He Huan, Chai Xue, Li Juan, Li Changsheng, Wu Xinran, Ye Xiaoli, Ma Hang, Li Xuegang
Engineering Research Center of Coptis Development and Utilization, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, China.
School of Life Sciences, Southwest University, Chongqing 400715, China.
Life Sci. 2023 May 15;321:121595. doi: 10.1016/j.lfs.2023.121595. Epub 2023 Mar 20.
Nonalcoholic steatohepatitis (NASH) is becoming one of the most common causes of liver transplantation and hepatocellular carcinoma, but no specific drugs are FDA-approved to treat it. 8-cetylberberine (CBBR), which is a long-chain alkane derivative of berberine, exhibits potent pharmacological activities and improves metabolism performance. The aim of this study is to explore the function and mechanism of CBBR against NASH.
L02 and HepG2 hepatocytes were treated with the medium containing palmitic acids and oleic acids (PO) and incubated with CBBR for 12 h, then the levels of lipid accumulation were tested by kits or western blots. C57BL/6 J mice were fed with a high-fat diet or a high-fat/high-cholesterol diet. CBBR (15 mg/kg or 30 mg/kg) was orally administered for 8 weeks. Liver weight, steatosis, inflammation, and fibrosis were evaluated. Transcriptomic indicated the target of CBBR in NASH.
CBBR significantly reduced lipid accumulation, inflammation, liver injury, and fibrosis in NASH mice. CBBR also decreased lipid accumulation and inflammation in PO-induced L02 and HepG2 cells. RNA sequencing and bioinformatics analysis indicated that CBBR inhibited the pathways and key regulators associated with lipid accumulation, inflammation, and fibrosis in the pathogenesis of NASH. Mechanically, CBBR may prevent NASH via inhibiting LCN2, as proved by the finding that the anti-NASH effect of CBBR was more obvious in PO-stimulated HepG2 cells treated with LCN2 overexpression.
Our work provides an insight into the effectiveness of CBBR in improving metabolic-stress-caused NASH as well as the mechanism by regulating LCN2.
非酒精性脂肪性肝炎（NASH）正成为肝移植和肝细胞癌最常见的病因之一，但尚无FDA批准的特异性药物用于治疗。8-十六烷基小檗碱（CBBR）是小檗碱的长链烷烃衍生物，具有强大的药理活性并能改善代谢性能。本研究旨在探讨CBBR抗NASH的作用及机制。
用含棕榈酸和油酸（PO）的培养基处理L02和HepG2肝细胞，并与CBBR孵育12小时，然后通过试剂盒或蛋白质免疫印迹法检测脂质积累水平。给C57BL/6 J小鼠喂食高脂饮食或高脂/高胆固醇饮食。口服给予CBBR（15毫克/千克或30毫克/千克），持续8周。评估肝脏重量、脂肪变性、炎症和纤维化情况。转录组学分析表明了CBBR在NASH中的作用靶点。
CBBR显著降低了NASH小鼠的脂质积累、炎症、肝损伤和纤维化。CBBR还减少了PO诱导的L02和HepG细胞中的脂质积累和炎症。RNA测序和生物信息学分析表明，CBBR在NASH发病机制中抑制了与脂质积累、炎症和纤维化相关的信号通路及关键调节因子。机制上，CBBR可能通过抑制LCN2预防NASH，这一发现证明在过表达LCN2的PO刺激的HepG2细胞中，CBBR的抗NASH作用更明显。
我们的研究为CBBR改善代谢应激引起的NASH的有效性以及通过调节LCN2的机制提供了见解。
