The imidazoline-like drug S23515 affects lipid metabolism in hepatocyte by inhibiting the oxidosqualene: lanosterol cyclase activity.
Imidazoline-like drugs are centrally-acting antihypertensive agents that inhibit the activity of the sympathetic nervous system by interacting with the alpha2-adrenoreceptor and also with a non-adrenergic imidazoline binding site called the imidazoline 1 receptor. Recently, these molecules were proposed to play an additional role in cardiovascular diseases by acting on glucose and lipid metabolism. We used S23515, a potent imidazoline-like molecule acting selectively on blood pressure through the imidazoline 1 receptor, to decipher the effects of these drugs on lipid metabolism. We found that S23515 inhibited specifically and dose-dependently cholesterol synthesis in cultured rodent and primate hepatocytes. This hypocholesterolemic effect was likely due to the inhibition of the oxido:lanosterol cyclase (OSC), a rate-limiting enzyme in the cholesterol biosynthetic pathway. Partial OSC inhibition induced by S23515 led to the generation of 24(S),25-epoxycholesterol, a potent ligand for the liver X receptor (LXR). Furthermore, S23515 increased in human macrophages the expression of both ABCA1 and G1, the 2 ATP binding cassette transporters, which play a pivotal role in the reverse cholesterol transport. Thus, these results suggest that S23515, and potentially other imidazoline-like drugs, could exert hypolipidemic effects in addition to their hypotensive activities.
Venteclef
Nicolas
N
GlaxoSmithKline, 25 Avenue du Québec, Les Ulis, Cedex 91951, France.
Guillard
Raphaelle
R
Issandou
Marc
M
D000818:Animals; D000069059:Atorvastatin; D006528:Carcinoma, Hepatocellular; D045744:Cell Line, Tumor; D017931:DNA Primers; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology*; D006538:Heptanoic Acids / Q000494:pharmacology; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors*; D007700:Kinetics; D050356:Lipid Metabolism; D008113:Liver Neoplasms; D010080:Oxazoles / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats
C431511:5-(2-bnromophenoxy)methyl-2-amino-4,5-dihydro-1,3-oxazole; D017931:DNA Primers; D004791:Enzyme Inhibitors; D006538:Heptanoic Acids; D010080:Oxazoles; D011758:Pyrroles; D000069059:Atorvastatin; D019751:Intramolecular Transferases; C021924:lanosterol synthase