Abstract 5522: Niacin Increases HDL Through Reduced Phospholipase A1 Activtiy And CETP mRNA Stability In The Mice Expressing Human ApoA-I And CETP
Introduction: Niacin is one of the most potent drugs available to increase high density lipoprotein cholesterol (HDL-C) levels. However the mechanism responsible for the HDL-C increase in response to niacin is not fully understood. We examined the effect of niacin on HDL-C using a humanized mouse model of HDL metabolism, human apoA-I transgenic mice expressing CETP.
Methods and Results: Human apolipoprotein A-I transgenic (hA-I tg) mice (n=18) were transduced with adeno-associated virus (AAV2/8; 1.0 x 1010 gene copies) containing CETP with a liver-specific thyroxine binding globulin (TBG) promoter or control virus. Two weeks following transduction, mice were fed either a chow or chow containing 3% niacin for 2 weeks. Niacin treatment significantly increased HDL-C (34%; p<0.01) in hA-I tg mice expressing CETP. We did not see HDL-C increase in mice injected with control virus following treatment with niacin. Niacin reduced CETP protein mass 78% (p<0.01) and mRNA by 97% (p<0.01) compared to chow in hA-I tg mice expressing CETP, but did not change mRNA levels of endogenous TBG mRNA. Niacin significantly reduced plasma PLA1 activity, of which hepatic lipase and endothelial lipase activity are major contributors, by 19% (p<0.01) in hA-I tg mice expressing CETP compared to chow fed mice. EL mRNA and HL mRNA expression in the liver significantly reduced with niacin treatment. There was no effect of niacin on LCAT or SR-BI expression in liver.
Conclusion: Treatment of hA-I tg mice expressing CETP with niacin significantly increased HDL-C. This increase was due to reduced PLA1 activity and a novel effect of niacin on reducing CETP mRNA stability. These results suggest that multiple effects contribute to the niacin-mediated increase in HDL-C.