Introduction
Berberine is a naturally occurring compound found in the stem, root, and bark of several plants and herbs, such as Amur cork tree (Phellodendron amurense) and Huanglian (Coptis chinensis Franch).
Berberine has been used in traditional Chinese and Ayurvedic medicine for centuries for the treatment of indigestion, dysentery, and a wide range of infections.1 In the 1980s, the hypoglycemic effect of berberine was discovered.2 Since then, a robust amount of research on this alkaloid’s pharmacological effects have been elucidated, including its antimicrobial, anti-inflammatory, and antioxidative properties as well as its hypoglycemic action and beneficial effects on lipid metabolism.1,3
Research Highlights
» Berberine is a natural alkaloid found in a wide variety of herbs with antimicrobial, anti-inflammatory, and antioxidative effects.
» Berberine exerts its metabolic and cardioprotective effects by regulating multiple mechanisms involving glucose and insulin metabolism, lipid metabolism, endothelial function, and gut microbiota modulation.
» The clinical efficacy and safety of berberine has been demonstrated in multiple human clinical trials.
Mechanisms of action
Berberine exerts its metabolic and cardioprotective effects by regulating multiple molecular targets and pathways. For example:
Glucose and insulin metabolism
- Berberine activates adenosine monophosphate kinase (AMPK), a key regulator in energy metabolism in adipocytes and muscle cells, leading to improved insulin sensitivity, reduced fat accumulation, and energy 4
- Berberine upregulates the expression of insulin-receptor gene through activation of protein kinase C (PKC) in the liver and muscle cells, leading to improved cellular glucose utilization and reduced insulin resistance5
Lipid metabolism
- Berberine increases the expression of the liver low-density lipoprotein receptor (LDLR) gene by stabilizing its mRNA, which leads to improved clearance of LDL-cholesterol.6
- The pro-protein convertase subtilisin/kexin type 9 (PCSK9) downregulates LDLR by promoting degradation of Berberine decreases PCSK9 mRNA and protein levels, thereby blocking the PCSK9-mediated LDLR degradation.7
Endothelial function
- High oxidative stress and low nitric oxide production due to dysregulated glucose, lipid metabolism, and proinflammatory factors contribute to endothelial dysfunction.8 Via activation of AMPK, berberine increases endothelial nitric oxide synthase (eNOS) expression and suppresses oxidative stress.9
- Berberine reduces oxidized LDL (oxLDL)-stimulated production of reactive oxygen species and monocyte adhesion to endothelial cells via suppression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1).10
Gut microbiota modulation
- Berberine increases the amount of gut bacteria that produce short- chain fatty acids (SCFAs). Increased levels of SCFAs contribute to numerous benefits for the host.11,12
- Berberine increases abundance of Akkermansia spp. (which regulates inflammation and gut barrier integrity) and decreases endotoxemia as well as reduces intestinal and arterial proinflammatory mediators in mice fed a high-fat diet.13
Safety
- The safety of berberine has been demonstrated in multiple meta-analyses involving subjects with dyslipidemia, hyperlipidemia, or type 2 diabetes; no severe adverse events associated with berberine were reported.19,20,28
- In a meta-analysis involving women with polycystic ovary syndrome and insulin resistance, the adverse event profile of berberine is less severe than that of 24
- The main complaints associated with berberine consumption were gastrointestinal, such as diarrhea, constipation, and flatulence.14,19
Potential drug interactions
- Two weeks of berberine administration (300 mg i.d.) decreased cytochrome P450 (CYP)2D6, CYP2C9, and CYP3A4 activities in 17 healthy male subjects, although variability among subjects was relatively large.29
- Combined administration of berberine (300 mg/d) with simvastatin (40 mg/d) or with fenofibrate (200 mg/d) for seven days did not result in clinically obvious pharmacokinetic30
- Potential interaction between berberine and metformin has not been studied in humans, although metformin is not metabolized by CYP enzymes and is excreted unchanged in the31
- One study found berberine increased bioavailability of P-glycoprotein substrates digoxin and cyclosporine in rats.32 However, the effect of berberine on P-glycoprotein expression/activity depends on the cell line studied.33 Therefore, potential interactions between berberine and P-glycoprotein substrates in humans remain to be studied.
