S-Allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signaling.
S-Allylmercaptocysteine improves alcoholic liver disease partly through a direct modulation of insulin receptor signaling.
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DOI：
10.1016/j.apsb.2020.11.006
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Xiao J
中科院分区：
文献类型：
--
作者：
Luo P;Zheng M;Zhang R;Zhang H;Liu Y;Li W;Sun X;Yu Q;Tipoe GL;Xiao J
酒精性肝病（ALD）会导致胰岛素抵抗、脂质代谢功能障碍和炎症。我们研究了陈蒜中的S-烯丙基硫代半胱氨酸（SAMC）对肝细胞损伤的保护作用及其直接调控靶点。使用慢性乙醇喂养的 ALD 体内模型（NIAAA 模型）来测试 SAMC 的保护功能。组织学、生化和分子生物学检测表明，SAMC（300 mg/kg，通过灌胃法）可有效改善 ALD 诱导的体重减轻、脂肪变性、胰岛素抵抗和炎症，而不影响对照小鼠的健康状况。通过使用生物物理测定和分子对接，我们证明SAMC直接靶向细胞膜上的胰岛素受体（INSR）蛋白，然后恢复下游IRS-1/AKT/GSK3β信号传导。小鼠肝脏特异性敲低和 siRNA 介导的 Insr AML-12 细胞敲低显着损害了 SAMC（细胞中 250 μmol/L）介导的保护。 IRS-1/AKT 信号传导的恢复部分恢复了肝损伤，并进一步促进了 SAMC 的有益作用。 AKT 激动剂和重组 IGF-1 与 SAMC 联合连续给药在小鼠模型中显示出肝保护作用。长期（90天）服用SAMC对健康小鼠没有明显的不良影响。我们得出的结论是，SAMC 是一种有效且安全的抗 ALD 保肝补充药物，部分通过 INSR 的直接结合和 IRS-1/AKT/GSK3β 途径的部分调节。 S-烯丙基巯基半胱氨酸是一种从陈蒜中提取的水溶性成分，是一种有效且安全的保肝补充剂，可部分通过直接调节胰岛素受体信号传导来对抗酒精性肝病。
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. S-Allylmercaptocysteine, a water-soluble component extracted from aged garlic, is an effective and safe hepato-protective complimentary agent against alcoholic liver disease partly through a direct modulation of insulin receptor signaling.
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