How could Goldenseal assist in maintaining a balanced metabolic system?

Potential beneficial effects of goldenseal on metabolic balance.

A person with an unbalanced metabolic system usually manifests a number of conditions collectively referred to as “Metabolic Syndrome”.  Those imbalances include increased fat generation and storage, elevated cholesterol levels, cardiovascular degeneration, and wild swings in blood glucose levels caused by the way the body metabolizes, or utilizes energy.

The body metabolizes fuel in two ways by either breaking it down for immediate use as cellular energy (catabolic) or storing the energy through the construction of fats and other cell components such as protein (anabolic).  The body switches between the two pathways based on cellular energy needs and fuel availability.  This switching activity is controlled by the AMP-activated protein kinase (AMPK) system.

AMPK acts as both a sensor and regulator of cellular energy status. It is activated by increases in the ratio of the number of depleted energy transporters compared to the number of charged energy transporters within the cell and triggers processes which tend to restore energy balance not only just at the cellular level but also throughout the whole body.    

For example, in response to a reduction in cellular energy such as caused by muscle contraction during exercise or work, AMPK switches off very efficient processes that store excess energy such as fatty acid, triglyceride, and cholesterol synthesis.   Simultaneously, destructive pathways such as fatty acid oxidation and glucose breakdown are switched on so the body begins drawing on stored energy to meet the additional energy needs. The AMPK system is thought to be partly responsible for the health benefits of exercise and is the target for the antidiabetic drug metformin.

AMPK can also be activated by other cellular processes and external stimuli including berberine, one of the active alkaloids in goldenseal.  In 2004 a group of Chinese researchers observed that berberine had cholesterol lowering effects similar to statin drugs but worked through a different pathway which avoided the adverse side effects seen with statin use (Kong, 2004).  A couple of years later, one of those researchers, Dr. Jingwen Liu, came to the US and continued her berberine studies at the VA Medical Facility in Palo Alto, CA. 

In 2006, Dr. Liu’s group published a report indicating that goldenseal was a natural LDL-lowering agent with multiple bioactive compounds besides berberine acting through entirely new pathways (Abidi, 2006).  In fact, the group reported that, on weight to weight basis, raw goldenseal root was more active than an equivalent quantity of pure, isolated berberine. 

Goldenseal was shown to stabilize the messenger RNA (nRNA) that carried the code for the LDLc receptor in the liver resulting in more receptors.  More LDL cholesterol receptors in the liver results in less LDL cholesterol in the bloodstream. Dr. Liu also speculated that AMPK activation played a role.

At about the same time a group of researchers for GlaxoSmithCline in France reported that in addition to LDLr mRNA stabilization berberine inhibited cholesterol and triglyceride synthesis in a manner similar to a known AMPK activator (Brusq, 2006).  Treatment of hyperlipidemic hamsters with berberine decreased plasma LDL cholesterol and strongly reduced fat storage in the liver. The report concluded that, in addition to upregulating the LDLR, berberine inhibits lipid synthesis in human liver cells through the activation of AMPK. 

Since that time numerous articles have confirmed and expanded this finding.  Subsequent articles have reported:

Berberine reduced body weight and caused a significant improvement in glucose tolerance without altering food intake in db/db mice. Similarly, berberine reduced body weight and plasma triglycerides and improved insulin action in high-fat-fed Wistar rats. Berberine downregulated the expression of genes involved in lipogenesis and upregulated those involved in energy expenditure in adipose tissue and muscle. Berberine treatment resulted in increased AMP-activated protein kinase (AMPK) and reduced lipid accumulation. The report concluded that berberine displays beneficial effects in the treatment of diabetes and obesity at least in part via stimulation of AMPK activity (Lee, 2006).

Yin (2008) suggested that berberine-induced AMPK activation is likely a consequence of mitochondria inhibition that increases the AMP/ATP ratio.  The data revealed that berberine enhances glucose metabolism by stimulation of glycolysis, which is related to inhibition of glucose oxidation in mitochondria.

Another study demonstrated that berberine stimulates glucose uptake in a time- and dose-dependent manner. Intriguingly, berberine-stimulated glucose uptake did not vary as insulin concentration increased, and could not be blocked by the PI 3-kinase inhibitor wortmannin  suggesting that berberine circumvents insulin signaling pathways and stimulates glucose uptake through the AMP-AMPK-p38 MAPK pathway, which may account for berberine’s antihyperglycemic effects (Cheng, 2006).

Berberine dose-dependently inhibited respiration in L6 myotubes and muscle mitochondria, through a specific effect on respiratory complex I, similar to that observed with metformin and rosiglitazone.  In addition, activation of AMPK by berberine did not rely on the activity of either LKB1 or CAMKKbeta, consistent with major regulation at the level of the AMPK phosphatase (Turner, 2008).

The Kong group had previously identified berberine as a novel cholesterol-lowering drug acting through stabilization of the low-density lipoprotein receptor (LDLR) messenger RNA. Because the mechanism differs from that of statins, the group decided to examine the lipid-lowering activity of berberine in combination with statins. The results indicated that combination of BBR with simvastatin (SIMVA) increased the LDLR gene expression to a level significantly higher than that in monotherapies.

In the treatment of food-induced hyperlipidemic rats, combination of berberine (90 mg/[kg d], oral) with SIMVA (6 mg/[kg d], oral) reduced serum LDL cholesterol by 46.2%, which was more effective than that of the SIMVA (28.3%) or berberine (26.8%) monotherapy (P < .01 for both) and similar to that of SIMVA at 12 mg/(kg d) (43.4%). More effective reduction of serum triglyceride was also achieved with the combination as compared with either monotherapy. Combination of berberine with SIMVA up-regulated the LDLR messenger RNA in rat livers to a level about 1.6-fold higher than the monotherapies did. Significant reduction of liver fat storage and improved liver histology were found after the combination therapy.

The therapeutic efficacy of the combination was then evaluated in 63 hypercholesterolemic patients. As compared with monotherapies, the combination showed an improved lipid-lowering effect with 31.8% reduction of serum LDL cholesterol (P < .05 vs berberine alone, P < .01 vs SIMVA alone). Similar efficacies were observed in the reduction of total cholesterol as well as triglyceride in the patients. Overall, the results display the rationale, effectiveness, and safety of the combination therapy for hyperlipidemia using berberine and SIMVA. It could be a new regimen for hypercholesterolemia (Kong, 2008).

Berberine was shown to improve lipid dysregulation and fatty liver in obese mice through both central and peripheral actions. In obese db/db and ob/ob mice, Berberine treatment reduced liver weight, hepatic and plasma triglyceride, and cholesterol contents. In the liver and muscle of db/db mice, berberine promoted AMPK activity and fatty acid oxidation and changed expression of genes involved in lipid metabolism (Kim, 2009)

Jeong (2009) reported  that berberine represses proinflammatory responses through AMPK activation in macrophages. In adipose (fat) tissue of obese db/db mice, berberine treatment significantly downregulated the expression of proinflammatory genes such as TNF-alpha, IL-1beta, IL-6, monocyte chemoattractant protein-1 (MCP-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Consistently, BBR inhibited LPS-induced expression of proinflammatory genes including IL-1beta, IL-6, iNOS, MCP-1, COX-2, and matrix metalloprotease-9 in peritoneal macrophages and RAW 264.7 cells. Upon various proinflammatory signals including LPS, free fatty acids, and hydrogen peroxide, berberine suppressed the phosphorylation of MAPKs, such as p38, ERK, and JNK, and the level of reactive oxygen species in macrophages.

Berberine protects against endothelial injury and enhances the endothelium-dependent vasodilatation, which is mediated in part through activation of the AMPK signalling cascade. Berberine or its derivatives may be useful for the treatment and/or prevention of endothelial dysfunction associated with diabetes and cardiovascular disease (Wang, 2009).

Chen (2010) reported that berberine mimics insulin action by increasing glucose uptake ability by 3T3-L1 adipocytes and L6 myocytes in an insulin-independent manner, inhibiting phosphatase activity of protein tyrosine phosphatase 1B (PTP1B), and increasing phosphorylation of IR, IRS1 and Akt in 3T3-L1 adipocytes. In diabetic mice, berberine lowers hyperglycemia and improves impaired glucose tolerance, but does not increase insulin release and synthesis. The results suggest that berberine represents a different class of anti-hyperglycemic agents.

Zhang (2011) suggested that berberine moderates glucose and lipid metabolism through a multipathway mechanism that includes AMP-activated protein kinase-(AMPK-) p38 MAPK-GLUT4, JNK pathway, and PPARα pathway.

A Canadian group reported that berberine regulates hepatic cholesterol biosynthesis via increased phosphorylation of HMG-CoA reductase (Wu, 2011).

The data from Xia (2011) suggested that berberine improves fasting blood glucose by direct inhibition of gluconeogenesis in liver. This activity is not dependent on insulin action. The gluconeogenic inhibition is likely a result of mitochondria inhibition by berberine. The observation supports that berberine improves glucose metabolism through an insulin-independent pathway.

Berberine is an alkaloid that affects glucose metabolism, increases insulin secretion, stimulates glycolysis, suppresses adipogenesis, inhibits mitochondrial function, activates the 5' adenosine monophosphate-activated protein kinase (AMPK) pathway, and increases glycokinase activity.

Berberine also increases glucose transporter-4 (GLUT-4) and glucagon-like peptide-1 (GLP-1) levels. On GLP-1 receptor activation, adenylyl cyclase is activated, and cyclic adenosine monophosphate is generated, leading to activation of second messenger pathways and closure of adenosine triphosphate-dependent potassium channels. Increased intracellular potassium causes depolarization, and calcium influx through the voltage-dependent calcium channels occurs.

This intracellular calcium increase stimulates the migration and exocytosis of the insulin granules. In glucose-consuming tissues, such as adipose, or liver or muscle cells, berberine affects both GLUT-4 and retinol-binding protein-4 in favor of glucose uptake into cells; stimulates glycolysis by AMPK activation; and has effects on the peroxisome proliferator-activated receptor γ molecular targets and on the phosphorylation of insulin receptor substrate-1, finally resulting in decreased insulin resistance.

Moreover, recent studies suggest that berberine could have a direct action on carbohydrate metabolism in the intestine. The antidiabetic and insulin-sensitizing effect of berberine has also been confirmed in a few relatively small, short-term clinical trials. The tolerability is high for low dosages. (Cicero, 2012).

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