New Application Of Berberine: Lipids Lowering Effect And Molecular Mechanism

The elevation of serum cholesterol especially LDL-c levels is by far one of the most relative risk factors that cause atherosclerosis and CHD. Lowering LDL-c levels by medication can reduce the mortality of CHD significantly. The majority of LDL-c are taken up and cleared by hepatic LDLR. LDLR is a transmembrane receptor located on cell surface, the expression level of which is tightly regulated by sterols or non-sterols both on the transcription and post-transcription level. Upregulation of hepatic LDLR is the most effective method to lower serum LDL-c levels. The most widely-used LDLR upregulator at present are statins. Statins can inhibit the enzymatic activity of HMG-CoA reductase competitively, then imhibit the cellular cholesterol synthesis, which in turn upregulate the transcription of LDLR gene through the SREBPs pathway. In general, statins have excellent effect in hypercholesterolaemia. However, a small part of patients can not tolerate statins because of adverse effects such as liver function damage, another part of patients need other lipid-altering agents because desirable LDL-c levels can not be achieved by statins alones. So, ongoing efforts for screening new types of LDLR upregulators have being done for a long time.By screening the pool of traditional Chinese herbals, we found for the first time that berberine (BBR), an alkaloid isolated form herbals such as Coptis chinensis, can upregulate hepatic LDLR expression, and low cholesterol levels in vivo. BBR has definite chemical structure and has various pharmacological effects. BBR has been clinically used in China for a long time to treat diarrhea, the effectiveness and safety of the drug has been widely accepted.We have designed a series of in vitro and in vivo experiments to study the mechanism by which BBR upregulates LDLR expression. BBR can upregulate the expression of LDLR mRNA to a significant extent in the human hepatoma cell line Bel-7402 and HepG2 cells. The activity of BBR is time and dose dependent, we can find the upregulation of LDLR just after 2 hours' BBR treatment, and the effect can last at least 24 hours. The upregulation of LDLR by BBR is independent of medium cholesterol levels. Also, BBR treatment can increase the LDLR protein levels on the cell surface and enhance the uptake of Dil-LDL by the cells. The upregulation of LDLR by BBR is specific, because BBR can not influence the expression levels of other...