State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, PO1 2DT, UK.
Acta Pharmacol Sin. 2018 Sep;39(9):1473-1482. doi: 10.1038/aps.2017.200. Epub 2018 Apr 12.
Berberine8998 is a newly synthesized berberine derivative with better lipid-lowering activity and improved absorption. The objective of this study was to investigate the effects of berberine8998 on serum cholesterol and lipid levels in vivo and to examine the mechanisms involved. Hamsters on high-fat diet (HFD) were administered berberine or berberine8998 (50 mg·kg·d, ig) for 3 weeks. Berberine8998 administration significantly lowered the total cholesterol, triglycerides and LDL-C levels in HFD hamsters. Bioinformatics revealed that berberine and berberine8998 shared similar metabolic pathways and fatty acid metabolism was the predominant pathway. Western blot validation results showed that peroxisomal acyl-coenzyme A oxidase 1 (ACOX1) and long-chain fatty acid-CoA ligase 1 (ACSL1), two proteins involved in fatty acid metabolism, were expressed differently in the berberine8998 group than in the untreated group and the berberine treatment group. Biochemistry results showed that berberine8998 significantly lowered the non-esterified fatty acid (NEFA) levels, which may lead to a reduction in TG levels in the berberine8998 treatment group and the differences observed in proteomics analyses. Pharmacokinetic analysis conducted in rats. After administration of berberine or berberine8998 (50 mg/kg, ig), berberine8998 exhibited a remarkably improved absorption with increasing bioavailability by 6.7 times compared with berberine. These findings suggest that berberine8998 lowers cholesterol and lipid levels via different mechanisms than berberine, and its improved absorption makes it a promising therapeutic candidate for the treatment of hypercholesterolemia and obesity.
小檗碱 8998 是一种新合成的小檗碱衍生物，具有更好的降脂活性和改善的吸收能力。本研究旨在探讨小檗碱 8998 对体内胆固醇和血脂水平的影响，并研究其作用机制。给予高脂饮食（HFD）的仓鼠小檗碱或小檗碱 8998（50mg·kg·d，ig）治疗 3 周。小檗碱 8998 给药可显著降低 HFD 仓鼠的总胆固醇、甘油三酯和 LDL-C 水平。生物信息学分析显示，小檗碱和小檗碱 8998 具有相似的代谢途径，脂肪酸代谢是主要途径。Western blot 验证结果表明，过氧化物酶体酰基辅酶 A 氧化酶 1（ACOX1）和长链脂肪酸-CoA 连接酶 1（ACSL1）两种参与脂肪酸代谢的蛋白在小檗碱 8998 组中的表达与未处理组和小檗碱治疗组不同。生化结果表明，小檗碱 8998 可显著降低非酯化脂肪酸（NEFA）水平，这可能导致小檗碱 8998 治疗组 TG 水平降低，以及蛋白质组学分析中观察到的差异。在大鼠中进行的药代动力学分析。给予小檗碱或小檗碱 8998（50mg/kg，ig）后，与小檗碱相比，小檗碱 8998 的吸收明显改善，生物利用度增加了 6.7 倍。这些发现表明，小檗碱 8998 通过与小檗碱不同的机制降低胆固醇和血脂水平，其改善的吸收使其成为治疗高胆固醇血症和肥胖症的有前途的治疗候选药物。
