School of Chinese Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing, 100029, China.
School of Life Sciences, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing, 100029, China.
Phytomedicine. 2022 Aug;103:154219. doi: 10.1016/j.phymed.2022.154219. Epub 2022 May 29.
Metabolic associated fatty liver disease (MAFLD) is a progressive chronic liver disease, yet there is still a lack of effective pharmacological therapies at present. Saikosaponin D (SSd) has been reported to exhibit hepatoprotective and anti-steatosis activities in our previous research.
The current study aims to further investigate the underlying mechanisms of SSd on MAFLD from the perspectives of the crosstalk between fatty acid (FA) biosynthesis and catabolism to provide strong support for further clinical management of MAFLD.
A MAFLD mouse model induced by a high-fat diet and glucose-fructose water (HFSW) was used for in vivo study. HepG2 cells, primary mouse hepatocytes and adipocytes were further employed for in vitro studies.
SSd improved intracellular lipid accumulation both in the liver and adipose tissues in HFSW-fed mice. Mechanistically, SSd may serve as a potent PPARα agonist, and the activation of PPARα by SSd in both hepatocytes and adipocytes not only promoted FA oxidation but also concurrently induced INSIG1/2 expression, which subsequently inhibited SREBP1c maturation and ultimately FA synthesis. Moreover, the regulative effect of SSd on lipid metabolism was abolished by the PPARα inhibitor, GW6471.
This study demonstrated that SSd improved lipid homeostasis by coordinately regulating PPARα activation-mediated both inhibition of SREBP1c-dependent FA biosynthesis and induction of FA degradation, and thus shed novel light on the discovery of SSd-based therapeutic strategies for MAFLD.
代谢相关脂肪性肝病（MAFLD）是一种进行性慢性肝病，但目前仍然缺乏有效的药物治疗方法。我们之前的研究表明柴胡皂苷 D（SSd）具有保肝和抗脂肪变性作用。
本研究旨在从脂肪酸（FA）合成与分解的相互作用角度进一步探讨 SSd 对 MAFLD 的作用机制，为进一步临床管理 MAFLD 提供有力支持。
采用高脂肪饮食和葡萄糖-果糖水（HFSW）诱导的 MAFLD 小鼠模型进行体内研究。进一步使用 HepG2 细胞、原代小鼠肝细胞和脂肪细胞进行体外研究。
SSd 改善了 HFSW 喂养小鼠肝脏和脂肪组织中的细胞内脂质积累。在机制上，SSd 可能作为一种有效的 PPARα 激动剂，SSd 在肝细胞和脂肪细胞中激活 PPARα 不仅促进 FA 氧化，而且同时诱导 INSIG1/2 表达，从而抑制 SREBP1c 成熟，最终抑制 FA 合成。此外，PPARα 抑制剂 GW6471 可消除 SSd 对脂质代谢的调节作用。
本研究表明，SSd 通过协调调节 PPARα 激活介导的 SREBP1c 依赖性 FA 生物合成抑制和 FA 降解诱导，改善了脂质稳态，为发现基于 SSd 的 MAFLD 治疗策略提供了新的思路。
