Effect of Berberine on promoting the excretion of cholesterol in high-fat diet-induced hyperlipidemic hamsters

Abstract

Background: Berberine (BBR), as a new medicine for hyperlipidemia, can reduce the blood lipids in patients. Mechanistic studies have shown that BBR activates the extracellular-signal regulated kinase pathway by stabilizing low-density-lipoprotein receptor mRNA. However, aside from inhibiting the intestinal absorption of cholesterol, the effects of BBR on other metabolic pathways of cholesterol have not been reported. This study aimed to investigate the action of BBR on the excretion of cholesterol in high-fat diet-induced hyperlipidemic hamsters.

Methods: Golden hamsters were fed a high-fat diet (HFD) for 6 weeks to induce hyperlipidemia, followed by oral treatment with 50 and 100 mg/kg/day of BBR or 10 and 30 mg/kg/day of lovastatin for 10 days, respectively. The levels of total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), transaminases, and total bile acid in the serum, liver, bile and feces were measured using an enzyme-linked immunosorbent assay. The cholesterol (as well as coprostanol) levels in the liver, bile and feces were determined by gas chromatography-mass spectrometry.

Results: The HFD hamsters showed significantly hyperlipidemic characteristics compared with the normal hamsters. Treatment with BBR for 10 days reduced the serum TC, TG and LDL-C levels in HFD hamsters by 44-70, 34-51 and 47-71%, respectively, and this effect was both dose- and time-dependent. Initially, a large amount of cholesterol accumulated in the hyperlipidemic hamster livers. After BBR treatment, reductions in the liver cholesterol were observed by day 3 and became significant by day 7 at both doses (P < 0.001). Meanwhile, bile cholesterol was elevated by day 3 and significantly increased at day 10 (P < 0.001). BBR promoted cholesterol excretion from the liver into the bile in hyperlipidemic hamsters but not in normal hamsters, and these results provide a link between the cholesterol-lowering effect of BBR with cholesterol excretion into the bile.

Conclusions: We conclude that BBR significantly promoted the excretion of cholesterol from the liver to the bile in hyperlipidemic hamsters, which led to large decreases in the serum TC, TG and LDL-C levels. Additionally, compared with lovastatin, the BBR treatment produced no obvious side effects on the liver function.

Fig. 1

Serum lipid levels at each time point. (a) BBR and lovastatin significantly reduced the serum TC levels in the hyperlipidemic hamsters. The serum TC levels in the lovastatin-treated HFD hamsters (10 mg/kg/day) were significantly different from those of the BBR-treated HFD hamsters (100 mg/kg/day) at day 10. (b) BBR and lovastatin significantly reduced the serum TG levels in the hyperlipidemic hamsters. (c) BBR and lovastatin significantly reduced the serum LDL-C levels in the hyperlipidemic hamsters. The data are shown as the mean ± SD. *P < 0.05, **P < 0.01 and ***P < 0.001 vs the ND controls; ^## P < 0.01 vs the BBR-treated HFD hamsters (100 mg/kg/day).

Fig. 2

Effects of BBR and lovastatin on the liver function of hyperlipidemic hamsters. (a) Lovastatin (30 mg/kg/day) increased the serum ALT level by 2.0-fold at day 10 compared with the HFD control group at day 0, whereas the BBR (100 mg/kg/day) group showed no significant differences over the entire period. (b) Lovastatin (30 mg/kg/day) elevated the serum AST level by 2.1-fold at day 10 compared with the HFD control group at day 0, whereas the BBR (100 mg/kg/day) group showed no significant differences over the entire period. (c) There were no significant differences in the serum GGT levels in any of the groups. The data are shown as the mean ± SD. **P < 0.01 and ***P < 0.001 vs the HFD controls; ^## P < 0.01 and ^### P < 0.001 vs the BBR-treated HFD hamsters (100 mg/kg/day).

Fig. 3

Reduced cholesterol in the liver and increased cholesterol in the bile after the BBR treatment. (a) The liver cholesterol levels in the BBR-treated ND hamsters. (b) The bile cholesterol levels in the BBR-treated ND hamsters. (c) Reductions in the liver cholesterol levels of the HFD hamsters were observed by day 3 and became significant by day 7 at both doses. (d) BBR resulted in significantly higher cholesterol levels in both BBR-treated HFD groups at day 10 than the HFD control group. (e) Lovastatin did not significantly decrease the cholesterol levels in the HFD hamster livers. (f) Lovastatin did not significantly increase the cholesterol levels in the HFD hamster bile. (g) In the feces, BBR decreased the levels of cholesterol, but significantly increased the levels of coprostanol from day 3 to day 10. The data are shown as the mean ± SD. *P < 0.05, **P < 0.01 and ***P < 0.001 vs the ND controls (c, e and g) or the HFD controls (d, f); ^### P < 0.001 vs the BBR-treated HFD hamsters (100 mg/kg/day).

Fig. 4

BBR increased TBA in both the livers and the bile of the hyperlipidemic hamsters. (a) BBR caused a significant increase in the liver TBA levels in the HFD hamsters. (b) The levels of bile TBA were markedly increased by BBR treatment. (c) In the feces, the levels of TBA were significantly decreased from day 3 to day 10. The data are shown as the mean ± SD. *P < 0.05, **P < 0.01 and ***P < 0.001 vs the HFD controls (a, b) or ND controls (c).