Feng Bin, Huang Bin, Jing Yali, Shen Shanmei, Feng Wenhuan, Wang Weimin, Meng Ran, Zhu Dalong
Department of Endocrinology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China; Department of Endocrinology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China.
Department of Endocrinology, Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital, Nanjing, Jiangsu, China; Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China.
Cell Signal. 2021 Aug;84:110023. doi: 10.1016/j.cellsig.2021.110023. Epub 2021 Apr 24.
Obesity-induced insulin resistance is the principal cause of type 2 diabetes worldwide. The use of natural products for the treatment of diabetes is increasingly attracting attention. Silymarin (SLM) is a flavonolignan compound that has been shown to have promise for the treatment of diabetes. In the present study, we aimed to investigate the mechanisms underlying its therapeutic effects. C57BL/6 mice were fed a high-fat diet (HFD) for 12 weeks and then orally administered SLM (30 mg/kg) daily for 1 month. The effects of SLM were also investigated in HepG2 cells that had been rendered insulin resistant by palmitic acid (PA) treatment. SLM ameliorated the dyslipidemia, hepatic steatosis, and insulin resistance of the HFD-fed mice. HFD-feeding and PA treatment reduced the expression of sirtuin-1 (SIRT1) in the livers of the mice and in HepG2 cells, respectively. SLM increased the phosphorylation of AKT and FOXO1, and reduced the level of FOXO1 acetylation in PA-treated cells. However, SIRT1 knockdown by RNA interference reduced these effects of SLM. Moreover, the results of molecular dynamic simulation and in vitro activity assays indicated that SLM may directly bind to SIRT1 and increase its enzymatic activity. These findings suggest that hepatic SIRT1 may be an important pharmacological target of SLM and mediate effects on insulin resistance and gluconeogenesis, which may underlie its anti-diabetic activity.
肥胖诱导的胰岛素抵抗是全球2型糖尿病的主要病因。使用天然产物治疗糖尿病越来越受到关注。水飞蓟素（SLM）是一种黄酮木脂素化合物，已显示出治疗糖尿病的潜力。在本研究中，我们旨在探讨其治疗作用的潜在机制。给C57BL/6小鼠喂食高脂饮食（HFD）12周，然后每天口服SLM（30mg/kg），持续1个月。还在经棕榈酸（PA）处理而产生胰岛素抵抗的HepG2细胞中研究了SLM的作用。SLM改善了高脂饮食喂养小鼠的血脂异常、肝脂肪变性和胰岛素抵抗。高脂饮食喂养和PA处理分别降低了小鼠肝脏和HepG2细胞中沉默调节蛋白1（SIRT1）的表达。SLM增加了PA处理细胞中AKT和FOXO1的磷酸化，并降低了FOXO1的乙酰化水平。然而，通过RNA干扰敲低SIRT1可降低SLM的这些作用。此外，分子动力学模拟和体外活性测定结果表明，SLM可能直接与SIRT1结合并增加其酶活性。这些发现表明，肝脏SIRT1可能是SLM的一个重要药理学靶点，并介导其对胰岛素抵抗和糖异生的作用，这可能是其抗糖尿病活性的基础。
