Li Hu, Liu Nan-Nan, Li Jian-Rui, Dong Biao, Wang Mei-Xi, Tan Jia-Li, Wang Xue-Kai, Jiang Jing, Lei Lei, Li Hong-Ying, Sun Han, Jiang Jian-Dong, Peng Zong-Gen
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Key Laboratory of Biotechnology of Antibiotics, The National Health and Family Planning Commission (NHFPC), Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Front Pharmacol. 2022 Feb 16;13:843872. doi: 10.3389/fphar.2022.843872. eCollection 2022.
Nonalcoholic fatty liver disease (NAFLD), ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), is a liver disease worldwide without approved therapeutic drugs. Anti-inflammatory and hepatoprotective drug bicyclol and multi-pharmacological active drug berberine, respectively, have shown beneficial effects on NAFLD in murine nutritional models and patients, though the therapeutic mechanisms remain to be illustrated. Here, we investigated the combined effects of bicyclol and berberine on mouse steatosis induced by Western diet (WD), and NASH induced by WD/CCl. The combined use of these was rather safe and better reduced the levels of transaminase in serum and triglycerides and cholesterol in the liver than their respective monotherapy, accompanied with more significantly attenuating hepatic inflammation, steatosis, and ballooning in mice with steatosis and NASH. The combined therapy also significantly inhibited fibrogenesis, characterized by the decreased hepatic collagen deposition and fibrotic surface. As per mechanism, bicyclol enhanced lipolysis and β-oxidation through restoring the p62-Nrf2-CES2 signaling axis and p62-Nrf2-PPARα signaling axis, respectively, while berberine suppressed lipogenesis through downregulating the expression of acetyl-CoA carboxylase and fatty acid synthetase, along with enrichment of lipid metabolism-related Bacteroidaceae (family) (genus). Of note, the combined use of bicyclol and berberine did not influence each other but enhanced the overall therapeutic role in the amelioration of NAFLD. : Combined use of bicyclol and berberine might be a new available strategy to treat NAFLD.
非酒精性脂肪性肝病（NAFLD），范围从单纯性脂肪变性到非酒精性脂肪性肝炎（NASH），是一种全球范围内都没有获批治疗药物的肝脏疾病。抗炎和保肝药物双环醇以及多药理活性药物黄连素，分别在小鼠营养模型和患者中对NAFLD显示出有益作用，尽管其治疗机制仍有待阐明。在此，我们研究了双环醇和黄连素联合使用对西方饮食（WD）诱导的小鼠脂肪变性以及WD/CCl诱导的NASH的影响。二者联合使用相当安全，与各自单一疗法相比，能更好地降低血清转氨酶水平以及肝脏中的甘油三酯和胆固醇水平，同时更显著地减轻脂肪变性和NASH小鼠的肝脏炎症、脂肪变性及气球样变。联合治疗还显著抑制了纤维化形成，其特征是肝脏胶原沉积减少和纤维化面积减小。就机制而言，双环醇分别通过恢复p62-Nrf2-CES2信号轴和p62-Nrf2-PPARα信号轴增强脂解作用和β-氧化，而黄连素通过下调乙酰辅酶A羧化酶和脂肪酸合成酶的表达抑制脂肪生成，同时富集与脂质代谢相关的拟杆菌科（家族）（属）。值得注意的是，双环醇和黄连素联合使用互不影响，但增强了改善NAFLD的整体治疗作用。双环醇和黄连素联合使用可能是治疗NAFLD的一种新的可行策略。
