Inhibition of lipid synthesis through activation of AMP kinase: an additional mechanism for the hypolipidemic effects of berberine.
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.
Brusq
Jean-Marie
JM
GlaxoSmithKline, 91951 Les Ulis, Cedex, France. jean-marie.g.brusq@gsk.com
Ancellin
Nicolas
N
Grondin
Pascal
P
Guillard
Raphaelle
R
Martin
Sandrine
S
Saintillan
Yannick
Y
Issandou
Marc
M
D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism*; D000620:Aminoimidazole Carboxamide / Q000494:pharmacology; D000818:Animals; D001599:Berberine / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006224:Cricetinae; D004789:Enzyme Activation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000096:biosynthesis*; D008297:Male; D010766:Phosphorylation / Q000187:drug effects; D011973:Receptors, LDL / Q000378:metabolism
D005227:Fatty Acids; D000960:Hypolipidemic Agents; D008055:Lipids; D011973:Receptors, LDL; D001599:Berberine; D000620:Aminoimidazole Carboxamide; D000263:Adenylate Kinase; D000103:Acetyl-CoA Carboxylase