AbstractBerberine (BBR), an herbal originated compound, has lipid-lowering activity. However, its low bioavailability and poor absorption characteristics have limited its clinical application. The aim of this research study was to investigate the lipid lowering effect of a novel berberine derivative, namely berberine8998, and its properties and underlying mechanisms.
For the purpose of this study, the pharmacodynamics of berberine8998 was evaluated on a hamster model of hypercholesterolemia by a high-fat diet. Our results showed that, compared with the other structurally related derivatives of the berberine group, berberine8998 significantly lowered the serum lipid levels in hamsters. Berberine8998 stimulated the uptake of low-density lipoprotein (LDL) in HepG2 cells in a dose-dependent manner. Isobaric tags for the relative and absolute quantitation (iTRAQ) labeling proteome methods was applied, using a TripleTOF 5600 mass spectrometer to compare the pharmacological basis of both berberine and berberine8998. The mechanisms of the actions of these two compounds were investigated by identifying and quantifying the differences in the proteins that were expressed (with respect to the untreated animals) in the liver tissues of hamsters treated with the compounds. The result of proteome study showed that peroxisomal acyl-coenzyme A oxidase 1 (ACOX1) and long-chain fatty acid—CoA ligase 1 (ACSL1), involved in fatty acid metabolism, were regulated by using berberine and berberine8998. Moreover, western blot validation results showed that ACOX1 and ACSL1, which are 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. Furthermore, a pharmacokinetic study was applied to investigate the absorption of two formulations of berberine8998.
These findings suggested that berberine8998 lowered cholesterol and lipid levels via different mechanisms from berberine, and its improved absorption made it a promising therapeutic candidate for the treatment of hypercholesterolemia and obesity.
|Date of Award||2018|
|Supervisor||Asmita Sautreau (Supervisor), Yiping Wang (Supervisor) & Darek Gorecki (Supervisor)|