Nicotinic acid inhibits hepatic APOA gene expression: studies in humans and in transgenic mice

Chennamsetty, Indumathi, Kostner, Karam M., Claudel, Thierry, Vinod, Manjula, Frank, Sasa, Weiss, Thomas S., Trauner, Michael and Kostner, Gerhard M. (2012) Nicotinic acid inhibits hepatic APOA gene expression: studies in humans and in transgenic mice. Journal of Lipid Research, 53 11: 2405-2412. doi:10.1194/jlr.M029769

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Author Chennamsetty, Indumathi
Kostner, Karam M.
Claudel, Thierry
Vinod, Manjula
Frank, Sasa
Weiss, Thomas S.
Trauner, Michael
Kostner, Gerhard M.
Title Nicotinic acid inhibits hepatic APOA gene expression: studies in humans and in transgenic mice
Journal name Journal of Lipid Research   Check publisher's open access policy
ISSN 0022-2275
Publication date 2012-11-01
Sub-type Article (original research)
DOI 10.1194/jlr.M029769
Open Access Status File (Publisher version)
Volume 53
Issue 11
Start page 2405
End page 2412
Total pages 8
Place of publication Bethesda, MD, United States
Publisher American Society for Biochemistry and Molecular Biology
Language eng
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.
Keyword Primary human hepatocytes
Reporter assay
mRNA expression
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
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Created: Thu, 15 Nov 2012, 21:03:50 EST by System User on behalf of School of Medicine