title: Metformin inhibits macrophage cholesterol biosynthesis rate: possible role for metformin-induced oxidative stress.
abstract: The aim of the present study was to analyze the metformin (MF) effect on two cellular atherogenic activities: cholesterol biosynthesis and oxidative-stress (OS) as studied in J774A.1 macrophage cell line. MF (2-5 mM) significantly and dose-dependently reduced macrophage cholesterol content and cholesterol biosynthesis rate from acetate, but not from mevalonate, by up to 68% and 71%, respectively. MF inhibitory effect on cholesterol biosynthesis was similar to that of simvastatin. In contrast to the above anti-atherogenic MF effect, MF significantly increased cellular OS as shown by enhancement of reactive oxygen species (ROS) production by up to 70%, and decrement in cellular reduced glutathione (GSH) levels by up to 67%. Macrophage paraoxonase2 (PON2) expression however, increased by MF, by up to 1.5 folds. To overcome the MF oxidation stimulation, macrophages were incubated with MF together with potent dietary antioxidants, i.e. -5 μg GAE/ml of pomegranate juice (PJ) or 30 μM of vitamin E (VE). Both of these potent antioxidants substantially reduced MF-induced OS, and in parallel, abolished MF inhibitory effect on cholesterol biosynthesis rate. We thus conclude that the inhibition of macrophage cholesterol biosynthesis by MF is related, at least in part, to MF-induced OS.
authors.affiliation: The Lipid Research Laboratory, Technion Faculty of Medicine, The Rappaport Family Institute for Research in the Medical Sciences, Rambam Medical Center, Haifa, Israel.
authors.forename: Marie
authors.initials: M
authors.lastname: Koren-Gluzer
authors.forename: Michael
authors.initials: M
authors.lastname: Aviram
authors.forename: Tony
authors.initials: T
authors.lastname: Hayek
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D014810:Vitamin E / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D007004:Hypoglycemic Agents; D014810:Vitamin E; D008687:Metformin; D002784:Cholesterol
keywords: 3-hydroxy-3-methyl-glutaryl-CoA; AMP-activated protein kinase; AMPK; Cholesterol biosynthesis; Diabetes; GSH; HMG-CoA; MF; Macrophages; Metformin; OS; Oxidative stress; PJ; PON2; ROS; T2DM; VE; glutathione; metformin; oxidative stress; paraoxonase2; pomegranate juice; reactive oxygen species; type 2 diabetes mellitus; vitamin E