School of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, People's Republic of China.
Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, Hebei, 050200, People's Republic of China.
Drug Des Devel Ther. 2023 Oct 3;17:3047-3060. doi: 10.2147/DDDT.S417378. eCollection 2023.
Metabolic associated fatty liver disease (MAFLD) is a chronic disease characterized by excessive lipid deposition in the liver without alcohol or other clear liver-damaging factors. AMP-activated protein kinase (AMPK)/silencing information regulator (SIRT)1 signaling pathway plays an important role in MAFLD development. Si-Ni-San (SNS), a traditional Chinese medicine, has shown reducing hepatic lipid deposition in MAFLD rats, however, the underlying mechanisms of SNS are barely understood.
The aim of this research was to investigate the mechanisms of SNS in reducing hepatic lipid deposition in MAFLD rats by regulating AMPK/SIRT1 signaling pathways.
The components of SNS were determined by high performance liquid chromatography with mass spectrometry (HPLC-MS) analysis. MAFLD rats were induced by high-fat and high-cholesterol diet (HFHCD), and treated by SNS. SNS-containing serum and Compound C (AMPK inhibitor) were used to treat palmitic acid (PA)-induced HepG2 cells. To elucidate the potential mechanism, lipid synthesis-related proteins (SREBP-1c and FAS), fatty acid oxidation (PPARα and CPT-1), and AMPK/SIRT1 signaling pathway (p-AMPK and SIRT1) were assessed by Western blot.
SNS improved serum lipid levels, liver function and reduced hepatic lipid deposition in MAFLD rats. SNS-containing serum reduced lipid deposition in PA-induced HepG2 cells. SNS could up-regulate protein expressions of PPARα, CPT-1, p-AMPK and SIRT1, and down-regulate protein expressions of SREBP-1c and FAS. Similar effects of SNS-containing serum were observed in PA-induced HepG2 cells. Meanwhile, Compound C weakened the therapeutic effects of SNS-containing serum on lipid deposition.
SNS could reduce hepatic lipid deposition by inhibiting lipid synthesis and promoting fatty acid oxidation, which might be related with activating the AMPK/SIRT1 signaling pathway. This study could provide a theoretical basis for the clinical use of SNS to treat MAFLD.
代谢相关脂肪性肝病（MAFLD）是一种以肝脏脂质过度沉积为特征的慢性疾病，不伴有饮酒或其他明确的肝损伤因素。AMP 激活的蛋白激酶（AMPK）/沉默信息调节因子（SIRT）1 信号通路在 MAFLD 的发生发展中起着重要作用。中药四逆散（SNS）已被证明可减少 MAFLD 大鼠的肝脂质沉积，但 SNS 的作用机制尚不清楚。
本研究旨在探讨 SNS 通过调节 AMPK/SIRT1 信号通路降低 MAFLD 大鼠肝脂质沉积的作用机制。
采用高效液相色谱-质谱联用（HPLC-MS）分析 SNS 的成分。采用高脂高胆固醇饮食（HFHCD）诱导 MAFLD 大鼠，并给予 SNS 治疗。用 SNS 含药血清和 Compound C（AMPK 抑制剂）处理棕榈酸（PA）诱导的 HepG2 细胞。采用 Western blot 检测脂质合成相关蛋白（SREBP-1c 和 FAS）、脂肪酸氧化（PPARα 和 CPT-1）以及 AMPK/SIRT1 信号通路（p-AMPK 和 SIRT1）的蛋白表达。
SNS 改善了 MAFLD 大鼠的血脂水平、肝功能，减少了肝脂质沉积。SNS 含药血清降低了 PA 诱导的 HepG2 细胞的脂质沉积。SNS 可上调 PPARα、CPT-1、p-AMPK 和 SIRT1 的蛋白表达，下调 SREBP-1c 和 FAS 的蛋白表达。SNS 含药血清在 PA 诱导的 HepG2 细胞中也有类似的作用。同时，Compound C 减弱了 SNS 含药血清对脂质沉积的治疗作用。
SNS 可通过抑制脂质合成和促进脂肪酸氧化来减少肝脂质沉积，这可能与激活 AMPK/SIRT1 信号通路有关。本研究可为 SNS 治疗 MAFLD 的临床应用提供理论依据。
