S-Allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signaling

• 作者: Pingping Luo Ming Zheng Rui Zhang Hong Zhang Yingxia Liu Wei Li Xiaoming Sun Qian Yu George L.Tipoe Jia Xiao
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2021,（3）
• 所属期刊栏目: Original articles
• 页码范围: 668-679
• 页数: 12页
• 语种: 英文

摘要

Alcoholic liver disease(ALD)causes insulin resistance,lipid metabolism dysfunction,and inflammation.We investigated the protective effects and direct regulating target of S-allylmercaptocys-teine(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 demon-strated by histological,biochemical,and molecular biology assays.By using biophysical assays and mo-lecular 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-l/AKT signaling partly recovered he-patic 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.