Abstract
The alkaloid drug berberine (BBR) was recently described to decrease plasma cholesterol and triglycerides (TGs) in hypercholesterolemic patients by increasing expression of the hepatic low density lipoprotein receptor (LDLR). Using HepG2 human hepatoma cells, we found that BBR inhibits cholesterol and TG synthesis in a similar manner to the AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide 1-beta-ribofuranoside (AICAR). Significant increases in AMPK phosphorylation and AMPK activity were observed when the cells were incubated with BBR. Activation of AMPK was also demonstrated by measuring the phosphorylation of acetyl-CoA carboxylase, a substrate of AMPK, correlated with a subsequent increase in fatty acid oxidation. All of these effects were abolished by the mitogen-activated protein kinase kinase inhibitor PD98059. Treatment of hyperlipidemic hamsters with BBR decreased plasma LDL cholesterol and strongly reduced fat storage in the liver. These findings indicate that BBR, in addition to upregulating the LDLR, inhibits lipid synthesis in human hepatocytes through the activation of AMPK. These effects could account for the strong reduction of plasma TGs observed with this drug in clinical trials.
Highlights
The alkaloid drug berberine (BBR) was recently described to decrease plasma cholesterol and triglycerides (TGs) in hypercholesterolemic patients by increasing expression of the hepatic low density lipoprotein receptor (LDLR)
They act through the inhibition of HMG-CoA reductase, a pivotal enzyme in the cholesterol biosynthetic pathway, leading to a reduction of cholesterol concentration and a subsequent increase in expression of the low density lipoprotein receptor (LDLR), the main receptor involved in the hepatic clearance of LDL cholesterol [5,6,7,8]
It was previously described that the effects of BBR on LDLR upregulation were dependent on the mitogen-activated protein kinase kinase (MAPK/extracellular regulated kinase (ERK)) cascade [13]
Summary
The alkaloid drug berberine (BBR) was recently described to decrease plasma cholesterol and triglycerides (TGs) in hypercholesterolemic patients by increasing expression of the hepatic low density lipoprotein receptor (LDLR). Treatment of hyperlipidemic hamsters with BBR decreased plasma LDL cholesterol and strongly reduced fat storage in the liver These findings indicate that BBR, in addition to upregulating the LDLR, inhibits lipid synthesis in human hepatocytes through the activation of AMPK. Statins represent the major class of hypolipidemic drugs on the market They act through the inhibition of HMG-CoA reductase, a pivotal enzyme in the cholesterol biosynthetic pathway, leading to a reduction of cholesterol concentration and a subsequent increase in expression of the low density lipoprotein receptor (LDLR), the main receptor involved in the hepatic clearance of LDL cholesterol [5,6,7,8]. The authors demonstrated that in a human hepatoma cell line (HepG2) as well as in hyperlipidemic hamsters, BBR upregulated the expression of LDLR
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