Abstract
This study was aimed to investigate the effect of human PON1 overexpression in mice on cholesterol efflux and reverse cholesterol transport. PON1 overexpression in PON1-Tg mice induced a significant 3-fold (p<0.0001) increase in plasma paraoxonase activity and a significant ~30% (p<0.0001) increase in the capacity of HDL to mediate cholesterol efflux from J774 macrophages compared to wild-type mice. It also caused a significant 4-fold increase (p<0.0001) in the capacity of macrophages to transfer cholesterol to apoA-1, a significant 2-fold (p<0.0003) increase in ABCA1 mRNA and protein expression, and a significant increase in the expression of PPARγ (p<0.0003 and p<0.04, respectively) and LXRα (p<0.0001 and p<0.01, respectively) mRNA and protein compared to macrophages from wild-type mice. Moreover, transfection of J774 macrophages with human PON1 also increased ABCA1, PPARγ and LXRα protein expression and stimulates macrophages cholesterol efflux to apo A1. In vivo measurements showed that the overexpression of PON1 significantly increases the fecal elimination of macrophage-derived cholesterol in PON1-Tg mice. Overall, our results suggested that the overexpression of PON1 in mice may contribute to the regulation of the cholesterol homeostasis by improving the capacity of HDL to mediate cholesterol efflux and by stimulating reverse cholesterol transport.
Highlights
Atherosclerosis is the primary factor involved in cardiovascular disease events
We explored the effect of human paraoxonase 1 (PON1) overexpression in mice on cholesterol homeostasis by measuring reverse cholesterol transport (RCT). [3H]-cholesterol-loaded J774 macrophages were injected into the peritoneal cavities of PON1-Tg and WT mice. [3H]-cholesterol counts in the plasma were
The main protective effect of HDL is due to their maintenance of cellular cholesterol homeostasis via RCT, a process by which HDL recover excess cholesterol in cells and transport it back to the liver to be eliminated in the feces
Summary
Atherosclerosis is the primary factor involved in cardiovascular disease events. Epidemiological studies have shown that there is an inverse relationship between HDL concentration and the risk of atherosclerotic lesion formation and cardiovascular disease events. This aroused interest to PLOS ONE | DOI:10.1371/journal.pone.0173385. PON1 overexpression stimulates reverse cholesterol transport develop pharmacological agents that increase HDL concentrations. While such agents do significantly increase HDL concentrations, their effect on cardiovascular protection has been very disappointing [1,2]. The idea that function plays an important role in the anti-atherosclerotic effect of HDL has increased interest in exploring factors that may improve HDL functionality
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