Activation of the AMPK-SIRT1 pathway contributes to protective effects of Salvianolic acid A against lipotoxicity in hepatocytes and NAFLD in mice
Background: Salvianolic acid A (Sal A), a natural polyphenol compound extracted from Radix Salvia miltiorrhiza (known as Danshen in China), possesses a variety of potential pharmacological activities. The aim of this study is to determine mechanisms of hepatoprotective effects of Sal A against lipot...
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Frontiers Media S.A.
2020-11-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2020.560905/full |
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| author | Songtao Li Songtao Li Qianyu Qian Qianyu Qian Na Ying Jianfei Lai Luyan Feng Sitong Zheng Fusheng Jiang Fusheng Jiang Qing Song Qing Song Hui Chai Hui Chai Xiaobing Dou Xiaobing Dou |
| author_facet | Songtao Li Songtao Li Qianyu Qian Qianyu Qian Na Ying Jianfei Lai Luyan Feng Sitong Zheng Fusheng Jiang Fusheng Jiang Qing Song Qing Song Hui Chai Hui Chai Xiaobing Dou Xiaobing Dou |
| author_sort | Songtao Li |
| collection | DOAJ |
| description | Background: Salvianolic acid A (Sal A), a natural polyphenol compound extracted from Radix Salvia miltiorrhiza (known as Danshen in China), possesses a variety of potential pharmacological activities. The aim of this study is to determine mechanisms of hepatoprotective effects of Sal A against lipotoxicity both in cultured hepatocytes and in a mouse model of fatty liver disease.Methods: High-fat and high-carbohydrate diet (HFCD)-fed C57BL/6J mice were employed to establish hepatic lipotoxicity in a mouse model. Two doses of Sal A were administered every other day via intraperitoneal injection (20 and 40 mg/kg BW, respectively). After a 10-week intervention, liver injury was detected by immunohistochemical and biochemical analyses. For in vitro studies, we used HepG2, a human hepatoma cell line, and exposed them to palmitic acid to induce lipotoxicity. The protective effects of Sal A on palmitic acid-induced lipotoxicity were examined in Sal A-pretreated HepG2 cells.Results: Sal A treatments attenuated body weight gain, liver injury, and hepatic steatosis in mice exposed to HFCD. Sal A pretreatments ameliorated palmitic acid-induced cell death but did not reverse effects of HFCD- or palmitate-induced activations of JNK, ERK1/2, and PKA. Induction of p38 phosphorylation was significantly reversed by Sal A in HFCD-fed mice but not in palmitate-treated HepG2 cells. However, Sal A rescued hepatic AMP-activated protein kinase (AMPK) suppression and sirtuin 1 (SIRT1) downregulation by both HFCD feeding in mice and exposure to palmitate in HepG2 cells. Sal A dose-dependently up-regulated p-AMPK and SIRT1 protein levels. Importantly, siRNA silencing of either AMPK or SIRT1 gene expression abolished the protective effects of Sal A on lipotoxicity. Moreover, while AMPK silencing blocked Sal A-induced SIRT1, silencing of SIRT1 had no effect on Sal A-triggered AMPK activation, suggesting SIRT1 upregulation by Sal A is mediated by AMPK activation.Conclusion: Our data uncover a novel mechanism for hepatoprotective effects of Sal A against lipotoxicity both in livers from HFCD-fed mice and palmitic acid-treated hepatocytes. |
| first_indexed | 2024-12-14T15:48:20Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-14T15:48:20Z |
| publishDate | 2020-11-01 |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-34e32008501f406b9facc0f28bb4f9112022-12-21T22:55:25ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122020-11-011110.3389/fphar.2020.560905560905Activation of the AMPK-SIRT1 pathway contributes to protective effects of Salvianolic acid A against lipotoxicity in hepatocytes and NAFLD in miceSongtao Li0Songtao Li1Qianyu Qian2Qianyu Qian3Na Ying4Jianfei Lai5Luyan Feng6Sitong Zheng7Fusheng Jiang8Fusheng Jiang9Qing Song10Qing Song11Hui Chai12Hui Chai13Xiaobing Dou14Xiaobing Dou15College of Basic Medicine and Public Health, Zhejiang Chinese Medical University, Hangzhou, ChinaMolecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, ChinaMolecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, ChinaCollege of Life Science, Zhejiang Chinese Medical University, Hangzhou, ChinaCollege of Life Science, Zhejiang Chinese Medical University, Hangzhou, ChinaCollege of Life Science, Zhejiang Chinese Medical University, Hangzhou, ChinaCollege of Life Science, Zhejiang Chinese Medical University, Hangzhou, ChinaCollege of Life Science, Zhejiang Chinese Medical University, Hangzhou, ChinaMolecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, ChinaCollege of Life Science, Zhejiang Chinese Medical University, Hangzhou, ChinaMolecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, ChinaCollege of Life Science, Zhejiang Chinese Medical University, Hangzhou, ChinaMolecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, ChinaCollege of Life Science, Zhejiang Chinese Medical University, Hangzhou, ChinaMolecular Medicine Institute, Zhejiang Chinese Medical University, Hangzhou, ChinaCollege of Life Science, Zhejiang Chinese Medical University, Hangzhou, ChinaBackground: Salvianolic acid A (Sal A), a natural polyphenol compound extracted from Radix Salvia miltiorrhiza (known as Danshen in China), possesses a variety of potential pharmacological activities. The aim of this study is to determine mechanisms of hepatoprotective effects of Sal A against lipotoxicity both in cultured hepatocytes and in a mouse model of fatty liver disease.Methods: High-fat and high-carbohydrate diet (HFCD)-fed C57BL/6J mice were employed to establish hepatic lipotoxicity in a mouse model. Two doses of Sal A were administered every other day via intraperitoneal injection (20 and 40 mg/kg BW, respectively). After a 10-week intervention, liver injury was detected by immunohistochemical and biochemical analyses. For in vitro studies, we used HepG2, a human hepatoma cell line, and exposed them to palmitic acid to induce lipotoxicity. The protective effects of Sal A on palmitic acid-induced lipotoxicity were examined in Sal A-pretreated HepG2 cells.Results: Sal A treatments attenuated body weight gain, liver injury, and hepatic steatosis in mice exposed to HFCD. Sal A pretreatments ameliorated palmitic acid-induced cell death but did not reverse effects of HFCD- or palmitate-induced activations of JNK, ERK1/2, and PKA. Induction of p38 phosphorylation was significantly reversed by Sal A in HFCD-fed mice but not in palmitate-treated HepG2 cells. However, Sal A rescued hepatic AMP-activated protein kinase (AMPK) suppression and sirtuin 1 (SIRT1) downregulation by both HFCD feeding in mice and exposure to palmitate in HepG2 cells. Sal A dose-dependently up-regulated p-AMPK and SIRT1 protein levels. Importantly, siRNA silencing of either AMPK or SIRT1 gene expression abolished the protective effects of Sal A on lipotoxicity. Moreover, while AMPK silencing blocked Sal A-induced SIRT1, silencing of SIRT1 had no effect on Sal A-triggered AMPK activation, suggesting SIRT1 upregulation by Sal A is mediated by AMPK activation.Conclusion: Our data uncover a novel mechanism for hepatoprotective effects of Sal A against lipotoxicity both in livers from HFCD-fed mice and palmitic acid-treated hepatocytes.https://www.frontiersin.org/articles/10.3389/fphar.2020.560905/fullsalvianolic acid Aadenosine monophosphate activated protein kinasesirtuin 1lipotoxicitynon-alcoholic fatty liver disease |
| spellingShingle | Songtao Li Songtao Li Qianyu Qian Qianyu Qian Na Ying Jianfei Lai Luyan Feng Sitong Zheng Fusheng Jiang Fusheng Jiang Qing Song Qing Song Hui Chai Hui Chai Xiaobing Dou Xiaobing Dou Activation of the AMPK-SIRT1 pathway contributes to protective effects of Salvianolic acid A against lipotoxicity in hepatocytes and NAFLD in mice Frontiers in Pharmacology salvianolic acid A adenosine monophosphate activated protein kinase sirtuin 1 lipotoxicity non-alcoholic fatty liver disease |
| title | Activation of the AMPK-SIRT1 pathway contributes to protective effects of Salvianolic acid A against lipotoxicity in hepatocytes and NAFLD in mice |
| title_full | Activation of the AMPK-SIRT1 pathway contributes to protective effects of Salvianolic acid A against lipotoxicity in hepatocytes and NAFLD in mice |
| title_fullStr | Activation of the AMPK-SIRT1 pathway contributes to protective effects of Salvianolic acid A against lipotoxicity in hepatocytes and NAFLD in mice |
| title_full_unstemmed | Activation of the AMPK-SIRT1 pathway contributes to protective effects of Salvianolic acid A against lipotoxicity in hepatocytes and NAFLD in mice |
| title_short | Activation of the AMPK-SIRT1 pathway contributes to protective effects of Salvianolic acid A against lipotoxicity in hepatocytes and NAFLD in mice |
| title_sort | activation of the ampk sirt1 pathway contributes to protective effects of salvianolic acid a against lipotoxicity in hepatocytes and nafld in mice |
| topic | salvianolic acid A adenosine monophosphate activated protein kinase sirtuin 1 lipotoxicity non-alcoholic fatty liver disease |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2020.560905/full |
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