School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China.
School of Basic Medical Science, Nanjing Medical University, Nanjing, China.
Phytother Res. 2022 Jan;36(1):433-447. doi: 10.1002/ptr.7344. Epub 2021 Dec 2.
Nonalcoholic fatty liver disease is the most prevalent liver disease characterized by excessive lipid accumulation in hepatocytes. Endoplasmic reticulum (ER) stress and autophagy play an important role in lipid accumulation. In this study, scutellarin (Scu) was examined in palmitic acid-treated HepG2 cells and C57/BL6 mice fed a high-fat diet (HFD). Scu reduced intracellular lipid content and inhibited sterol regulatory element binding protein-1c (SREBP-1c)-mediated lipid synthesis and fatty acid translocase-mediated lipid uptake in HepG2 cells. Additionally, Scu restored impaired autophagy and inhibited excessive activation of ER stress in vivo and in vitro. Moreover, Scu upregulated forkhead box O transcription factor 1-mediated autophagy by inhibiting inositol-requiring enzyme 1α (IRE1α)/X-box-binding protein 1 (XBP1) branch activation, while XBP1s overexpression exacerbated the lipid accumulation and impaired autophagy in HepG2 cells and also weakened the positive effects of Scu. Furthermore, Scu attenuated ER stress by activating autophagy, ultimately downregulating SREBP-1c-mediated lipid synthesis, and autophagy inhibitors offset these beneficial effects. Scu inhibited the crosstalk between autophagy and ER stress and downregulated saturated fatty acid-induced lipid accumulation in hepatocytes. These findings demonstrate that Scu ameliorates hepatic lipid accumulation by enhancing autophagy and suppressing ER stress via the IRE1α/XBP1 pathway.
非酒精性脂肪性肝病是最常见的肝脏疾病，其特征是肝细胞内脂质蓄积过多。内质网（ER）应激和自噬在脂质蓄积中起重要作用。在这项研究中，研究了野黄芩苷（Scu）在棕榈酸处理的 HepG2 细胞和高脂肪饮食（HFD）喂养的 C57/BL6 小鼠中的作用。Scu 降低了细胞内脂质含量，并抑制了固醇调节元件结合蛋白-1c（SREBP-1c）介导的脂质合成和脂肪酸易位酶介导的脂质摄取。此外，Scu 在体内和体外恢复了受损的自噬，并抑制了 ER 应激的过度激活。此外，Scu 通过抑制肌醇需求酶 1α（IRE1α）/X 盒结合蛋白 1（XBP1）分支激活而上调叉头框 O 转录因子 1 介导的自噬，而过表达 XBP1s 加剧了 HepG2 细胞中的脂质蓄积和自噬受损，也削弱了 Scu 的积极作用。此外，Scu 通过激活自噬来减轻 ER 应激，最终下调 SREBP-1c 介导的脂质合成，自噬抑制剂抵消了这些有益作用。Scu 抑制了自噬和 ER 应激之间的串扰，并下调了饱和脂肪酸诱导的肝细胞内脂质蓄积。这些发现表明，Scu 通过 IRE1α/XBP1 通路增强自噬和抑制 ER 应激来改善肝脏脂质蓄积。
