Original articles
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[J]. Acta Pharmaceutica Sinica B, 2021, 11(3): 668-679

S-Allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signaling
Pingping Luoa, Ming Zhengb, Rui Zhanga, Hong Zhangb, Yingxia Liuc, Wei Lid, Xiaoming Sune, Qian Yuf, George L. Tipoef, Jia Xiaoa,f
a Clinical Medicine Research Institute, the First Affiliated Hospital of Jinan University, Guangzhou 510632, China;
b Department of Interventional Surgery, the First Affiliated Hospital of Jinan University, Guangzhou 510632, China;
c State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen 518000, China;
d Faculty of Pharmaceutical Sciences, Toho University, Chiba 2748510, Japan;
e School of Integrative Pharmacy, Institute of Integrative Pharmaceutical Research, Guangdong Pharmaceutical University, Guangzhou 510000, China;
f School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong 999077, China
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.
Key words:    Alcoholic liver disease    S-Allylmercaptocysteine    Insulin receptor    Insulin resistance    IRS-1    AKT    GSK3β    Safety   
Received: 2020-06-29     Revised: 2020-08-31
DOI: 10.1016/j.apsb.2020.11.006
Funds: This work was supported by National Natural Science Foundation of China (81970515) and Guangdong Natural Science Funds for Distinguished Young Scholar (2019B151502013, China).
Corresponding author: George L. Tipoe, Jia Xiao     Email:edwinsiu@connect.hku.hk;tgeorge@hku.hk
Author description:
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Pingping Luo
Ming Zheng
Rui Zhang
Hong Zhang
Yingxia Liu
Wei Li
Xiaoming Sun
Qian Yu
George L. Tipoe
Jia Xiao

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