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.
Highlights
Elevated plasma lipoprotein(a) (LPA) levels are recognized as an independent risk factor for cardiovascular diseases
To verify the validity of our mouse model for studying the Nicotinic acid (NA)-lowering effect on LPA, six Transgenic APOA (tg-APOA) mice were fed for 2 weeks with normal chow diet or chow diet supplemented with 1% NA
Supplementation with 1% NA resulted in significantly decreased plasma APOA levels by 43% (Fig. 1A) and hepatic APOA mRNA by 65% (Fig. 1B) as compared with controls
Summary
Elevated plasma lipoprotein(a) (LPA) levels are recognized as an independent risk factor for cardiovascular diseases. 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. It is suggested that cAMP signaling might be involved in reducing APOA transcription, which leads to the lowering of plasma LPA.—Chennamsetty, I., K. Nicotinic acid inhibits hepatic APOA gene expression: studies in humans and in transgenic mice. Turnover studies in humans revealed that the rate of APOA biosynthesis greatly determines plasma LPA levels, whereas LPA catabolism appears to play only a minor role [8, 9]. Due to its high atherogenicity, numerous studies have been conducted to find drugs that lower plasma LPA.
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