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Journal of Lipid Research, Vol. 47, 2134-2147, October 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

The medicinal plant goldenseal is a natural LDL-lowering agent with multiple bioactive components and new action mechanisms

Parveen Abidi¹, Wei Chen¹, Fredric B. Kraemer, Hai Li and Jingwen Liu²

Department of Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304

Published, JLR Papers in Press, August 2, 2006.

¹ P. Abidi and W. Chen contributed equally to this work.

² To whom correspondence should be addressed. e-mail: jingwen.liu{at}med.va.gov

Our previous studies have identified berberine (BBR), an alkaloid isolated from the Chinese herb huanglian, as a unique cholesterol-lowering drug that upregulates hepatic low density lipoprotein receptor (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 low density lipoprotein cholesterol (LDL-c) in hyperlipidemic hamsters, with greater activities than the pure compound BBR. By conducting bioassay-driven semipurifications, we demonstrate that the higher potency of goldenseal is achieved through concerted actions of multiple bioactive compounds in addition to BBR. We identify canadine (CND) 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 multiple drug resistance-1 (MDR1)-mediated efflux from liver cells, whereas CND is resistant to MDR1. This finding defines a molecular mechanism for the higher activity of CND 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-c-lowering agent, and our studies provide a molecular basis for the mechanisms of action.

Supplementary key words low density lipoprotein cholesterol • canadine • berberine • mRNA stabilization • multiple drug resistance-1 • extracellular signal-regulated kinase activation • hypercholesterolemia

Abbreviations: BBR, berberine; CND, canadine; ELSD, evaporative light-scattering detection; ERK, extracellular signal-regulated kinase; HC, high-cholesterol; HDT, hydrastine; HDTN, hydrastinine; LDL-c, low density lipoprotein cholesterol; LDLR, low density lipoprotein receptor; MDR, multiple drug resistance; OM, oncostatin M; PMT, palmatine; siRNA, small interfering RNA; TC, total cholesterol; TG, triglyceride; VRPM, verapamil

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