Department of Pharmacology of Chinese Materia Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.
Department of Pharmacognosy, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.
FASEB J. 2024 Oct 15;38(19):e70095. doi: 10.1096/fj.202400961R.
Bergenin is the main active ingredient of Bergenia purpurascens, a medicinal plant which has long been used to treat a variety of Th17 cell-related diseases in China, such as allergic airway inflammation and colitis. This study aimed to uncover the underlying mechanisms by which bergenin impedes Th17 cell response in view of cellular metabolism. In vitro, bergenin treatment reduced the frequency of Th17 cells generated from naïve CD4 T cells of mice. Mechanistically, bergenin preferentially restrained fatty acid synthesis (FAS) but not other metabolic pathways in differentiating Th17 cells, and exogenous addition of either palmitic acid (PA) or oleic acid (OA) and combination with acetyl-CoA carboxylase 1 (ACC1) activator citric acid dampened the inhibition of bergenin on Th17 cell differentiation. Bergenin inhibited FAS through downregulating the expression of SREBP1 via restriction of histone H3K27 acetylation in the SREBP1 promoter, and SREBP1 overexpression weakened the inhibition of bergenin on Th17 differentiation. Furthermore, bergenin was shown to directly interact with SIRT1 and result in activation of SIRT1. Either combination with SIRT1 inhibitor EX527 or point mutation plasmid of SIRT1 diminished the inhibitory effect of bergenin on FAS and Th17 cell differentiation. Finally, the inhibitory effect of bergenin on Th17 cell response and SIRT1 dependence were verified in mice with dextran sulfate sodium-induced colitis. In short, bergenin repressed Th17 cell response by downregulating FAS via activation of SIRT1, which might find therapeutic use in Th17 cell-related diseases.
没食子酰基 Bergenin 是中药雪胆的主要活性成分，长期以来，雪胆被用于治疗中国的多种与 Th17 细胞相关的疾病，如过敏性气道炎症和结肠炎。本研究旨在从细胞代谢的角度揭示 Bergenin 抑制 Th17 细胞反应的潜在机制。在体外， Bergenin 处理可降低从小鼠幼稚 CD4 T 细胞中产生的 Th17 细胞的频率。从机制上讲，Bergenin 优先限制分化中的 Th17 细胞中的脂肪酸合成 (FAS)，但不限制其他代谢途径，外源性添加棕榈酸 (PA)或油酸 (OA)以及与乙酰辅酶 A 羧化酶 1 (ACC1)激活剂柠檬酸组合可减弱 Bergenin 对 Th17 细胞分化的抑制作用。Bergenin 通过限制 SREBP1 启动子中组蛋白 H3K27 的乙酰化来下调 SREBP1 的表达，从而抑制 FAS，并且 SREBP1 的过表达减弱了 Bergenin 对 Th17 分化的抑制作用。此外，Bergenin 被证明可直接与 SIRT1 相互作用，从而激活 SIRT1。SIRT1 抑制剂 EX527 的组合或 SIRT1 的点突变质粒均可减弱 Bergenin 对 FAS 和 Th17 细胞分化的抑制作用。最后，在葡聚糖硫酸钠诱导的结肠炎小鼠中验证了 Bergenin 对 Th17 细胞反应的抑制作用和 SIRT1 的依赖性。总之，Bergenin 通过激活 SIRT1 下调 FAS 来抑制 Th17 细胞反应，这可能在与 Th17 细胞相关的疾病中具有治疗作用。
