Supplementation with Branched-Chain Amino Acids Induces Unexpected Deleterious Effects on Astrocyte Survival and Intracellular Metabolism with or without Hyperammonemia: A Preliminary In Vitro Study
Introduction. Ammonia is a key component in the pathogenesis of hepatic encephalopathy. Branched-chain amino acids (BCAA) have been reported to improve the symptoms of HE induced by hyperammonemia; however, we recently reported that ammonia increases intracellular levels of BCAA and exerts toxic eff...
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| Format: | Article |
| Language: | English |
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Wiley
2021-01-01
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| Series: | International Journal of Hepatology |
| Online Access: | http://dx.doi.org/10.1155/2021/7615126 |
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| author | Ting Wang Kazuyuki Suzuki Toshimi Chiba Keisuke Kakisaka Yasuhiro Takikawa |
| author_facet | Ting Wang Kazuyuki Suzuki Toshimi Chiba Keisuke Kakisaka Yasuhiro Takikawa |
| author_sort | Ting Wang |
| collection | DOAJ |
| description | Introduction. Ammonia is a key component in the pathogenesis of hepatic encephalopathy. Branched-chain amino acids (BCAA) have been reported to improve the symptoms of HE induced by hyperammonemia; however, we recently reported that ammonia increases intracellular levels of BCAA and exerts toxic effects on astrocytes. Objectives. This follow-up study was designed to confirm the direct effects of BCAA on human astrocytes and clarify their underlying mechanisms using metabolome analysis and evaluation of associated signaling. Methods. We performed cytotoxicity and cell proliferation tests on astrocytes following BCAA treatment with and without ammonium chloride (NH4Cl) and then compared the results with the effects of BCAA on hepatocytes and neurons. Subsequently, we used metabolomic analysis to investigate intracellular metabolite levels in astrocytes with and without BCAA treatment. Results. The astrocytes showed increased leakage of intracellular lactate dehydrogenase and reduced proliferation rate upon BCAA treatment. Interestingly, our analysis showed a BCAA-induced impairment of intracellular glycolysis/glyconeogenesis as well as amino acid and butyric acid metabolism. Furthermore, BCAA treatment was found to cause decreased levels of Glut-1 and phosphorylated GSK-3β and mTOR in astrocytes. Conclusions. Although further investigations of the effect of BCAA on human astrocytes with hyperammonemia are needed, our work demonstrates that BCAA supplementation has direct negative effects on astrocyte survival and intracellular metabolism. |
| format | Article |
| id | doaj-art-ead595f60fe9451ca7387fea69871ee0 |
| institution | Kabale University |
| issn | 2090-3448 2090-3456 |
| language | English |
| publishDate | 2021-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | International Journal of Hepatology |
| spelling | doaj-art-ead595f60fe9451ca7387fea69871ee02025-02-03T07:24:04ZengWileyInternational Journal of Hepatology2090-34482090-34562021-01-01202110.1155/2021/76151267615126Supplementation with Branched-Chain Amino Acids Induces Unexpected Deleterious Effects on Astrocyte Survival and Intracellular Metabolism with or without Hyperammonemia: A Preliminary In Vitro StudyTing Wang0Kazuyuki Suzuki1Toshimi Chiba2Keisuke Kakisaka3Yasuhiro Takikawa4Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Iwate, JapanDivision of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Iwate, JapanDivision of Internal Medicine, Department of Oral Medicine, Iwate Medical University, Morioka, Iwate, JapanDivision of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Iwate, JapanDivision of Hepatology, Department of Internal Medicine, Iwate Medical University, Morioka, Iwate, JapanIntroduction. Ammonia is a key component in the pathogenesis of hepatic encephalopathy. Branched-chain amino acids (BCAA) have been reported to improve the symptoms of HE induced by hyperammonemia; however, we recently reported that ammonia increases intracellular levels of BCAA and exerts toxic effects on astrocytes. Objectives. This follow-up study was designed to confirm the direct effects of BCAA on human astrocytes and clarify their underlying mechanisms using metabolome analysis and evaluation of associated signaling. Methods. We performed cytotoxicity and cell proliferation tests on astrocytes following BCAA treatment with and without ammonium chloride (NH4Cl) and then compared the results with the effects of BCAA on hepatocytes and neurons. Subsequently, we used metabolomic analysis to investigate intracellular metabolite levels in astrocytes with and without BCAA treatment. Results. The astrocytes showed increased leakage of intracellular lactate dehydrogenase and reduced proliferation rate upon BCAA treatment. Interestingly, our analysis showed a BCAA-induced impairment of intracellular glycolysis/glyconeogenesis as well as amino acid and butyric acid metabolism. Furthermore, BCAA treatment was found to cause decreased levels of Glut-1 and phosphorylated GSK-3β and mTOR in astrocytes. Conclusions. Although further investigations of the effect of BCAA on human astrocytes with hyperammonemia are needed, our work demonstrates that BCAA supplementation has direct negative effects on astrocyte survival and intracellular metabolism.http://dx.doi.org/10.1155/2021/7615126 |
| spellingShingle | Ting Wang Kazuyuki Suzuki Toshimi Chiba Keisuke Kakisaka Yasuhiro Takikawa Supplementation with Branched-Chain Amino Acids Induces Unexpected Deleterious Effects on Astrocyte Survival and Intracellular Metabolism with or without Hyperammonemia: A Preliminary In Vitro Study International Journal of Hepatology |
| title | Supplementation with Branched-Chain Amino Acids Induces Unexpected Deleterious Effects on Astrocyte Survival and Intracellular Metabolism with or without Hyperammonemia: A Preliminary In Vitro Study |
| title_full | Supplementation with Branched-Chain Amino Acids Induces Unexpected Deleterious Effects on Astrocyte Survival and Intracellular Metabolism with or without Hyperammonemia: A Preliminary In Vitro Study |
| title_fullStr | Supplementation with Branched-Chain Amino Acids Induces Unexpected Deleterious Effects on Astrocyte Survival and Intracellular Metabolism with or without Hyperammonemia: A Preliminary In Vitro Study |
| title_full_unstemmed | Supplementation with Branched-Chain Amino Acids Induces Unexpected Deleterious Effects on Astrocyte Survival and Intracellular Metabolism with or without Hyperammonemia: A Preliminary In Vitro Study |
| title_short | Supplementation with Branched-Chain Amino Acids Induces Unexpected Deleterious Effects on Astrocyte Survival and Intracellular Metabolism with or without Hyperammonemia: A Preliminary In Vitro Study |
| title_sort | supplementation with branched chain amino acids induces unexpected deleterious effects on astrocyte survival and intracellular metabolism with or without hyperammonemia a preliminary in vitro study |
| url | http://dx.doi.org/10.1155/2021/7615126 |
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