title: Nicotinic acid inhibits hepatic APOA gene expression: studies in humans and in transgenic mice.
abstract: Elevated plasma lipoprotein(a) (LPA) levels are recognized as an independent risk factor for cardiovascular diseases. Our knowledge on LPA metabolism is incomplete, which makes it difficult to develop LPA-lowering medications. Nicotinic acid (NA) is the main drug recommended for the treatment of patients with increased plasma LPA concentrations. The mechanism of NA in lowering LPA is virtually unknown. To study this mechanism, we treated transgenic (tg) APOA mice with NA and measured plasma APOA and hepatic mRNA levels. In addition, mouse and human primary hepatocytes were incubated with NA, and the expression of APOA was followed. Feeding 1% NA reduced plasma APOA and hepatic expression of APOA in tg-APOA mice. Experiments with cultured human and mouse primary hepatocytes in addition to reporter assays performed in HepG2 cells revealed that NA suppresses APOA transcription. The region between -1446 and -857 of the human APOA promoter harboring several cAMP response element binding sites conferred the negative effect of NA. In accordance, cAMP stimulated APOA transcription, and NA reduced hepatic cAMP levels. It is suggested that cAMP signaling might be involved in reducing APOA transcription, which leads to the lowering of plasma LPA.
authors.affiliation: Institute of Molecular Biology and Biochemistry,  Medical University of Graz,  Austria.
authors.forename: Indumathi
authors.initials: I
authors.lastname: Chennamsetty
authors.forename: Karam M
authors.initials: KM
authors.lastname: Kostner
authors.forename: Thierry
authors.initials: T
authors.lastname: Claudel
authors.forename: Manjula
authors.initials: M
authors.lastname: Vinod
authors.forename: Sasa
authors.initials: S
authors.lastname: Frank
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Weiss
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.forename: Gerhard M
authors.initials: GM
authors.lastname: Kostner
mesh_terms: D000818:Animals; D001054:Apolipoproteins A / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009525:Niacin / Q000494:pharmacology*; D012333:RNA, Messenger
chemical_list: D001054:Apolipoproteins A; D012333:RNA, Messenger; D009525:Niacin; D000242:Cyclic AMP