title: Metformin reduces the endotoxin-induced down-regulation of apolipoprotein E gene expression in macrophages.
abstract: The atheroprotective role of macrophage-derived apolipoprotein E (apoE) is well known. Our previous reports demonstrated that inflammatory stress down-regulates apoE expression in macrophages, aggravating atherogenesis. Metformin, extensively used as an anti-diabetic drug, has also anti-inflammatory properties, and thus confers vascular protection. In this study, we questioned whether metformin could have an effect on apoE expression in macrophages in normal conditions or under lipopolysaccharide (LPS)-induced stress. The results showed that metformin slightly increases the apoE expression only at high doses (5-10 mM). Low doses of metformin (1-3 mM) significantly reduce the LPS down-regulatory effect on apoE expression in macrophages. Our experiments demonstrated that LPS-induced NF-κB binds to the macrophage-specific distal regulatory element of apoE gene, namely to the multienhancer 2 (ME.2) and its 5'-deletion fragments. The NF-κB binding on ME.2 and apoE promoter has a down-regulatory effect. In addition, data revealed that metformin impairs NF-κB nuclear translocation, and thus, improves the apoE levels in macrophages under inflammatory stress. The positive effect of metformin in the inflammatory states, its clinical safety and low cost, make this drug a potential adjuvant in the therapeutic strategies for atherosclerosis.
authors.affiliation: Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania.
authors.forename: Simona
authors.initials: S
authors.lastname: Stavri
authors.affiliation: Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania.
authors.forename: Violeta G
authors.initials: VG
authors.lastname: Trusca
authors.affiliation: Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania.
authors.forename: Maya
authors.initials: M
authors.lastname: Simionescu
authors.affiliation: Institute of Cellular Biology and Pathology "Nicolae Simionescu", Bucharest, Romania. Electronic address: anca.gafencu@icbp.ro.
authors.forename: Anca V
authors.initials: AV
authors.lastname: Gafencu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000235:genetics*; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D001057:Apolipoproteins E; D007004:Hypoglycemic Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D008687:Metformin
keywords: Apolipoprotein E; LPS; Macrophages; Metformin; Multienhancer; NF-κB