Abstract 16: ApoA5 Reduces Atherosclerosis in LDL Receptor-Deficient Mice
Apolipoprotein A5 (ApoA5) is a lipid-binding protein that is associated mainly with high-density lipoprotein (HDL) and to a lesser extent with very low-density lipoprotein (VLDL). ApoA5 gene variants are linked to altered lipid metabolism and increased risk of cardiovascular disease in humans. To investigate the role of ApoA5 in lipid metabolism, we placed transgenic mice expressing human ApoA5 and age/sex-matched control littermates on high fat diet for 20 weeks. We show that transgenic production of human ApoA5 resulted in significant improvement in hepatic and plasma lipid metabolism, protecting against the development of dyslipidemia and fatty liver disease in high fat-fed mice. To address the underlying mechanism, we determined hepatic triglyceride production vs. systemic triglyceride clearance. ApoA5 transgenic mice, as opposed to control littermates, exhibited significantly reduced hepatic output and enhanced clearance of triglyceride-rich particles. Furthermore, we show that purified ApoA5 proteins were capable of stimulating lipoprotein lipase (LPL) activity, contributing to accelerated VLDL-TG hydrolysis in a cell-free system. To determine the potential beneficial effect of ApoA5 on atherogenesis, we crossed the human ApoA5 transgene into LDL receptor knockout (LDLR-/-) mice. We demonstrate that transgenic ApoA5 production resulted in significant reduction in plasma lipid levels in LDLR-/- mice on high fat and high cholesterol diet. This effect translated into a significant reduction in atherosclerotic lesion in the aortic root of LDLR-/- mice.
From our studies we conclude: 1) ApoA5 acts to inhibit hepatic lipogenesis and limit hepatic VLDL-TG output, 2) ApoA5 augments LPL activity and enhances the systemic clearance of TG-rich particles, and 3) ApoA5 possesses anti-atherogenic property, protecting against the development of atherosclerosis in LDLR-/- mice.
- © 2012 by American Heart Association, Inc.