Silymarin ameliorates the disordered glucose metabolism of mice with diet-induced obesity by activating the hepatic SIRT1 pathway
Silymarin ameliorates the disordered glucose metabolism of mice with diet-induced obesity by activating the hepatic SIRT1 pathway
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水飞蓟素通过激活肝脏 SIRT1 通路改善饮食诱导肥胖小鼠的葡萄糖代谢紊乱
DOI：
10.1016/j.cellsig.2021.110023
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发表时间：
2021-04-28
影响因子：
4.8
通讯作者：
Zhu, Dalong
中科院分区：
文献类型：
--
作者：
Feng, Bin;Huang, Bin;Zhu, Dalong
肥胖引起的胰岛素抵抗是世界范围内2型糖尿病的主要原因。使用天然产品治疗糖尿病正日益引起人们的注意。水飞蓟素(SLM)是一种黄酮类化合物，已被证明有希望用于糖尿病的治疗。在本研究中，我们旨在探讨其治疗作用的机制。C57BL/6小鼠喂饲高脂饲料12周后，每天灌胃给予SLM(30 mg/kg)，连续1个月。此外，还研究了SLM对经棕榈酸(PA)处理后出现胰岛素抵抗的HepG2细胞的影响。SLM可改善高脂饲料喂养小鼠的血脂异常、肝脏脂肪变性和胰岛素抵抗。高脂饲料喂养和PA处理分别降低了小鼠肝脏和HepG2细胞中sirtuin-1(SIRT1)的表达。SLM使PA2细胞AKT和FOXO1的磷酸化水平增加，FOXO1乙酰化水平降低。然而，通过RNA干扰敲除SIRT1可以减少SLM的这些作用。此外，分子动力学模拟和体外活性测定的结果表明，SLM可以直接与SIRT1结合，提高其酶活性。这些结果提示，肝脏SIRT1可能是SLM的一个重要药理作用靶点，并介导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。
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 PAtreated 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.