiol 2017; 43:649-58. [PMID: 27115677 DOI: 10.1111/1440-1681.12579] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2016] [Revised: 03/28/2016] [Accepted: 04/08/2016] [Indexed: 11/30/2022]
Abstract
Cardiomyocytes mainly depend on energy produced from the oxidation of fatty acids and mitochondrial oxidative phosphorylation. Shortage of energy or excessive fat accumulation can lead to cardiac disorders. High saturated fat intake and a sedentary life style have a major influence in the development of cardiovascular disease (CVD). Peroxisome proliferator-activated receptors (PPARs), one of the nuclear receptor super family members, play critical role in the metabolism of lipids by regulating their oxidation and storage. Furthermore, they are involved in glucose homeostasis as well. PPARs, mainly alpha (α) and beta/delta (β/δ), have a significant effect on the lipid metabolism and anti-inflammation in endothelial cells (ECs), vascular smooth muscle cells, and also in cardiomyocytes. Pro-inflammatory cytokines, mainly tumour necrosis factor-α, released at the site of inflammation in the sub-ECs of coronary arteries can inactivate the PPARs which can eventually lead to decreased energy production in the myocardium. Various synthetic ligands of PPAR-α and β/δ have many favourable effects in modulating the vascular diseases and heart failure. Despite the adverse effects from therapy using PPAR- gamma ligands, several laboratories are now focused on synthesizing partial activators which may combine their beneficial effects with lowering of undesirable side effects. This review discusses the role of isoforms of PPAR in the cardiomyocytes energy balance and CVD. The knowledge will help in the synthesis of ligands for their partial activation in order to render energy balance and protection from CVD.
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Haczeyni F, Wang H, Barn V, Mridha AR, Yeh MM, Haigh WG, Ioannou GN, Choi YJ, McWherter CA, Teoh NCH, Farrell GC. The selective peroxisome proliferator-activated receptor-delta agonist seladelpar reverses nonalcoholic steatohepatitis pathology by abrogating lipotoxicity in diabetic obese mice. Hepatol Commun 2017; 1:663-674. [PMID: 29404484 PMCID: PMC5721439 DOI: 10.1002/hep4.1072] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2017] [Revised: 06/18/2017] [Accepted: 06/23/2017] [Indexed: 12/23/2022] Open
Abstract
Lipotoxicity associated with insulin resistance is central to nonalcoholic steatohepatitis (NASH) pathogenesis. To date, only weight loss fully reverses NASH pathology, but mixed peroxisome proliferator–activated receptor‐alpha/delta (PPAR‐α/δ) agonists show some efficacy. Seladelpar (MBX‐8025), a selective PPAR‐δ agonist, improves atherogenic dyslipidemia. We therefore used this agent to test whether selective PPAR‐δ activation can reverse hepatic lipotoxicity and NASH in an obese, dyslipidemic, and diabetic mouse model. From weaning, female Alms1 mutant (foz/foz) mice and wild‐type littermates were fed an atherogenic diet for 16 weeks; groups (n = 8‐12) were then randomized to receive MBX‐8025 (10 mg/kg) or vehicle (1% methylcellulose) by gavage for 8 weeks. Despite minimally altering body weight, MBX‐8025 normalized hyperglycemia, hyperinsulinemia, and glucose disposal in foz/foz mice. Serum alanine aminotransferase ranged 300‐600 U/L in vehicle‐treated foz/foz mice; MBX‐8025 reduced alanine aminotransferase by 50%. In addition, MBX‐8025 normalized serum lipids and hepatic levels of free cholesterol and other lipotoxic lipids that were increased in vehicle‐treated foz/foz versus wild‐type mice. This abolished hepatocyte ballooning and apoptosis, substantially reduced steatosis and liver inflammation, and improved liver fibrosis. In vehicle‐treated foz/foz mice, the mean nonalcoholic fatty liver disease activity score was 6.9, indicating NASH; MBX‐8025 reversed NASH in all foz/foz mice (nonalcoholic fatty liver disease activity score 3.13). Conclusion: Seladelpar improves insulin sensitivity and reverses dyslipidemia and hepatic storage of lipotoxic lipids to improve NASH pathology in atherogenic diet–fed obese diabetic mice. Selective PPAR‐δ agonists act independently of weight reduction, but counter lipotoxicity related to insulin resistance, thereby providing a novel therapy for NASH. (Hepatology Communications 2017;1:663–674)
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Affiliation(s)
- Fahrettin Haczeyni
- Liver Research Group Australian National University Medical School at the Canberra Hospital Canberra ACT Australia
| | - Hans Wang
- Liver Research Group Australian National University Medical School at the Canberra Hospital Canberra ACT Australia
| | - Vanessa Barn
- Liver Research Group Australian National University Medical School at the Canberra Hospital Canberra ACT Australia
| | - Auvro R Mridha
- Liver Research Group Australian National University Medical School at the Canberra Hospital Canberra ACT Australia
| | - Matthew M Yeh
- Department of Pathology University of Washington Seattle WA
| | - W Geoffrey Haigh
- VA Medical Center Department of Medicine, University of Washington Seattle WA
| | - George N Ioannou
- VA Medical Center Department of Medicine, University of Washington Seattle WA
| | | | | | - Narcissus C-H Teoh
- Liver Research Group Australian National University Medical School at the Canberra Hospital Canberra ACT Australia
| | - Geoffrey C Farrell
- Liver Research Group Australian National University Medical School at the Canberra Hospital Canberra ACT Australia
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24
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Lee JS, Park JM, Lee S, Lee HJ, Yang HS, Yeo J, Lee KR, Choi BH, Hong EK. Hispidin rescues palmitate‑induced insulin resistance in C2C12 myotubes. Mol Med Rep 2017; 16:4229-4234. [PMID: 28731188 DOI: 10.3892/mmr.2017.7042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2016] [Accepted: 03/01/2017] [Indexed: 11/06/2022] Open
Abstract
Skeletal muscle serves an important role in the utilization of glucose during insulin‑stimulated conditions. Excessive saturated fatty acids are considered to be a major contributing factor to insulin resistance in skeletal muscle cells. The present study investigated the effects of hispidin on palmitate‑induced insulin resistance in C2C12 skeletal muscle myotubes via an MTT assay, glucose uptake assay, Oil‑Red‑O staining and western blot analysis. Hispidin reversed the palmitate‑induced inhibition of glucose uptake, and inhibited palmitate‑induced intracellular lipid accumulation. Hispidin suppressed insulin receptor substrate‑1 Ser307 phosphorylation, and significantly promoted the activation of phosphatidylinositol‑3‑kinase and Akt, via inhibition of protein kinase C theta. Furthermore, hispidin treatment of C2C12 muscle cells increased glucose uptake via activation of adenosine monophosphate‑activated protein kinase. These findings indicated that hispidin may improve palmitate‑induced insulin resistance in skeletal muscle myotubes, and therefore hispidin treatment may be beneficial for patients with diabetes.
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Affiliation(s)
- Jong Seok Lee
- National Institute of Biological Resources, Incheon, Gyeonggi 22689, Republic of Korea
| | - Jun Myoung Park
- Department of Bioengineering and Technology, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea
| | - Sarah Lee
- National Institute of Biological Resources, Incheon, Gyeonggi 22689, Republic of Korea
| | - Hye Jin Lee
- National Institute of Biological Resources, Incheon, Gyeonggi 22689, Republic of Korea
| | - Hee-Sun Yang
- National Institute of Biological Resources, Incheon, Gyeonggi 22689, Republic of Korea
| | - Joohong Yeo
- National Institute of Biological Resources, Incheon, Gyeonggi 22689, Republic of Korea
| | - Ki Rim Lee
- Department of Bioengineering and Technology, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea
| | - Byung Hyun Choi
- Department of Bioengineering and Technology, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea
| | - Eock Kee Hong
- Department of Bioengineering and Technology, Kangwon National University, Chuncheon, Gangwon 24341, Republic of Korea
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Abstract
There is increasing evidence that an active lifestyle benefits both body and brain. However, not everyone may be able to exercise due to disease, injury or aging-related frailty. Identification of cellular targets activated by physical activity may lead to the development of new compounds that can, to some extent, mimic systemic and central effects of exercise. This review will focus on factors relevant to energy metabolism in muscle, such as the 5’ adenosine monophosphate-activated protein kinase (AMPK) - sirtuin (SIRT1) - Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) pathway, and the molecules affecting it. In particular, putative exercise-mimetics such as AICAR, metformin, and GW501516 will be discussed. Moreover, plant-derived polyphenols such as resveratrol and (-)epicatechin, with exercise-like effects on the body and brain will be evaluated.
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Affiliation(s)
- Davide Guerrieri
- Neuroplasticity and Behavior Unit, Laboratory of Neurosciences, National Institute on Aging, Baltimore, MD, USA
| | - Hyo Youl Moon
- Institute of Sport Science, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul, Republic of Korea
| | - Henriette van Praag
- Neuroplasticity and Behavior Unit, Laboratory of Neurosciences, National Institute on Aging, Baltimore, MD, USA
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26
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Abstract
Obesity is a worldwide epidemic that predisposes individuals to cardiometabolic complications, such as type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), which are all related to inappropriate ectopic lipid deposition. Identification of the pathogenic molecular mechanisms and effective therapeutic approaches are highly needed. The peroxisome proliferator-activated receptors (PPARs) modulate several biological processes that are perturbed in obesity, including inflammation, lipid and glucose metabolism and overall energy homeostasis. Here, we review how PPARs regulate the functions of adipose tissues, such as adipogenesis, lipid storage and adaptive thermogenesis, under healthy and pathological conditions. We also discuss the clinical use and mechanism of PPAR agonists in the treatment of obesity comorbidities such as dyslipidaemia, T2DM and NAFLD. First generation PPAR agonists, primarily those acting on PPARγ, are associated with adverse effects that outweigh their clinical benefits, which led to the discontinuation of their development. An improved understanding of the physiological roles of PPARs might, therefore, enable the development of safe, new PPAR agonists with improved therapeutic potential.
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Affiliation(s)
- Barbara Gross
- Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Michal Pawlak
- International Institute of Molecular and Cell Biology, 4 Ks. Trojdena Street, 02-109 Warsaw, Poland
| | - Philippe Lefebvre
- Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
| | - Bart Staels
- Université de Lille, INSERM, CHU Lille, Institut Pasteur de Lille, U1011-EGID, F-59000 Lille, France
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27
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Klingler C, Zhao X, Adhikary T, Li J, Xu G, Häring HU, Schleicher E, Lehmann R, Weigert C. Lysophosphatidylcholines activate PPARδ and protect human skeletal muscle cells from lipotoxicity. Biochim Biophys Acta Mol Cell Biol Lipids 2016; 1861:1980-1992. [PMID: 27697477 DOI: 10.1016/j.bbalip.2016.09.020] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2016] [Revised: 09/19/2016] [Accepted: 09/29/2016] [Indexed: 12/30/2022]
Abstract
Metabolomics studies of human plasma demonstrate a correlation of lower plasma lysophosphatidylcholines (LPC) concentrations with insulin resistance, obesity, and inflammation. This relationship is not unraveled on a molecular level. Here we investigated the effects of the abundant LPC(16:0) and LPC(18:1) on human skeletal muscle cells differentiated to myotubes. Transcriptome analysis of human myotubes treated with 10μM LPC for 24h revealed enrichment of up-regulated peroxisome proliferator-activated receptor (PPAR) target transcripts, including ANGPTL4, PDK4, PLIN2, and CPT1A. The increase in both PDK4 and ANGPTL4 RNA expression was abolished in the presence of either PPARδ antagonist GSK0660 or GSK3787. The induction of PDK4 by LPCs was blocked with siRNA against PPARD. The activation of PPARδ transcriptional activity by LPC was shown as PPARδ-dependent luciferase reporter gene expression and enhanced DNA binding of the PPARδ/RXR dimer. On a functional level, further results show that the LPC-mediated activation of PPARδ can reduce fatty acid-induced inflammation and ER stress in human skeletal muscle cells. The protective effect of LPC was prevented in the presence of the PPARδ antagonist GSK0660. Taking together, LPCs can activate PPARδ, which is consistent with the association of high plasma LPC levels and PPARδ-dependent anti-diabetic and anti-inflammatory effects.
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Affiliation(s)
- Christian Klingler
- Division of Pathobiochemistry and Clinical Chemistry, University Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstrasse 1, 85764 München-Neuherberg, Germany
| | - Xinjie Zhao
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
| | - Till Adhikary
- Institute of Molecular Biology and Tumor Research (IMT), Center for Tumor Biology and Immunology (ZTI), Hans-Meerwein-Strasse 3, Philipps University, 35043 Marburg, Germany
| | - Jia Li
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
| | - Guowang Xu
- CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
| | - Hans-Ulrich Häring
- Division of Pathobiochemistry and Clinical Chemistry, University Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstrasse 1, 85764 München-Neuherberg, Germany
| | - Erwin Schleicher
- Division of Pathobiochemistry and Clinical Chemistry, University Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany
| | - Rainer Lehmann
- Division of Pathobiochemistry and Clinical Chemistry, University Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstrasse 1, 85764 München-Neuherberg, Germany
| | - Cora Weigert
- Division of Pathobiochemistry and Clinical Chemistry, University Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Zentrum München at the University of Tübingen, Otfried-Müller-Strasse 10, 72076 Tübingen, Germany; German Center for Diabetes Research (DZD), Ingolstädter Landstrasse 1, 85764 München-Neuherberg, Germany.
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Namgaladze D, Brüne B. Macrophage fatty acid oxidation and its roles in macrophage polarization and fatty acid-induced inflammation. Biochim Biophys Acta Mol Cell Biol Lipids 2016; 1861:1796-1807. [PMID: 27614008 DOI: 10.1016/j.bbalip.2016.09.002] [Citation(s) in RCA: 103] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Revised: 08/26/2016] [Accepted: 09/02/2016] [Indexed: 12/14/2022]
Abstract
Recent research considerably changed our knowledge how cellular metabolism affects the immune system. We appreciate that metabolism not only provides energy to immune cells, but also actively influences diverse immune cell phenotypes. Fatty acid metabolism, particularly mitochondrial fatty acid oxidation (FAO) emerges as an important regulator of innate and adaptive immunity. Catabolism of fatty acids also modulates the progression of disease, such as the development of obesity-driven insulin resistance and type II diabetes. Here, we summarize (i) recent developments in research how FAO modulates inflammatory signatures in macrophages in response to saturated fatty acids, and (ii) the role of FAO in regulating anti-inflammatory macrophage polarization. In addition, we define the contribution of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptors (PPARs), in controlling macrophage biology towards fatty acid metabolism and inflammation.
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Affiliation(s)
- Dmitry Namgaladze
- Goethe-University Frankfurt, Faculty of Medicine, Institute of Biochemistry I, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany.
| | - Bernhard Brüne
- Goethe-University Frankfurt, Faculty of Medicine, Institute of Biochemistry I, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
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29
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Vázquez-Carrera M. Unraveling the Effects of PPARβ/δ on Insulin Resistance and Cardiovascular Disease. Trends Endocrinol Metab 2016; 27:319-334. [PMID: 27005447 DOI: 10.1016/j.tem.2016.02.008] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 02/16/2016] [Accepted: 02/25/2016] [Indexed: 12/27/2022]
Abstract
Insulin resistance precedes dyslipidemia and type 2 diabetes mellitus (T2DM) development. Preclinical evidence suggests that peroxisome proliferator-activated receptor (PPAR) β/δ activators may prevent and treat obesity-induced insulin resistance and T2DM, while clinical trials highlight their potential utility in dyslipidemia. This review summarizes recent mechanistic insights into the antidiabetic effects of PPARβ/δ activators, including their anti-inflammatory actions, their ability to inhibit endoplasmic reticulum (ER) stress and hepatic lipogenesis, and to improve atherogenesis and insulin sensitivity, as well as their capacity to activate pathways that are also stimulated by exercise. Findings from clinical trials are also examined. Dissecting the effects of PPARβ/δ ligands on insulin sensitivity and atherogenesis may provide a basis for the development of therapies for the prevention and treatment of T2DM and cardiovascular disease (CVD).
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Affiliation(s)
- Manuel Vázquez-Carrera
- Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, Institute of Biomedicine of the University of Barcelona (IBUB), Pediatric Research Institute, Hospital Sant Joan de Déu, Barcelona, Spain; Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Diagonal 643, 08028 Barcelona, Spain.
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30
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Palomer X, Barroso E, Zarei M, Botteri G, Vázquez-Carrera M. PPARβ/δ and lipid metabolism in the heart. Biochim Biophys Acta Mol Cell Biol Lipids 2016; 1861:1569-78. [PMID: 26825692 DOI: 10.1016/j.bbalip.2016.01.019] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2015] [Revised: 12/23/2015] [Accepted: 01/22/2016] [Indexed: 12/13/2022]
Abstract
Cardiac lipid metabolism is the focus of attention due to its involvement in the development of cardiac disorders. Both a reduction and an increase in fatty acid utilization make the heart more prone to the development of lipotoxic cardiac dysfunction. The ligand-activated transcription factor peroxisome proliferator-activated receptor (PPAR)β/δ modulates different aspects of cardiac fatty acid metabolism, and targeting this nuclear receptor can improve heart diseases caused by altered fatty acid metabolism. In addition, PPARβ/δ regulates glucose metabolism, the cardiac levels of endogenous antioxidants, mitochondrial biogenesis, cardiomyocyte apoptosis, the insulin signaling pathway and lipid-induced myocardial inflammatory responses. As a result, PPARβ/δ ligands can improve cardiac function and ameliorate the pathological progression of cardiac hypertrophy, heart failure, cardiac oxidative damage, ischemia-reperfusion injury, lipotoxic cardiac dysfunction and lipid-induced cardiac inflammation. Most of these findings have been observed in preclinical studies and it remains to be established to what extent these intriguing observations can be translated into clinical practice. This article is part of a Special Issue entitled: Heart Lipid Metabolism edited by G.D. Lopaschuk.
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Affiliation(s)
- Xavier Palomer
- Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, Institut de Biomedicina de la UB (IBUB), Faculty of Pharmacy, University of Barcelona, Barcelona, Spain; Institut de Recerca Pediàtrica, Hospital Sant Joan de Déu, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain
| | - Emma Barroso
- Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, Institut de Biomedicina de la UB (IBUB), Faculty of Pharmacy, University of Barcelona, Barcelona, Spain; Institut de Recerca Pediàtrica, Hospital Sant Joan de Déu, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain
| | - Mohammad Zarei
- Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, Institut de Biomedicina de la UB (IBUB), Faculty of Pharmacy, University of Barcelona, Barcelona, Spain; Institut de Recerca Pediàtrica, Hospital Sant Joan de Déu, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain
| | - Gaia Botteri
- Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, Institut de Biomedicina de la UB (IBUB), Faculty of Pharmacy, University of Barcelona, Barcelona, Spain; Institut de Recerca Pediàtrica, Hospital Sant Joan de Déu, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain
| | - Manuel Vázquez-Carrera
- Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, Institut de Biomedicina de la UB (IBUB), Faculty of Pharmacy, University of Barcelona, Barcelona, Spain; Institut de Recerca Pediàtrica, Hospital Sant Joan de Déu, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Barcelona, Spain.
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31
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Sim S, Hibberd ML. Caenorhabditis elegans susceptibility to gut Enterococcus faecalis infection is associated with fat metabolism and epithelial junction integrity. BMC Microbiol 2016; 16:6. [PMID: 26769134 PMCID: PMC4714453 DOI: 10.1186/s12866-016-0624-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2015] [Accepted: 01/08/2016] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Gut bacteria-host interactions have been implicated in the pathogenesis of numerous human diseases, but few mechanisms have been described. The genetically tractable nematode worm Caenorhabditis elegans can be infected with pathogenic bacteria, such as the human gut commensal Enterococcus faecalis, via feeding, making it a good model for studying these interactions. RESULTS An RNAi screen of 17 worm candidate genes revealed that knockdown of the transcription factor nhr-49, a master regulator of fat metabolism, shortens worm lifespan upon infection with E. faecalis (and other potentially pathogenic bacteria) compared to Escherichia coli. The functional similarity of nhr-49 to the mammalian peroxisome proliferator-activated receptors (PPARs) suggests that this is mediated through a link between fatty acid metabolism and innate immunity. In addition, knockdown of either dlg-1 or ajm-1, which encode physically interacting proteins in the C. elegans epithelial junction, also reduces worm lifespan upon E. faecalis challenge, demonstrating the importance of the intestinal epithelium as an immune barrier. CONCLUSIONS The protective roles identified for nhr-49, dlg-1, and ajm-1 suggest mechanistic interactions between the gut microbiota, host fatty acid metabolism, innate immunity, and epithelial junction integrity that are remarkably similar to those implicated in human metabolic and inflammatory diseases.
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Affiliation(s)
- Shuzhen Sim
- Infectious Diseases, Genome Institute of Singapore, 60 Biopolis Street, #02-01 Genome, Singapore, 138672, Singapore.
| | - Martin L Hibberd
- Infectious Diseases, Genome Institute of Singapore, 60 Biopolis Street, #02-01 Genome, Singapore, 138672, Singapore.,Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, United Kingdom
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Barlaka E, Galatou E, Mellidis K, Ravingerova T, Lazou A. Role of Pleiotropic Properties of Peroxisome Proliferator-Activated Receptors in the Heart: Focus on the Nonmetabolic Effects in Cardiac Protection. Cardiovasc Ther 2016; 34:37-48. [DOI: 10.1111/1755-5922.12166] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
- Eleftheria Barlaka
- School of Biology; Aristotle University of Thessaloniki; Thessaloniki Greece
| | - Eleftheria Galatou
- School of Biology; Aristotle University of Thessaloniki; Thessaloniki Greece
| | - Kyriakos Mellidis
- School of Biology; Aristotle University of Thessaloniki; Thessaloniki Greece
| | - Tanya Ravingerova
- Institute for Heart Research; Slovak Academy of Sciences; Bratislava Slovak Republic
| | - Antigone Lazou
- School of Biology; Aristotle University of Thessaloniki; Thessaloniki Greece
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Lee HJ, Yeon JE, Ko EJ, Yoon EL, Suh SJ, Kang K, Kim HR, Kang SH, Yoo YJ, Je J, Lee BJ, Kim JH, Seo YS, Yim HJ, Byun KS. Peroxisome proliferator-activated receptor-delta agonist ameliorated inflammasome activation in nonalcoholic fatty liver disease. World J Gastroenterol 2015; 21:12787-12799. [PMID: 26668503 PMCID: PMC4671034 DOI: 10.3748/wjg.v21.i45.12787] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Revised: 07/24/2015] [Accepted: 10/13/2015] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the inflammasome activation and the effect of peroxisome proliferator-activated receptors (PPAR)-δ agonist treatment in nonalcoholic fatty liver disease (NAFLD) models.
METHODS: Male C57BL/6J mice were classified according to control or high fat diet (HFD) with or without PPAR-δ agonist (GW) over period of 12 wk [control, HFD, HFD + lipopolysaccharide (LPS), HFD + LPS + GW group]. HepG2 cells were exposed to palmitic acid (PA) and/or LPS in the absence or presence of GW.
RESULTS: HFD caused glucose intolerance and hepatic steatosis. In mice fed an HFD with LPS, caspase-1 and interleukin (IL)-1β in the liver were significantly increased. Treatment with GW ameliorated the steatosis and inhibited overexpression of pro-inflammatory cytokines. In HepG2 cells, PA and LPS treatment markedly increased mRNA of several nucleotide-binding and oligomerization domain-like receptor family members (NLRP3, NLRP6, and NLRP10), caspase-1 and IL-1β. PA and LPS also exaggerated reactive oxygen species production. All of the above effects of PA and LPS were reduced by GW. GW also enhanced the phosphorylation of AMPK-α.
CONCLUSION: PPAR-δ agonist reduces fatty acid-induced inflammation and steatosis by suppressing inflammasome activation. Targeting the inflammasome by the PPAR-δ agonist may have therapeutic implication for NAFLD.
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34
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Carnitine palmitoyltransferase-1 up-regulation by PPAR-β/δ prevents lipid-induced endothelial dysfunction. Clin Sci (Lond) 2015; 129:823-37. [PMID: 26253087 DOI: 10.1042/cs20150111] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Fatty acids cause endothelial dysfunction involving increased ROS (reactive oxygen species) and reduced NO (nitric oxide) bioavailability. We show that in MAECs (mouse aortic endothelial cells), the PPARβ/δ (peroxisome- proliferator-activated receptor β/δ) agonist GW0742 prevented the decreased A23187-stimulated NO production, phosphorylation of eNOS (endothelial nitric oxide synthase) at Ser1177 and increased intracellular ROS levels caused by exposure to palmitate in vitro. The impaired endothelium-dependent relaxation to acetylcholine in mouse aorta induced by palmitate was restored by GW0742. In vivo, GW0742 treatment prevented the reduced aortic relaxation, phosphorylation of eNOS at Ser1177, and increased ROS production and NADPH oxidase in mice fed on a high-fat diet. The PPARβ/δ antagonist GSK0660 abolished all of these protective effects induced by GW0742. This agonist enhanced the expression of CPT (carnitine palmitoyltransferase)-1. The effects of GW0742 on acetylcholine- induced relaxation in aorta and on NO and ROS production in MAECs exposed to palmitate were abolished by the CPT-1 inhibitor etomoxir or by siRNA targeting CPT-1. GW0742 also inhibited the increase in DAG (diacylglycerol), PKCα/βII (protein kinase Cα/βII) activation, and phosphorylation of eNOS at Thr495 induced by palmitate in MAECs, which were abolished by etomoxir. In conclusion, PPARβ/δ activation restored the lipid-induced endothelial dysfunction by up-regulation of CPT-1, thus reducing DAG accumulation and the subsequent PKC-mediated ROS production and eNOS inhibition.
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Tumova J, Andel M, Trnka J. Excess of free fatty acids as a cause of metabolic dysfunction in skeletal muscle. Physiol Res 2015; 65:193-207. [PMID: 26447514 DOI: 10.33549/physiolres.932993] [Citation(s) in RCA: 91] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Obesity is often associated with metabolic impairments in peripheral tissues. Evidence suggests an excess of free fatty acids (FFA) as one factor linking obesity and related pathological conditions and the impact of FFA overload on skeletal muscle metabolism is described herein. Obesity is associated with dysfunctional adipose tissue unable to buffer the flux of dietary lipids. Resulting increased levels and fluxes of plasma FFA lead to ectopic lipid deposition and lipotoxicity. FFA accumulated in skeletal muscle are associated with insulin resistance and overall cellular dysfunction. Mechanisms supposed to be involved in these conditions include the Randle cycle, intracellular accumulation of lipid metabolites, inflammation and mitochondrial dysfunction or mitochondrial stress. These mechanisms are described and discussed in the view of current experimental evidence with an emphasis on conflicting theories of decreased vs. increased mitochondrial fat oxidation associated with lipid overload. Since different types of FFA may induce diverse metabolic responses in skeletal muscle cells, this review also focuses on cellular mechanisms underlying the different action of saturated and unsaturated FFA.
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Affiliation(s)
- J Tumova
- Department of Nutrition and Centre for Research on Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
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Tumova J, Malisova L, Andel M, Trnka J. Protective Effect of Unsaturated Fatty Acids on Palmitic Acid-Induced Toxicity in Skeletal Muscle Cells is not Mediated by PPARδ Activation. Lipids 2015; 50:955-64. [DOI: 10.1007/s11745-015-4058-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 07/22/2015] [Indexed: 11/28/2022]
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LI XIULI, LI JIN, LU XIAOLAN, MA HUIHUI, SHI HAITAO, LI HONG, XIE DANHONG, DONG LEI, LIANG CHUNLIAN. Treatment with PPARδ agonist alleviates non-alcoholic fatty liver disease by modulating glucose and fatty acid metabolic enzymes in a rat model. Int J Mol Med 2015; 36:767-75. [DOI: 10.3892/ijmm.2015.2270] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2014] [Accepted: 06/11/2015] [Indexed: 11/06/2022] Open
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Su X, Zhou G, Wang Y, Yang X, Li L, Yu R, Li D. The PPARβ/δ agonist GW501516 attenuates peritonitis in peritoneal fibrosis via inhibition of TAK1-NFκB pathway in rats. Inflammation 2015; 37:729-37. [PMID: 24337677 DOI: 10.1007/s10753-013-9791-z] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Peritoneal fibrosis is a common consequence of long-term peritoneal dialysis (PD), and peritonitis is a factor in its onset. Agonist-bound peroxisome proliferator-activated receptors (PPARs) function as key regulators of energy metabolism and inflammation. Here, we examined the effects of PPARβ/δ agonist GW501516 on peritonitis in a rat peritoneal fibrosis model. Peritoneal fibrosis secondary to inflammation was induced into uremic rats by daily injection of Dianeal 4.25% PD solutions along with six doses of lipopolysaccharide before commencement of GW501516 treatment. Normal non-uremic rats served as control, and all rats were fed with a control diet or a GW501516-containing diet. Compared to control group, exposure to PD fluids caused peritoneal fibrosis that was accompanied by increased mRNA levels of monocyte chemoattractant protein-1, tumor necrotic factor-α, and interleukin-6 in the uremic rats, and these effects were prevented by GW501516 treatment. Moreover, GW501516 was found to attenuate glucose-stimulated inflammation in cultured rat peritoneal mesothelial cells via inhibition of transforming growth factor-β-activated kinase 1 (TAK1), and nuclear factor kappa B (NFκB) signaling pathway (TAK1-NFκB pathway), a main inflammation regulatory pathway. In conclusion, inhibition of TAK1-NFκB pathway with GW501516 may represent a novel therapeutic approach to ameliorate peritonitis-induced peritoneal fibrosis for patients on PD.
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Affiliation(s)
- Xuesong Su
- Department of Nephrology, Shengjing Hospital, China Medical University, 36 Sanhao Street, Shenyang, 110004, People's Republic of China
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Stoynev N, Dimova I, Rukova B, Hadjidekova S, Nikolova D, Toncheva D, Tankova T. Gene expression in peripheral blood of patients with hypertension and patients with type 2 diabetes. J Cardiovasc Med (Hagerstown) 2015; 15:702-9. [PMID: 23337395 DOI: 10.2459/jcm.0b013e32835dbcc8] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
AIM To evaluate the expression of atherosclerosis-associated genes in patients with hypertension and type 2 diabetes mellitus. MATERIAL AND METHODS Twenty-seven patients (14 men, 13 women), mean age 43.26 ± 11.69 years, were included in the study, which was divided into three groups: group 1 - patients with newly diagnosed hypertension and normal glucose tolerance (n = 9), group 2 - normotensive individuals with newly diagnosed type 2 diabetes (n = 9), and control group - normotensive individuals with normal glucose tolerance (n = 9). Gene expression analysis was performed with Human Atherosclerosis RT2 Profiler PCR Array. RESULTS In patients with hypertension, we found eight genes with increased expression - FABP3, FAS, FN1, IL1R2, LPL, SERPINE1, TGFB1, and VCAM1. Decreased expression was observed for two genes - SELPLG and SERPINEB2. In patients with type 2 diabetes we found seven up-regulated genes - APOE, BAX, MMP1, NFKB1, PDGFB, SPP1, and TGFB2, whereas no specifically down-regulated genes were observed. Three genes - KLF2, PDGFRB, and PPARD were found to be expressed only in groups 1 and 2. CONCLUSION Hypertension is associated with increased expression of FABP3, FAS, FN1, IL1R2, LPL, SERPINE1, TGFB1, and VCAM1 and decreased expression of SELPLG and SERPINEB2. The up-regulation of FAS, FN1, SERPINE1, TGFB1, and VCAM1 might be associated with an increased cardiovascular risk. Type 2 diabetes is associated with increased expression of APOE, BAX, MMP1, NFKB1, PDGFB, SPP1, and TGFB2. KLF2 and PPARD might be part of protective mechanisms that limit target organ damage in both disease conditions. Expression of PDGFRB might play an important role in the pathogenesis of both hypertension and type 2 diabetes.
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Affiliation(s)
- Nikolay Stoynev
- aDepartment of Diabetology, Clinical Center of Endocrinology bDepartment of Medical Genetics cDepartment of Physiology, Medical University Sofia, Bulgaria
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Zizola C, Kennel PJ, Akashi H, Ji R, Castillero E, George I, Homma S, Schulze PC. Activation of PPARδ signaling improves skeletal muscle oxidative metabolism and endurance function in an animal model of ischemic left ventricular dysfunction. Am J Physiol Heart Circ Physiol 2015; 308:H1078-85. [PMID: 25713305 DOI: 10.1152/ajpheart.00679.2014] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2014] [Accepted: 02/18/2015] [Indexed: 01/06/2023]
Abstract
Exercise intolerance in heart failure has been linked to impaired skeletal muscle oxidative capacity. Oxidative metabolism and exercise capacity are regulated by PPARδ signaling. We hypothesized that PPARδ stimulation reverts skeletal muscle oxidative dysfunction. Myocardial infarction (MI) was induced in C57BL/6 mice and the development of ventricular dysfunction was monitored over 8 wk. Mice were randomized to the PPARδ agonist GW501516 (5 mg/kg body wt per day for 4 wk) or placebo 8 wk post-MI. Muscle function was assessed through running tests and grip strength measurements. In muscle, we analyzed muscle fiber cross-sectional area and fiber types, metabolic gene expression, fatty acid (FA) oxidation and ATP content. Signaling pathways were studied in C2C12 myotubes. FA oxidation and ATP levels decreased in muscle from MI mice compared with sham- operated mice. GW501516 administration increased oleic acid oxidation levels in skeletal muscle of the treated MI group compared with placebo treatment. This was accompanied by transcriptional changes including increased CPT1 expression. Further, the PPARδ-agonist improved running endurance compared with placebo. Cell culture experiments revealed protective effects of GW501516 against the cytokine-induced decrease of FA oxidation and changes in metabolic gene expression. Skeletal muscle dysfunction in HF is associated with impaired PPARδ signaling and treatment with the PPARδ agonist GW501516 corrects oxidative capacity and FA metabolism and improves exercise capacity in mice with LV dysfunction. Pharmacological activation of PPARδ signaling could be an attractive therapeutic intervention to counteract the progressive skeletal muscle dysfunction in HF.
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Affiliation(s)
- Cynthia Zizola
- Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, New York; and
| | - Peter J Kennel
- Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, New York; and
| | - Hirokazu Akashi
- Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, New York; and
| | - Ruiping Ji
- Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, New York; and
| | - Estibaliz Castillero
- Division of Cardiothoracic Surgery, Columbia University Medical Center, New York, New York
| | - Isaac George
- Division of Cardiothoracic Surgery, Columbia University Medical Center, New York, New York
| | - Shunichi Homma
- Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, New York; and
| | - P Christian Schulze
- Department of Medicine, Division of Cardiology, Columbia University Medical Center, New York, New York; and
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Quintela AM, Jiménez R, Piqueras L, Gómez-Guzmán M, Haro J, Zarzuelo MJ, Cogolludo A, Sanz MJ, Toral M, Romero M, Pérez-Vizcaíno F, Duarte J. PPARβ activation restores the high glucose-induced impairment of insulin signalling in endothelial cells. Br J Pharmacol 2015; 171:3089-102. [PMID: 24527778 DOI: 10.1111/bph.12646] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Revised: 02/05/2014] [Accepted: 02/11/2014] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND AND PURPOSE PPARβ enhances insulin sensitivity in adipocytes and skeletal muscle cells, but its effects on insulin signalling in endothelial cells are not known. We analysed the effects of the PPARβ/δ (PPARβ) agonists, GW0742 and L165041, on impaired insulin signalling induced by high glucose in HUVECs and aortic and mesenteric arteries from diabetic rats. EXPERIMENTAL APPROACH Insulin-stimulated NO production, Akt-Ser(473) and eNOS-Ser(1177) phosphorylation, and reactive oxygen species (ROS) production were studied in HUVECs incubated in low- or high-glucose medium. Insulin-stimulated relaxations and protein phosphorylation in vessels from streptozotocin (STZ)-induced diabetic rats were also analysed. KEY RESULTS HUVECs incubated in high-glucose medium showed a significant reduction in insulin-stimulated production of NO. High glucose also reduced insulin-induced Akt-Ser(473) and eNOS-Ser(1177) phosphorylation, increased IRS-1-Ser(636) and ERK1/2-Thr(183) -Tyr(185) phosphorylation and increased ROS production. The co-incubation with the PPARβ agonists GW0742 or L165041 prevented all these effects induced by high glucose. In turn, the effects induced by the agonists were suppressed when HUVEC were also incubated with the PPARβ antagonist GSK0660, the pyruvate dehydrogenase kinase (PDK)4 inhibitor dichloroacetate or after knockdown of both PPARβ and PDK4 with siRNA. The ERK1/2 inhibitor PD98059, ROS scavenger catalase, inhibitor of complex II thenoyltrifluoroacetone or uncoupler of oxidative phosphorylation, carbonyl cyanide m-chlorophenylhydrazone, also prevented glucose-induced insulin resistance. In STZ diabetic rats, oral GW0742 also improved insulin signalling and the impaired NO-mediated vascular relaxation. CONCLUSION AND IMPLICATIONS PPARβ activation in vitro and in vivo restores the endothelial function, preserving the insulin-Akt-eNOS pathway impaired by high glucose, at least in part, through PDK4 activation.
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Affiliation(s)
- A M Quintela
- Department of Pharmacology, University of Granada, 18071, Granada, Spain
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Salvadó L, Barroso E, Gómez-Foix AM, Palomer X, Michalik L, Wahli W, Vázquez-Carrera M. PPARβ/δ prevents endoplasmic reticulum stress-associated inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism. Diabetologia 2014; 57:2126-35. [PMID: 25063273 DOI: 10.1007/s00125-014-3331-8] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Accepted: 06/26/2014] [Indexed: 12/12/2022]
Abstract
AIM/HYPOTHESIS Endoplasmic reticulum (ER) stress, which is involved in the link between inflammation and insulin resistance, contributes to the development of type 2 diabetes mellitus. In this study, we assessed whether peroxisome proliferator-activated receptor (PPAR)β/δ prevented ER stress-associated inflammation and insulin resistance in skeletal muscle cells. METHODS Studies were conducted in mouse C2C12 myotubes, in the human myogenic cell line LHCN-M2 and in skeletal muscle from wild-type and PPARβ/δ-deficient mice and mice exposed to a high-fat diet. RESULTS The PPARβ/δ agonist GW501516 prevented lipid-induced ER stress in mouse and human myotubes and in skeletal muscle of mice fed a high-fat diet. PPARβ/δ activation also prevented thapsigargin- and tunicamycin-induced ER stress in human and murine skeletal muscle cells. In agreement with this, PPARβ/δ activation prevented ER stress-associated inflammation and insulin resistance, and glucose-intolerant PPARβ/δ-deficient mice showed increased phosphorylated levels of inositol-requiring 1 transmembrane kinase/endonuclease-1α in skeletal muscle. Our findings demonstrate that PPARβ/δ activation prevents ER stress through the activation of AMP-activated protein kinase (AMPK), and the subsequent inhibition of extracellular-signal-regulated kinase (ERK)1/2 due to the inhibitory crosstalk between AMPK and ERK1/2, since overexpression of a dominant negative AMPK construct (K45R) reversed the effects attained by PPARβ/δ activation. CONCLUSIONS/INTERPRETATION Overall, these findings indicate that PPARβ/δ prevents ER stress, inflammation and insulin resistance in skeletal muscle cells by activating AMPK.
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Affiliation(s)
- Laia Salvadó
- Department of Pharmacology and Therapeutic Chemistry, Faculty of Pharmacy, University of Barcelona, Diagonal 643, 08028, Barcelona, Spain
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Mosti MP, Stunes AK, Ericsson M, Pullisaar H, Reseland JE, Shabestari M, Eriksen EF, Syversen U. Effects of the peroxisome proliferator-activated receptor (PPAR)-δ agonist GW501516 on bone and muscle in ovariectomized rats. Endocrinology 2014; 155:2178-89. [PMID: 24708238 DOI: 10.1210/en.2013-1166] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Estrogen deficiency promotes bone loss and skeletal muscle dysfunction. Peroxisome proliferator-activated receptors (PPARs) have 3 subtypes (α, δ, and γ). PPARγ agonists induce bone loss, whereas PPARα agonists increase bone mass. Although PPARδ agonists are known to influence skeletal muscle metabolism, the skeletal effects are unsettled. This study investigated the musculoskeletal effects of the PPARδ agonist GW501516 in ovariectomized (OVX) rats. Female Sprague Dawley rats, 12 weeks of age, were allocated to a sham-operated group and 3 OVX groups; high-dose GW501516 (OVX-GW5), low-dose GW501516 (OVX-GW1), and a control group (OVX-CTR), respectively (n = 12 per group). Animals received GW501516 or vehicle (methylcellulose) daily for 4 months by gavage. Bone mineral density (BMD) was assessed by dual x-ray absorptiometry at the femur, spine, and whole body. Bone microarchitecture at the proximal tibia was assessed by microcomputed tomography, and dynamic histomorphometry was performed. Quadriceps muscle morphology and the relative expression of mitochondrial proteins were analyzed. Bone metabolism markers and metabolic markers were measured in plasma. After 4 months, the OVX-GW5 group displayed lower femoral BMD than OVX-CTR. Trabecular separation was higher in the GW-treated groups, compared with OVX-CTR. The OVX-GW5 group also exhibited lower cortical area fraction and a higher structure model index than OVX-CTR. These effects coincided with impaired bone formation in both GW groups. The OVX-GW5 group displayed elevated triglyceride levels and reduced adiponectin levels, whereas no effects on muscle morphology or mitochondrial gene expression appeared. In summary, the PPARδ agonist GW501516 negatively affected bone properties in OVX rats, whereas no effects were detected in skeletal muscle.
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Affiliation(s)
- M P Mosti
- Department of Cancer Research and Molecular Medicine (M.P.M., A.K.S., U.S.), Norwegian University of Science and Technology, N-7491 Trondheim, Norway; Department of Medical Biosciences, Physiological Chemistry (M.E.), Umeå University, SE-901 85 Umeå, Sweden; Department of Biomaterials (H.P., J.E.R., M.S.), Institute for Clinical Dentistry, University of Oslo, 0317 Oslo, Norway; Department of Endocrinology (E.F.E.), Oslo University Hospital, 0424 Oslo, Norway; and Department of Endocrinology (U.S.), St Olav's University Hospital HF, 7030 Trondheim, Norway
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Telmisartan activates endogenous peroxisome proliferator-activated receptor-δ and may have anti-fibrotic effects in human mesangial cells. Hypertens Res 2013; 37:422-31. [DOI: 10.1038/hr.2013.157] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2013] [Revised: 09/19/2013] [Accepted: 11/14/2013] [Indexed: 01/17/2023]
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Dietary stimulators of the PGC-1 superfamily and mitochondrial biosynthesis in skeletal muscle. A mini-review. J Physiol Biochem 2013; 70:271-84. [DOI: 10.1007/s13105-013-0301-4] [Citation(s) in RCA: 260] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Accepted: 11/21/2013] [Indexed: 11/26/2022]
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Yang Y, Tong Y, Gong M, Lu Y, Wang C, Zhou M, Yang Q, Mao T, Tong N. Activation of PPARβ/δ protects pancreatic β cells from palmitate-induced apoptosis by upregulating the expression of GLP-1 receptor. Cell Signal 2013; 26:268-78. [PMID: 24269940 DOI: 10.1016/j.cellsig.2013.11.019] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2013] [Revised: 10/27/2013] [Accepted: 11/11/2013] [Indexed: 02/05/2023]
Abstract
We previously showed that activated peroxisome proliferator-activated receptor (PPAR)β/δ can protect pancreatic β cells against lipotoxic apoptosis. However, the molecular mechanism remained unclear. Glucagon-like peptide-1 receptor (GLP-1R) has been reported to exhibit a protective effect against lipotoxic apoptosis in pancreatic β cells. In the present study, we aimed to investigate the underlying molecular mechanisms that PPARβ/δ activation suppressed apoptosis and improved β cell function impaired by fatty acids, focusing on contribution of GLP-1R. Isolated rat islets and rat insulin-secreting INS-1 cells were treated with the PPARβ/δ agonist GW501516 (GW) in the presence or absence of palmitate (PA) and transfected with siRNA for PPARβ/δ or treated with the PPARβ/δ antagonist GSK0660. Apoptosis was assessed by DNA fragmentation, Hoechst 33342 staining and flow cytometry. GLP-1R expression in INS-1 cells and islets was assayed by immunoblotting, quantitative PCR (qPCR) and immunofluorescence staining. SREBP-1c, Caveolin-1, Akt, Bcl-2, Bcl-xl and caspase-3 expression was measured using immunoblotting and qPCR. Our results showed that PPARβ/δ activation decreased apoptosis in β cells and robustly stimulated GLP-1R expression under lipotoxic conditions. GW enhanced glucose-stimulated insulin secretion (GSIS) impaired by PA through stimulation of GLP-1R expression in β cells. Moreover, SREBP-1c/Caveolin-1 signaling was involved in PPARβ/δ-regulated GLP-1R expression. Finally, GW exerted anti-apoptotic effects via interfering with GLP-1R-dependent Akt/Bcl-2 and Bcl-xl/caspase-3 signaling pathways. Our study suggested that the anti-apoptotic action of GW may involve its transcriptional regulation of GLP-1R, and PPARβ/δ activation may represent a new therapeutic method for protecting pancreatic β cells from lipotoxicity.
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Affiliation(s)
- Yan Yang
- Division of Endocrinology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yuzhen Tong
- West China School of Medicine, Sichuan University, Chengdu, Sichuan, China
| | - Meng Gong
- Laboratory of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Yanrong Lu
- Laboratory of Transplantation Engineering, West China Hospital of Sichuan University, Chengdu, China
| | - Chengshi Wang
- Laboratory of Transplantation Engineering, West China Hospital of Sichuan University, Chengdu, China
| | - Mingliang Zhou
- Laboratory of Endocrinology and Metabolism, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Qiu Yang
- Division of Endocrinology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Tingrui Mao
- Division of Endocrinology, West China Hospital of Sichuan University, Chengdu, Sichuan, China
| | - Nanwei Tong
- Division of Endocrinology, West China Hospital of Sichuan University, Chengdu, Sichuan, China.
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Macrae K, Stretton C, Lipina C, Blachnio-Zabielska A, Baranowski M, Gorski J, Marley A, Hundal HS. Defining the role of DAG, mitochondrial function, and lipid deposition in palmitate-induced proinflammatory signaling and its counter-modulation by palmitoleate. J Lipid Res 2013; 54:2366-78. [PMID: 23833248 PMCID: PMC3735935 DOI: 10.1194/jlr.m036996] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 07/03/2013] [Indexed: 12/27/2022] Open
Abstract
Chronic exposure of skeletal muscle to saturated fatty acids, such as palmitate (C16:0), enhances proinflammatory IKK-NFκB signaling by a mechanism involving the MAP kinase (Raf-MEK-ERK) pathway. Raf activation can be induced by its dissociation from the Raf-kinase inhibitor protein (RKIP) by diacylglycerol (DAG)-sensitive protein kinase C (PKC). However, whether these molecules mediate the proinflammatory action of palmitate, an important precursor for DAG synthesis, is currently unknown. Here, involvement of DAG-sensitive PKCs, RKIP, and the structurally related monounsaturated fatty acid palmitoleate (C16:1) on proinflammatory signaling are investigated. Palmitate, but not palmitoleate, induced phosphorylation/activation of the MEK-ERK-IKK axis and proinflammatory cytokine (IL-6, CINC-1) expression. Palmitate increased intramyocellular DAG and invoked PKC-dependent RKIP(Ser153) phosphorylation, resulting in RKIP-Raf1 dissociation and MEK-ERK signaling. These responses were mimicked by PMA, a DAG mimetic and PKC activator. However, while pharmacological inhibition of PKC suppressed PMA-induced activation of MEK-ERK-IKK signaling, activation by palmitate was upheld, suggesting that DAG-sensitive PKC and RKIP were dispensable for palmitate's proinflammatory action. Strikingly, the proinflammatory effect of palmitate was potently repressed by palmitoleate. This repression was not due to reduced palmitate uptake but linked to increased neutral lipid storage and enhanced cellular oxidative capacity brought about by palmitoleate's ability to restrain palmitate-induced mitochondrial dysfunction.
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Affiliation(s)
- Katherine Macrae
- Division of Cell Signalling and Immunology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom
| | - Clare Stretton
- Division of Cell Signalling and Immunology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom
| | - Christopher Lipina
- Division of Cell Signalling and Immunology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom
| | | | - Marcin Baranowski
- Department of Physiology, Medical University of Bialystok, 15-222 Bialystok, Poland
| | - Jan Gorski
- Department of Physiology, Medical University of Bialystok, 15-222 Bialystok, Poland
| | - Anna Marley
- Department of Physiology, AstraZeneca, Cheshire SK10 4TG, United Kingdom
| | - Harinder S. Hundal
- Division of Cell Signalling and Immunology, Sir James Black Centre, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom
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Castillero E, Alamdari N, Aversa Z, Gurav A, Hasselgren PO. PPARβ/δ regulates glucocorticoid- and sepsis-induced FOXO1 activation and muscle wasting. PLoS One 2013; 8:e59726. [PMID: 23555761 PMCID: PMC3605288 DOI: 10.1371/journal.pone.0059726] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2012] [Accepted: 02/17/2013] [Indexed: 01/01/2023] Open
Abstract
FOXO1 is involved in glucocorticoid- and sepsis-induced muscle wasting, in part reflecting regulation of atrogin-1 and MuRF1. Mechanisms influencing FOXO1 expression in muscle wasting are poorly understood. We hypothesized that the transcription factor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) upregulates muscle FOXO1 expression and activity with a downstream upregulation of atrogin-1 and MuRF1 expression during sepsis and glucocorticoid treatment and that inhibition of PPARβ/δ activity can prevent muscle wasting. We found that activation of PPARβ/δ in cultured myotubes increased FOXO1 activity, atrogin-1 and MuRF1 expression, protein degradation and myotube atrophy. Treatment of myotubes with dexamethasone increased PPARβ/δ expression and activity. Dexamethasone-induced FOXO1 activation and atrogin-1 and MuRF1 expression, protein degradation, and myotube atrophy were inhibited by PPARβ/δ blocker or siRNA. Importantly, muscle wasting induced in rats by dexamethasone or sepsis was prevented by treatment with a PPARβ/δ inhibitor. The present results suggest that PPARβ/δ regulates FOXO1 activation in glucocorticoid- and sepsis-induced muscle wasting and that treatment with a PPARβ/δ inhibitor may ameliorate loss of muscle mass in these conditions.
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Affiliation(s)
- Estibaliz Castillero
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Nima Alamdari
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Zaira Aversa
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Aniket Gurav
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
| | - Per-Olof Hasselgren
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
- * E-mail:
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Yan Z, Ni Y, Wang P, Chen J, He H, Sun J, Cao T, Chen J, Zhao Z, Luo Z, Chen L, Liu D, Zhu Z. Peroxisome proliferator-activated receptor delta protects against obesity-related glomerulopathy through the P38 MAPK pathway. Obesity (Silver Spring) 2013; 21:538-45. [PMID: 23592661 DOI: 10.1002/oby.20103] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2012] [Accepted: 08/23/2012] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Obesity is a prominent component of metabolic syndrome and a major risk factor for renal disease. The aim of this study was to explore the effect of cross-talk between peroxisome proliferator-activated receptor (PPAR)δ and p38 mitogen-activated protein kinase (p38 MAPK) on obesity-related glomerulopathy. DESIGN AND METHODS Male Wistar rats were randomly assigned to standard laboratory chow or a high-fat diet for 32 weeks. Glomerular mesangial cells HBZY-1 and mature differentiation 3T3-L1 cells were cocultured and were transfected with PPARδ-expressing vectors or treated with agonist or inhibitor of PPARδ or p38 MAPK. RESULTS Rats on a high-fat diet showed typical characteristics of metabolic syndrome including obesity, dyslipidemia, insulin resistance, and hypertension. Rats on a high-fat diet also had significant glomerular hypertrophy and extracellular matrix accumulation, which were accompanied by increased p38 MAPK phosphorylation and decreased PPARδ expression in the kidney tissue. The roles of p38 MAPK and PPARδ in a coculture system of mesangial cells and mature differentiation 3T3-L1 cells were further explored. PPARδ suppression promoted laminin and type IV collagen secretion through p38 MAPK phosphorylation in mesangial cells, whereas PPARδ overexpression or PPARδ agonist attenuated phosphorylation of p38 MAPK and laminin and type IV collagen secretion. CONCLUSIONS The characteristics of obesity-related glomerulopathy, which might be partly caused by PPARδ suppression-induced p38 MAPK activation and laminin and type IV collagen secretion was demonstrated.
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Affiliation(s)
- Zhencheng Yan
- Center for Hypertension and Metabolic Diseases, Department of Hypertension and Endocrinology, Chongqing Hypertension Institut, Chongqing 400042, China
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Feeding a DHA-enriched diet increases skeletal muscle protein synthesis in growing pigs: association with increased skeletal muscle insulin action and local mRNA expression of insulin-like growth factor 1. Br J Nutr 2013; 110:671-80. [PMID: 23433177 DOI: 10.1017/s0007114512005740] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Dietary n-3 PUFA have been demonstrated to promote muscle growth in growing animals. In the present study, fractional protein synthesis rates (FSR) in the skeletal muscle of growing pigs fed a DHA-enriched (DE) diet (DE treatment) or a soyabean oil (SO) diet (SO treatment) were evaluated in the fed and feed-deprived states. Feeding-induced increases in muscle FSR, as well as the activation of the mammalian target of rapamycin and protein kinase B, were higher in the DE treatment as indicated by the positive interaction between diet and feeding. In the fed state, the activation of eIF4E-binding protein 1 in the skeletal muscle of pigs on the DE diet was higher than that in pigs on the SO diet (P<0·05). Feeding the DE diet increased muscle insulin-like growth factor 1 (IGF-1) expression (P<0·05) and insulin action (as demonstrated by increased insulin receptor (IR) phosphorylation, P<0·05), resulting in increased IR substrate 1 activation in the fed state. However, no difference in plasma IGF-1 concentration or hepatic IGF-1 expression between the two treatments was associated. The increased IGF-1 expression in the DE treatment was associated with increased mRNA expression of the signal transducer and activator of transcription 5A and decreased mRNA expression of protein tyrosine phosphatase, non-receptor type 3 in skeletal muscle. Moreover, mRNA expression of protein tyrosine phosphatase, non-receptor type 1 (PTPN1), the activation of PTPN1 and the activation of NF-κB in muscle were significantly lower in the DE treatment (P<0·05). The results of the present study suggest that feeding a DE diet increased feeding-induced muscle protein synthesis in growing pigs, and muscle IGF-1 expression and insulin action were involved in this action.
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