J. Lipid Res.
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Papers In Press, published online ahead of print August 2, 2006
J. Lipid Res., doi:10.1194/jlr.M600195-JLR200
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Submitted on May 4, 2006
Revised on August 2, 2006
Accepted on August 2, 2006

Identification of medicinal plant goldenseal as a natural cholesterol-lowering agent: Mechanisms of actions and new modulators of LDL receptor expression

Parveen Abidi, Wei Chen, Fredric B. Kraemer, Hai Li, and Jingwen Liu

Research, VA Palo Alto Health Care System (154P), Palo Alto, CA 94304

Corresponding Author: Jingwen.Liu{at}med.va.gov

Our previous studies have identified berberine (BBR), an alkaloid isolated from Chinese herb Huanglian, as a unique cholesterol-lowering drug that upregulates hepatic LDLR expression through a mechanism of mRNA stabilization. Here we demonstrate that the root extract of goldenseal, a BBR-containing medicinal plant, is highly effective in upregulation of liver LDLR expression in HepG2 cells and in reducing plasma cholesterol and LDL-cholesterol in hyperlipidemic hamsters with greater activities than the pure compound BBR. By conducting bioassay driven semi-purifications we demonstrate that the higher potency of goldenseal is achieved through concerted actions of multiple bioactive compounds in addition to BBR. We identify canadine and two other constituents of goldenseal as new upregulators of LDLR expression. We further show that the activity of BBR on LDLR expression is attenuated by MDR1-mediated efflux from liver cells, whereas canadine is resistant to MDR1. This finding defines a molecular mechanism for the higher activity of canadine than BBR. We also provide substantial evidence to show that goldenseal contains natural MDR1 antagonist(s) that accentuate the upregulatory effect of BBR on LDLR mRNA expression. These new findings identify goldenseal as a natural LDL-cholesterol lowering agent and our studies provide a molecular basis for the mechanisms of actions.


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