Allspice and Clove As Source of Triterpene Acids Activating the G Protein-Coupled Bile Acid Receptor TGR5
Worldwide, metabolic diseases such as obesity and type 2 diabetes have reached epidemic proportions. A major regulator of metabolic processes that gained interest in recent years is the bile acid receptor TGR5 (Takeda G protein-coupled receptor 5). This G protein-coupled membrane receptor can be fou...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-07-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fphar.2017.00468/full |
| _version_ | 1818142012092710912 |
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| author | Angela Ladurner Martin Zehl Martin Zehl Martin Zehl Ulrike Grienke Christoph Hofstadler Nadina Faur Fátima C. Pereira David Berry Verena M. Dirsch Judith M. Rollinger |
| author_facet | Angela Ladurner Martin Zehl Martin Zehl Martin Zehl Ulrike Grienke Christoph Hofstadler Nadina Faur Fátima C. Pereira David Berry Verena M. Dirsch Judith M. Rollinger |
| author_sort | Angela Ladurner |
| collection | DOAJ |
| description | Worldwide, metabolic diseases such as obesity and type 2 diabetes have reached epidemic proportions. A major regulator of metabolic processes that gained interest in recent years is the bile acid receptor TGR5 (Takeda G protein-coupled receptor 5). This G protein-coupled membrane receptor can be found predominantly in the intestine, where it is mainly responsible for the secretion of the incretins glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). The aim of this study was (i) to identify plant extracts with TGR5-activating potential, (ii) to narrow down their activity to the responsible constituents, and (iii) to assess whether the intestinal microbiota produces transformed metabolites with a different activity profile. Chenodeoxycholic acid (CDCA) served as positive control for both, the applied cell-based luciferase reporter gene assay for TGR5 activity and the biotransformation assay using mouse fecal slurry. The suitability of the workflow was demonstrated by the biotransformation of CDCA to lithocholic acid resulting in a distinct increase in TGR5 activity. Based on a traditional Tibetan formula, 19 plant extracts were selected and investigated for TGR5 activation. Extracts from the commonly used spices Syzygium aromaticum (SaroE, clove), Pimenta dioica (PdioE, allspice), and Kaempferia galanga (KgalE, aromatic ginger) significantly increased TGR5 activity. After biotransformation, only KgalE showed significant differences in its metabolite profile, which, however, did not alter its TGR5 activity compared to non-transformed KgalE. UHPLC-HRMS (high-resolution mass spectrometry) analysis revealed triterpene acids (TTAs) as the main constituents of the extracts SaroE and PdioE. Identification and quantification of TTAs in these two extracts as well as comparison of their TGR5 activity with reconstituted TTA mixtures allowed the attribution of the TGR5 activity to TTAs. EC50s were determined for the main TTAs, i.e., oleanolic acid (2.2 ± 1.6 μM), ursolic acid (1.1 ± 0.2 μM), as well as for the hitherto unknown TGR5 activators corosolic acid (0.5 ± 1.0 μM) and maslinic acid (3.7 ± 0.7 μM). In conclusion, extracts of clove, allspice, and aromatic ginger activate TGR5, which might play a pivotal role in their therapeutic use for the treatment of metabolic diseases. Moreover, the TGR5 activation of SaroE and PdioE could be pinpointed solely to TTAs. |
| first_indexed | 2024-12-11T11:09:00Z |
| format | Article |
| id | doaj.art-69e7342045254c139686c949575403c0 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-11T11:09:00Z |
| publishDate | 2017-07-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-69e7342045254c139686c949575403c02022-12-22T01:09:36ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122017-07-01810.3389/fphar.2017.00468261859Allspice and Clove As Source of Triterpene Acids Activating the G Protein-Coupled Bile Acid Receptor TGR5Angela Ladurner0Martin Zehl1Martin Zehl2Martin Zehl3Ulrike Grienke4Christoph Hofstadler5Nadina Faur6Fátima C. Pereira7David Berry8Verena M. Dirsch9Judith M. Rollinger10Department of Pharmacognosy, Faculty of Life Sciences, University of ViennaVienna, AustriaDepartment of Pharmacognosy, Faculty of Life Sciences, University of ViennaVienna, AustriaDepartment of Pharmaceutical Chemistry, University of ViennaVienna, AustriaDepartment of Analytical Chemistry, University of ViennaVienna, AustriaDepartment of Pharmacognosy, Faculty of Life Sciences, University of ViennaVienna, AustriaDepartment of Pharmacognosy, Faculty of Life Sciences, University of ViennaVienna, AustriaDepartment of Pharmacognosy, Faculty of Life Sciences, University of ViennaVienna, AustriaDepartment of Microbiology and Ecosystem Science, University of ViennaVienna, AustriaDepartment of Microbiology and Ecosystem Science, University of ViennaVienna, AustriaDepartment of Pharmacognosy, Faculty of Life Sciences, University of ViennaVienna, AustriaDepartment of Pharmacognosy, Faculty of Life Sciences, University of ViennaVienna, AustriaWorldwide, metabolic diseases such as obesity and type 2 diabetes have reached epidemic proportions. A major regulator of metabolic processes that gained interest in recent years is the bile acid receptor TGR5 (Takeda G protein-coupled receptor 5). This G protein-coupled membrane receptor can be found predominantly in the intestine, where it is mainly responsible for the secretion of the incretins glucagon-like peptide 1 (GLP-1) and peptide YY (PYY). The aim of this study was (i) to identify plant extracts with TGR5-activating potential, (ii) to narrow down their activity to the responsible constituents, and (iii) to assess whether the intestinal microbiota produces transformed metabolites with a different activity profile. Chenodeoxycholic acid (CDCA) served as positive control for both, the applied cell-based luciferase reporter gene assay for TGR5 activity and the biotransformation assay using mouse fecal slurry. The suitability of the workflow was demonstrated by the biotransformation of CDCA to lithocholic acid resulting in a distinct increase in TGR5 activity. Based on a traditional Tibetan formula, 19 plant extracts were selected and investigated for TGR5 activation. Extracts from the commonly used spices Syzygium aromaticum (SaroE, clove), Pimenta dioica (PdioE, allspice), and Kaempferia galanga (KgalE, aromatic ginger) significantly increased TGR5 activity. After biotransformation, only KgalE showed significant differences in its metabolite profile, which, however, did not alter its TGR5 activity compared to non-transformed KgalE. UHPLC-HRMS (high-resolution mass spectrometry) analysis revealed triterpene acids (TTAs) as the main constituents of the extracts SaroE and PdioE. Identification and quantification of TTAs in these two extracts as well as comparison of their TGR5 activity with reconstituted TTA mixtures allowed the attribution of the TGR5 activity to TTAs. EC50s were determined for the main TTAs, i.e., oleanolic acid (2.2 ± 1.6 μM), ursolic acid (1.1 ± 0.2 μM), as well as for the hitherto unknown TGR5 activators corosolic acid (0.5 ± 1.0 μM) and maslinic acid (3.7 ± 0.7 μM). In conclusion, extracts of clove, allspice, and aromatic ginger activate TGR5, which might play a pivotal role in their therapeutic use for the treatment of metabolic diseases. Moreover, the TGR5 activation of SaroE and PdioE could be pinpointed solely to TTAs.http://journal.frontiersin.org/article/10.3389/fphar.2017.00468/fullTGR5Syzygium aromaticumPimenta dioicaKaempferia galangatriterpene acids |
| spellingShingle | Angela Ladurner Martin Zehl Martin Zehl Martin Zehl Ulrike Grienke Christoph Hofstadler Nadina Faur Fátima C. Pereira David Berry Verena M. Dirsch Judith M. Rollinger Allspice and Clove As Source of Triterpene Acids Activating the G Protein-Coupled Bile Acid Receptor TGR5 Frontiers in Pharmacology TGR5 Syzygium aromaticum Pimenta dioica Kaempferia galanga triterpene acids |
| title | Allspice and Clove As Source of Triterpene Acids Activating the G Protein-Coupled Bile Acid Receptor TGR5 |
| title_full | Allspice and Clove As Source of Triterpene Acids Activating the G Protein-Coupled Bile Acid Receptor TGR5 |
| title_fullStr | Allspice and Clove As Source of Triterpene Acids Activating the G Protein-Coupled Bile Acid Receptor TGR5 |
| title_full_unstemmed | Allspice and Clove As Source of Triterpene Acids Activating the G Protein-Coupled Bile Acid Receptor TGR5 |
| title_short | Allspice and Clove As Source of Triterpene Acids Activating the G Protein-Coupled Bile Acid Receptor TGR5 |
| title_sort | allspice and clove as source of triterpene acids activating the g protein coupled bile acid receptor tgr5 |
| topic | TGR5 Syzygium aromaticum Pimenta dioica Kaempferia galanga triterpene acids |
| url | http://journal.frontiersin.org/article/10.3389/fphar.2017.00468/full |
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