. The medicinal plant goldenseal is a natural LDL-lowering agent with multiple components and new action mechanisms. J Lipid Res . 2006;47:2134-2147.

Goldenseal (Hydrastis canadensis) is a native American plant prized in herbal medicine as a treatment for nasal congestion, hemorrhoids, skin and mouth sores, acne, eye problems, and more. Berberine, an alkaloid found in goldenseal, has been shown to upregulate hepatic low density lipoprotein receptor (LDLR) expression in prior studies.1,2 A clinical trial has shown that administration of 1 g/day of berberine reduces LDL cholesterol in hypercholesterolemic individuals.2 A high level of LDL cholesterol is a risk factor for coronary heart disease and atherosclerosis. About 70% of LDL cholesterol is removed from blood plasma by the LDLR uptake in the liver. Therefore, increased expression of hepatic LDLR is a mechanism for lowering LDL cholesterol and a target for drug and dietary supplement development. In a series of in vivo and in vitro studies, this research group has examined the LDL-lowering effects of goldenseal and its phytochemical constituents, including berberine.

The authors confirmed the presence of berberine, canadine, and hydrastinine, as well as the absence of palmatine in commercial goldenseal root extracts using HPLC and LC-MS methods. Nine lots from 6 manufacturers were examined: Lot 1- Solgar Vitamin and Herb (Leonia, NJ), Lots 2,8, and 9- Country Sun (Palo Alto, CA), Lot 3- Now Foods (Bloomingdale, IL), Lot 4- The Vitamin Shoppe (North Bergen, NJ), Lots 5 and 6- Nature's Way Products, Inc. (Springville, UT), and Lot 7- Gaia Herbs (Brevard, NC).

Northern blot analysis showed that berberine and canadine are strong inducers of LDLR mRNA expression. Pure berberine was shown to be a less potent inducer of LDLR mRNA than goldenseal root extracts containing an equivalent amount of berberine. HepG2 cells from hamster livers were treated with 10 µL/ml of Lots 3 and 6 goldenseal extract. Interestingly, goldenseal extracts showed 2-3 times the activity of pure berberine. In fact findings indicated that "goldenseal extract is highly effective in the upregulation of LDLR expression through mRNA stabilization, with greater activity than the pure compound BBR [berberine]." Additionally, findings also indicated that canadine increases LDLR mRNA expression to greater degree than berberine. However, the low ratios of canadine to berberine in the goldenseal root extracts (10:1 to 60:1 berberine: canadine) indicate that canadine's LDLR mRNA activity does not explain the two to three times higher activity of goldenseal LDLR mRNA upregulation, compared with pure berberine. Multiple extract fractions on LDLR mRNA expression were examined in order to determine the presence other active constituents. Fraction 3 increased LDLR mRNA expression by 4.3 times, and Fraction 6 produced a more modest increase. The data suggest that compound(s) present in Fraction 3 may be more potent inducers of LDLR mRNA expression than berberine. The investigators are attempting to isolate and identify the active constituent(s).

Goldenseal extracts were also found to increase cellular levels of LDLR mRNA faster than pure berberine. The authors examined the amount of green fluorescence due to berberine in HepG2 cells over time after treatment with berberine versus a goldenseal extract containing an equivalent amount of berberine. Cells treated with goldenseal extract increased green fluorescence more quickly than cells treated with pure berberine. After five minutes, fluorescence increased by 13 times in goldenseal-treated cells, and increased by two times in the berberine-treated cells. The authors examined the possibility that the low accumulation rate of pure berberine was due to exclusion by multi-drug resistance (MDR1) transporter pgp-170, which may be prevented by other compounds found in goldenseal extract. When the MDR1 inhibitor verapamil (VRPM) was added to HepG2 cells treated with berberine, the green fluorescence increased by 49%. Cells treated with VRPM containing the goldenseal extract showed only an 8% increase. The addition of VRPM increased upregulation of LDLR mRNA in cells treated with berberine in a dose-dependent manner. VRPM did not affect cells treated with canadine or goldenseal extract. In addition, the cellular retention of berberine in cells transfected with MDR1 siRNA was significantly increased by 47% (P<0.01), compared with the control cells. This shows that MDR1 reduces the activity of berberine by actively excreting it from cells. However, berberine in goldenseal extract is not actively excreted by MDR1, suggesting that goldenseal extract contains MDR1 inhibitor(s). This effectively increases the effect of berberine on the upregulation of LDLR mRNA.

The authors also studied the LDL cholesterol-lowering effects of goldenseal extract on 27 Golden Syrian male hamsters. The hamsters received a high cholesterol diet and were divided into the following three groups: the first received a daily dose of 15 mg/kg berberine, the second received a daily dose of 125 µL/animal of goldenseal extract Lot 9 providing 7.5 mg/kg berberine, and the third group was a control, receiving an equivalent amount of inactive substance. The goldenseal extract reduced plasma levels of total cholesterol by 31.3%, LDL cholesterol by 25.1%, triglycerides by 32.6%, and free fatty acids (FFA) by 33.8%, compared with the control group. The effect of the goldenseal extract was nearly equivalent to that of the pure berberine, despite providing half the dose of berberine. In addition, the goldenseal extract reduced serum levels of VLDL cholesterol, LDL cholesterol, and chylomicron-associated cholesterol without reducing levels of high density lipoprotein (HDL) cholesterol, the so called "good" cholesterol fraction. After the study period (d=24 days), the hamsters were euthanized and LDLR mRNA expression in their livers examined. The expression of LDLR mRNA was increased by 3.2 times in the goldenseal group (P<0.0001) and by 3.7 times in the berberine group (P<0.0001), when compared with the control group.

In addition, the authors examined extracellular signal-regulated kinase (ERK) phosphorylation in the hamster livers. The ERK signaling pathway is important in the upregulation of LDLR expression by berberine. Levels of phosphorylated ERK were higher in the livers of hamsters in the goldenseal and berberine groups. A further in vitro analysis reveled that ERK phosphorylation in HepG2 cells was induced by goldenseal extract from different lots and manufacturers. The ERK phosphorylation was induced by berberine and canadine, but not by beta-hydrastine. The authors conclude that these data provide "a solid link between ERK activation and LDLR upregulation" by goldenseal extract. Treatment with goldenseal extract and with pure berberine also reduced lipid accumulation in the hamsters' hepatocytes. Treatment with goldenseal reduced hepatic total cholesterol by 46.3% and hepatic triglycerides by 54.3%, compared with the control animals. Treatment with berberine resulted in a 68.7% reduction in hepatic total cholesterol and a 70.6% reduction in hepatic triglycerides, compared with the controls. These results confirm that treatment with goldenseal and berberine reduce hepatic total cholesterol and triglyceride accumulation.

This study shows that goldenseal root extracts reduce plasma and hepatic levels of LDL cholesterol by increasing hepatic LDLR expression. Multiple constituents act synergistically to produce this effect, including berberine, canadine, and other unidentified constituents. The authors are currently in the process of isolating and identifying these unknown constituents.

-Marissa Oppel, MS

References
1.Abidi P, Zhou Y, Jiang JD, Liu J. Extracellular signal-regulated kinase-dependent stabilization of hepatic low-density lipoprotein receptor mRNA by herbal medicine berberine. Arterioscler Thromb Vasc Biol. Oct 2005;25(10):2170-2176.
2. Kong W, Wei J, Abidi P, et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med. 2004 Dec;10(12):1344-51.