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Proteomics analysis reveals a potential new target protein for the lipid-lowering effect of Berberine8998

Authors: Cheng-yin YU1,2, Gang-yi LIU3, Xiao-hui LIU4, Yu-zhou GUI1, Hai-ming LIU3, Hong-chao ZHENG3, Darek C GORECKI2, Asmita V PATEL2, Chen YU3, Yi-ping WANG1
1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
2 School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth PO1 2DT, UK
3 Xuhui Central Hospital, Shanghai Clinical Center, Chinese Academy of Sciences, Shanghai 200031, China
4 Department of Proteomics Research, College of Life Sciences and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China
Corresponding to: Cheng-yin YU: chengyin.yu@port.ac.uk,
DOI: 10.1038/aps.2017.200
Received: 13 July 2017
Accepted: 8 November 2017
Advance online: 12 April 2018

Abstract

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-1·d-1, 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.
Keywords: berberine; berberine8998; proteomics; lipid-lowering; cholesterol; triglycerides; LDL-C; fatty acid metabolism; hypercholesterolemia; obesity

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