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

Journal of Lipid Research

Thomas S. Weiss¹  Karam M. Kostner²  Thierry Claudel³  Michael Trauner³  Sasa Frank⁴  Indumathi Chennamsetty⁴  Manjula Vinod⁴  Gerhard M. Kostner⁵ 

[1] Center for Liver Cell Research, Department of Pediatrics, University Medical Center Regensburg, Germany;Department of Cardiology, University of Queensland, Mater Adult Hospital, 4101 Brisbane, Australia;Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria;Institute of Molecular Biology and Biochemistry, Medical University of Graz, Austria;To whom correspondence should be addressed;

关键词: primary human hepatocytes;    reporter assay;    apolipoprotein(a);    mRNA expression;    atherosclerosis;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown