Human paraoxonase 1 overexpression in mice stimulates HDL cholesterol efflux and reverse cholesterol transport

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.

The role of paraoxonase 1 in regulating high-density lipoprotein functionality during aging

“…The coexistence of PON1 and oxLDL decreases the atherogenicity of plaque by inhibiting the bioactivity of oxidized lipids (Cohen et al 2014), while the upregulation of ABCA1 expression on macrophages stimulates the efflux of cholesterol from these macrophages (Ikhlef et al 2016). An investigation by Ikhlef et al using transgenic mice that over-express human PON1 confirmed the involvement of this HDL-associated protein in the stimulation of RCT (Ikhlef et al 2017). RCT is significantly higher in transgenic mice over-expressing PON1 than in wild-type mice (Ikhlef et al 2017).…”

“…An investigation by Ikhlef et al using transgenic mice that over-express human PON1 confirmed the involvement of this HDL-associated protein in the stimulation of RCT (Ikhlef et al 2017). RCT is significantly higher in transgenic mice over-expressing PON1 than in wild-type mice (Ikhlef et al 2017). In addition, HDL from PON1-Tg mice have a higher capacity to mediate cholesterol efflux than HDL from wild-type mice (Ikhlef et al 2017).…”

Dysregulated Lipid Transport Proteins Correlate With Pathogenesis and Outcome in Severe Alcoholic Hepatitis

“…Animal studies have also shown a high degree of macrophage oxidative stress in PON1‐knockout mice . Thus, even in the absence of a hyperlipidemic state, PON1 deficiency promotes lipid accumulation and inflammatory and oxidative changes in monocytes/macrophages . However, the correlation of circulating PON1 levels with the severity of liver diseases and short‐term mortality in SAH is not yet documented, and further data regarding the role of PON1 in the management of lipid‐laden macrophages and its functionality have not been investigated in SAH.…”

The Effects of Anthocyanins and Their Microbial Metabolites on the Expression and Enzyme Activities of Paraoxonase 1, an Important Marker of HDL Function

“…2 of 18 are inversely correlated with the incidence of cardiovascular disease (CVD), mainly coronary heart disease (CHD) [5][6][7]. However, more recent studies have suggested that the relationship between HDL and CVD markers extends beyond the concentration of HDL alone and that the function of HDL may be more important than HDL concentration in protecting against CVD [8][9][10][11]. HDL possesses a number of atheroprotective functions such as mediation of cholesterol efflux from cholesterol-loaded cells, protection against oxidation and inflammation, and promotion of nitric oxide synthesis [12].…”