S-Allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signaling
Alcoholic liver disease (ALD) causes insulin resistance, lipid metabolism dysfunction, and inflammation. We investigated the protective effects and direct regulating target of S-allylmercaptocysteine (SAMC) from aged garlic on liver cell injury. A chronic ethanol-fed ALD in vivo model (the NIAAA mod...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-03-01
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| Series: | Acta Pharmaceutica Sinica B |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211383520307978 |
| _version_ | 1828242358785802240 |
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| author | Pingping Luo Ming Zheng Rui Zhang Hong Zhang Yingxia Liu Wei Li Xiaoming Sun Qian Yu George L. Tipoe Jia Xiao |
| author_facet | Pingping Luo Ming Zheng Rui Zhang Hong Zhang Yingxia Liu Wei Li Xiaoming Sun Qian Yu George L. Tipoe Jia Xiao |
| author_sort | Pingping Luo |
| collection | DOAJ |
| description | Alcoholic liver disease (ALD) causes insulin resistance, lipid metabolism dysfunction, and inflammation. We investigated the protective effects and direct regulating target of S-allylmercaptocysteine (SAMC) from aged garlic on liver cell injury. A chronic ethanol-fed ALD in vivo model (the NIAAA model) was used to test the protective functions of SAMC. It was observed that SAMC (300 mg/kg, by gavage method) effectively ameliorated ALD-induced body weight reduction, steatosis, insulin resistance, and inflammation without affecting the health status of the control mice, as demonstrated by histological, biochemical, and molecular biology assays. By using biophysical assays and molecular docking, we demonstrated that SAMC directly targeted insulin receptor (INSR) protein on the cell membrane and then restored downstream IRS-1/AKT/GSK3β signaling. Liver-specific knock-down in mice and siRNA-mediated knock-down in AML-12 cells of Insr significantly impaired SAMC (250 μmol/L in cells)-mediated protection. Restoration of the IRS-1/AKT signaling partly recovered hepatic injury and further contributed to SAMC's beneficial effects. Continuous administration of AKT agonist and recombinant IGF-1 in combination with SAMC showed hepato-protection in the mice model. Long-term (90-day) administration of SAMC had no obvious adverse effect on healthy mice. We conclude that SAMC is an effective and safe hepato-protective complimentary agent against ALD partly through the direct binding of INSR and partial regulation of the IRS-1/AKT/GSK3β pathway. |
| first_indexed | 2024-04-12T22:13:59Z |
| format | Article |
| id | doaj.art-3bef314cd3574216b1bc73684a9dc5ba |
| institution | Directory Open Access Journal |
| issn | 2211-3835 |
| language | English |
| last_indexed | 2024-04-12T22:13:59Z |
| publishDate | 2021-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Acta Pharmaceutica Sinica B |
| spelling | doaj.art-3bef314cd3574216b1bc73684a9dc5ba2022-12-22T03:14:37ZengElsevierActa Pharmaceutica Sinica B2211-38352021-03-01113668679S-Allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signalingPingping Luo0Ming Zheng1Rui Zhang2Hong Zhang3Yingxia Liu4Wei Li5Xiaoming Sun6Qian Yu7George L. Tipoe8Jia Xiao9Clinical Medicine Research Institute, the First Affiliated Hospital of Jinan University, Guangzhou 510632, ChinaDepartment of Interventional Surgery, the First Affiliated Hospital of Jinan University, Guangzhou 510632, ChinaClinical Medicine Research Institute, the First Affiliated Hospital of Jinan University, Guangzhou 510632, ChinaDepartment of Interventional Surgery, the First Affiliated Hospital of Jinan University, Guangzhou 510632, ChinaState Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen 518000, ChinaFaculty of Pharmaceutical Sciences, Toho University, Chiba 2748510, JapanSchool of Integrative Pharmacy, Institute of Integrative Pharmaceutical Research, Guangdong Pharmaceutical University, Guangzhou 510000, ChinaSchool of Biomedical Sciences, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong 999077, ChinaSchool of Biomedical Sciences, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong 999077, China; Corresponding authors. Tel./fax: +86 20 85225180.Clinical Medicine Research Institute, the First Affiliated Hospital of Jinan University, Guangzhou 510632, China; School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong 999077, China; Corresponding authors. Tel./fax: +86 20 85225180.Alcoholic liver disease (ALD) causes insulin resistance, lipid metabolism dysfunction, and inflammation. We investigated the protective effects and direct regulating target of S-allylmercaptocysteine (SAMC) from aged garlic on liver cell injury. A chronic ethanol-fed ALD in vivo model (the NIAAA model) was used to test the protective functions of SAMC. It was observed that SAMC (300 mg/kg, by gavage method) effectively ameliorated ALD-induced body weight reduction, steatosis, insulin resistance, and inflammation without affecting the health status of the control mice, as demonstrated by histological, biochemical, and molecular biology assays. By using biophysical assays and molecular docking, we demonstrated that SAMC directly targeted insulin receptor (INSR) protein on the cell membrane and then restored downstream IRS-1/AKT/GSK3β signaling. Liver-specific knock-down in mice and siRNA-mediated knock-down in AML-12 cells of Insr significantly impaired SAMC (250 μmol/L in cells)-mediated protection. Restoration of the IRS-1/AKT signaling partly recovered hepatic injury and further contributed to SAMC's beneficial effects. Continuous administration of AKT agonist and recombinant IGF-1 in combination with SAMC showed hepato-protection in the mice model. Long-term (90-day) administration of SAMC had no obvious adverse effect on healthy mice. We conclude that SAMC is an effective and safe hepato-protective complimentary agent against ALD partly through the direct binding of INSR and partial regulation of the IRS-1/AKT/GSK3β pathway.http://www.sciencedirect.com/science/article/pii/S2211383520307978Alcoholic liver diseaseS-AllylmercaptocysteineInsulin receptorInsulin resistanceIRS-1AKT |
| spellingShingle | Pingping Luo Ming Zheng Rui Zhang Hong Zhang Yingxia Liu Wei Li Xiaoming Sun Qian Yu George L. Tipoe Jia Xiao S-Allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signaling Acta Pharmaceutica Sinica B Alcoholic liver disease S-Allylmercaptocysteine Insulin receptor Insulin resistance IRS-1 AKT |
| title | S-Allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signaling |
| title_full | S-Allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signaling |
| title_fullStr | S-Allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signaling |
| title_full_unstemmed | S-Allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signaling |
| title_short | S-Allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signaling |
| title_sort | s allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signaling |
| topic | Alcoholic liver disease S-Allylmercaptocysteine Insulin receptor Insulin resistance IRS-1 AKT |
| url | http://www.sciencedirect.com/science/article/pii/S2211383520307978 |
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