Rosiglitazone induces hepatocyte injury by increasing DCA accumulation through OATP1A4 inhibiting in mice
Rosiglitazone (RL), a second-generation thiazolidinedione (TZD), is an oral antidiabetic agent that is reportedly associated with hepatotoxicity. However, the molecular mechanism of Rosiglitazone induced hepatotoxicity has not been reported yet. To minimize clinical risk, in the present study, toxic...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-10-01
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| Series: | Arabian Journal of Chemistry |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1878535223006044 |
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| author | Daopeng Tan Lei Ling Lin Qin Yanliu Lu Di Wu Yuqi He |
| author_facet | Daopeng Tan Lei Ling Lin Qin Yanliu Lu Di Wu Yuqi He |
| author_sort | Daopeng Tan |
| collection | DOAJ |
| description | Rosiglitazone (RL), a second-generation thiazolidinedione (TZD), is an oral antidiabetic agent that is reportedly associated with hepatotoxicity. However, the molecular mechanism of Rosiglitazone induced hepatotoxicity has not been reported yet. To minimize clinical risk, in the present study, toxicity was evaluated initially in C57BL/6 mice to confirm the hepatotoxicity of Rosiglitazone. Subsequently, the transcription of genes, the up-regulated expression of proteins and changes of metabolite spectrum in bile acid system in accordance with system pharmacology and multi-omics profiling strategy were investigated to reveal its toxic mechanism. Results show an obvious Rosiglitazone induced hepatocyte injury in our experiment. Changes in bile acid profiles revealed that Rosiglitazone administration increased the concentration of deoxycholic acid (DCA) in the liver, but decreased those of other bile acids. Transcriptomic and proteomic data showed that while the expression of efflux transporters ABCC3, ABCC4 and ABCB11 was upregulated following Rosiglitazone treatment, the expression of two hepatic uptake transporters, OATP1A1 and OATP1A4, which were negatively associated with DCA accumulation, were significantly downregulated. These results indicated that cholestasis, especially the accumulation of DCA in the liver, is the primary factors responsible for Rosiglitazone induced hepatocyte injury. The mechanism of Rosiglitazone induced DCA accumulation in the liver may be the result of stimulated intestinal permeability and increased biosynthesis and uptake of DCA and weakening of DCA amidation to reduce DCA efflux due to the inhibition of OATP1A1 and OATP1A4 expression in the liver. |
| first_indexed | 2024-03-12T02:06:18Z |
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| id | doaj.art-8618f83eac764c708f74d84162234b3e |
| institution | Directory Open Access Journal |
| issn | 1878-5352 |
| language | English |
| last_indexed | 2024-03-12T02:06:18Z |
| publishDate | 2023-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Arabian Journal of Chemistry |
| spelling | doaj.art-8618f83eac764c708f74d84162234b3e2023-09-07T04:43:33ZengElsevierArabian Journal of Chemistry1878-53522023-10-011610105142Rosiglitazone induces hepatocyte injury by increasing DCA accumulation through OATP1A4 inhibiting in miceDaopeng Tan0Lei Ling1Lin Qin2Yanliu Lu3Di Wu4Yuqi He5Guizhou Engineering Research Center of Industrial Key-technology for Dendrobium Nobile, Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, ChinaGuizhou Engineering Research Center of Industrial Key-technology for Dendrobium Nobile, Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China; Zunyi Municipal Institute of Product Quality Inspection and Testing, Zunyi, Guizhou 563000, ChinaGuizhou Engineering Research Center of Industrial Key-technology for Dendrobium Nobile, Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, ChinaGuizhou Engineering Research Center of Industrial Key-technology for Dendrobium Nobile, Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, ChinaGuizhou Engineering Research Center of Industrial Key-technology for Dendrobium Nobile, Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, ChinaGuizhou Engineering Research Center of Industrial Key-technology for Dendrobium Nobile, Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou 563000, China; Zunyi Municipal Institute of Product Quality Inspection and Testing, Zunyi, Guizhou 563000, China; Corresponding author.Rosiglitazone (RL), a second-generation thiazolidinedione (TZD), is an oral antidiabetic agent that is reportedly associated with hepatotoxicity. However, the molecular mechanism of Rosiglitazone induced hepatotoxicity has not been reported yet. To minimize clinical risk, in the present study, toxicity was evaluated initially in C57BL/6 mice to confirm the hepatotoxicity of Rosiglitazone. Subsequently, the transcription of genes, the up-regulated expression of proteins and changes of metabolite spectrum in bile acid system in accordance with system pharmacology and multi-omics profiling strategy were investigated to reveal its toxic mechanism. Results show an obvious Rosiglitazone induced hepatocyte injury in our experiment. Changes in bile acid profiles revealed that Rosiglitazone administration increased the concentration of deoxycholic acid (DCA) in the liver, but decreased those of other bile acids. Transcriptomic and proteomic data showed that while the expression of efflux transporters ABCC3, ABCC4 and ABCB11 was upregulated following Rosiglitazone treatment, the expression of two hepatic uptake transporters, OATP1A1 and OATP1A4, which were negatively associated with DCA accumulation, were significantly downregulated. These results indicated that cholestasis, especially the accumulation of DCA in the liver, is the primary factors responsible for Rosiglitazone induced hepatocyte injury. The mechanism of Rosiglitazone induced DCA accumulation in the liver may be the result of stimulated intestinal permeability and increased biosynthesis and uptake of DCA and weakening of DCA amidation to reduce DCA efflux due to the inhibition of OATP1A1 and OATP1A4 expression in the liver.http://www.sciencedirect.com/science/article/pii/S1878535223006044RosiglitazoneDrug-induced liver injuryHepatotoxicityTranscriptomeProteome |
| spellingShingle | Daopeng Tan Lei Ling Lin Qin Yanliu Lu Di Wu Yuqi He Rosiglitazone induces hepatocyte injury by increasing DCA accumulation through OATP1A4 inhibiting in mice Arabian Journal of Chemistry Rosiglitazone Drug-induced liver injury Hepatotoxicity Transcriptome Proteome |
| title | Rosiglitazone induces hepatocyte injury by increasing DCA accumulation through OATP1A4 inhibiting in mice |
| title_full | Rosiglitazone induces hepatocyte injury by increasing DCA accumulation through OATP1A4 inhibiting in mice |
| title_fullStr | Rosiglitazone induces hepatocyte injury by increasing DCA accumulation through OATP1A4 inhibiting in mice |
| title_full_unstemmed | Rosiglitazone induces hepatocyte injury by increasing DCA accumulation through OATP1A4 inhibiting in mice |
| title_short | Rosiglitazone induces hepatocyte injury by increasing DCA accumulation through OATP1A4 inhibiting in mice |
| title_sort | rosiglitazone induces hepatocyte injury by increasing dca accumulation through oatp1a4 inhibiting in mice |
| topic | Rosiglitazone Drug-induced liver injury Hepatotoxicity Transcriptome Proteome |
| url | http://www.sciencedirect.com/science/article/pii/S1878535223006044 |
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