Department of Endocrinology and Metabolism, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai National Clinical Research Center for metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
FASEB J. 2020 Sep;34(9):13033-13048. doi: 10.1096/fj.202000546R. Epub 2020 Aug 10.
The increasing prevalence of nonalcoholic fatty liver disease (NAFLD) worldwide indicates the urgent need to develop novel and effective treatment strategies. Betulinic acid (BA), a naturally occurring plant-derived pentacyclic triterpenoid, has an outstanding effect in improving metabolism. However, the pharmacological action and mechanism of BA in NAFLD remain unclear. Here, we show that BA-treated high-fat diet mice and methionine-choline deficient diet-fed mice are resistant to hepatic steatosis when compared with vehicle-treated mice. BA alleviates fatty acid synthesis, fibrosis, and inflammation and promotes fatty acid oxidation. Meanwhile, fatty acid synthase (FAS) expression and activity are markedly inhibited with BA treatment both in vitro and in vivo. Moreover, BA inhibits FAS expression through transcriptional suppression of Yin Yang 1 (YY1), leading to retard hepatocytes triglyceride accumulation. Collectively, BA protects hepatocytes from abnormal lipid deposition in NAFLD through YY1/FAS pathway. Our findings establish a novel role of BA in representing a possible therapeutic strategy to reverse NAFLD.
非酒精性脂肪性肝病（NAFLD）在全球范围内的患病率不断上升，表明迫切需要开发新的有效治疗策略。白桦脂酸（BA）是一种天然存在的植物衍生五环三萜，在改善代谢方面具有出色的效果。然而，BA 在 NAFLD 中的药理作用和机制尚不清楚。在这里，我们发现与载体处理的小鼠相比，BA 处理的高脂肪饮食小鼠和蛋氨酸-胆碱缺乏饮食喂养的小鼠对肝脂肪变性具有抗性。BA 可减轻脂肪酸合成、纤维化和炎症，并促进脂肪酸氧化。同时，BA 在体外和体内均显著抑制脂肪酸合酶（FAS）的表达和活性。此外，BA 通过转录抑制 Yin Yang 1（YY1）抑制 FAS 的表达，导致肝细胞甘油三酯积累减少。总之，BA 通过 YY1/FAS 通路保护肝细胞免受 NAFLD 中异常脂质沉积的影响。我们的研究结果确立了 BA 在代表一种可能的治疗策略以逆转 NAFLD 方面的新作用。
