The natural compound berberine has been reported to exhibit anti-diabetic activity and to improve disordered lipid metabolism. In our previous study, we found that such compounds upregulate expression of sirtuin 1—a key molecule in caloric restriction, it is, therefore, of great interest to examine the lipid-lowering activity of berberine in combination with a sirtuin 1 activator resveratrol. Our results showed that combination of berberine with resveratrol had enhanced hypolipidemic effects in high fat diet-induced mice and was able to decrease the lipid accumulation in adipocytes to a level significantly lower than that in monotherapies. In the high fat diet-induced hyperlipidemic mice, combination of berberine (30 mg/kg/day, oral) with resveratrol (20 mg/kg/day, oral) reduced serum total cholesterol by 27.4% ± 2.2%, and low-density lipoprotein-cholesterol by 31.6% ± 3.2%, which was more effective than that of the resveratrol (8.4% ± 2.3%, 6.6% ± 2.1%) or berberine (10.5% ± 1.95%, 9.8% ± 2.58%) monotherapy (p < 0.05 for both). In 3T3-L1 adipocytes, the treatment of 12 µmol/L or 20 µmol/L berberine combined with 25 µmol/L resveratrol showed a more significant inhibition of lipid accumulation observed by Oil red O stain compared with individual compounds. Moreover, resveratrol could increase the amount of intracellular berberine in hepatic L02 cells. In addition, the combination of berberine with resveratrol significantly increases the low-density-lipoprotein receptor expression in HepG2 cells to a level about one-fold higher in comparison to individual compound. These results implied that the enhanced effect of the combination of berberine with resveratrol on lipid-lowering may be associated with upregulation of low-density-lipoprotein receptor, and could be an effective therapy for hyperlipidemia in some obese-associated disease, such as type II diabetes and metabolic syndrome.

It was well-known that Berberine, a major bioactive compound extracted from natural plants Coptis chinensis, has anti-diabetic effects for decades in china. Other types of pharmacological activities, such as anti-inflammatory, antimicrobial, hypolipidemic, and anti-cancer effects, have also been examined. At cellular level, these pharmacological activities were mostly an inhibitory effect. However, the cytoprotective effect of berberine was also observed in various types of cells, such as neurons, endothelial cells, fibroblasts, and β-cells. The paradoxical result may be closely associated with characteristics and distribution of berberine within cells, and they can be explained mechanically by mitohormesis, one particular form of hormesis. Here, we reviewed the mitohormetic response and assessed the berberine-induced effects and the possible signaling pathway involved. These findings may contribute to better clinical applications of berberine and indicate that some mitochondria-targeted conventional drugs should be considered carefully in clinical application.