Decreased Obesity and Atherosclerosis in Human Paraoxonase 3 Transgenic Mice

Abstract

Abstract-Paraoxonase 3 (PON3) is a member of the PON family, which includes PON1, PON2, and PON3. Recently, PON3 was shown to prevent the oxidation of low-density lipoprotein in vitro. To test the role of PON3 in atherosclerosis and related traits, 2 independent lines of human PON3 transgenic (Tg) mice on the C57BL/6J (B6) background were constructed. Human PON3 mRNA was detected in various tissues, including liver, lung, kidney, brain, adipose, and aorta, of both lines of Tg mice. The human PON3 mRNA levels in the livers of PON3 Tg mice were 4-to 7-fold higher as compared with the endogenous mouse Pon3 mRNA levels. Human PON3 protein and activity were detected in the livers of Tg mice as well. No significant differences in plasma total, high-density lipoprotein, and very-low-density lipoprotein/low-density lipoprotein cholesterol and triglyceride and glucose levels were observed between the PON3 Tg and non-Tg mice. Interestingly, atherosclerotic lesion areas were significantly smaller in both lines of male PON3 Tg mice as compared with the male non-Tg littermates on B6 background fed an atherogenic diet. When bred onto the low-density lipoprotein receptor knockout mouse background, the male PON3 Tg mice also exhibited decreased atherosclerotic lesion areas and decreased expression of monocyte chemoattractant protein-1 in the aorta as compared with the male non-Tg littermates. In addition, decreased adiposity and lower circulating leptin levels were observed in both lines of male PON3 Tg mice as compared with the male non-Tg mice. In an F2 cross, adipose Pon3 mRNA levels inversely correlated with adiposity and related traits. Our study demonstrates that elevated PON3 expression significantly decreases atherosclerotic lesion formation and adiposity in male mice. PON3 may play an important role in protection against obesity and atherosclerosis.

Human Paraoxonase Gene Cluster Transgenic Overexpression Represses Atherogenesis and Promotes Atherosclerotic Plaque Stability in ApoE-Null Mice

“…11,15,19 The present study demonstrates for the first time that the intact human PC transgenic overexpression not only repressed the development of atherosclerosis but also promoted the stability of atherosclerotic plaques that did form in vivo. Furthermore, such functions are independent of alterations of parameters of lipid metabolism, with respect to the present results, along with previous genomic modification researches of PONs.…”

“…11,15,19 Here, HDL from PC Tg mice and Wt mice were isolated by ultracentrifugation and analyzed in a 12-hour LDL copperinduced oxidation system at final concentrations of 0.25 mg/mL HDL and 0.5 mg/mL HDL, respectively. Relative hydroperoxide levels were detected every 2 hours.…”

“…18 PON3 transgenic (Tg) mice exhibit decreased atherogenesis compared to their littermates. 19 Moreover, PON2 and PON3 are also reported being able to reduce the accumulation of macrophages in the atherosclerotic plaques. 15,19 Based on these findings, Reddy et al concluded that all members of the paraoxonase gene family could be used as therapeutic targets for the treatment of atherosclerosis.…”

“…19 Moreover, PON2 and PON3 are also reported being able to reduce the accumulation of macrophages in the atherosclerotic plaques. 15,19 Based on these findings, Reddy et al concluded that all members of the paraoxonase gene family could be used as therapeutic targets for the treatment of atherosclerosis. 20 Nevertheless, as a gene cluster, the role of the entire PC in atherogenesis still remains to be elucidated.…”

Studies on protective effects of human paraoxonases 1 and 3 on atherosclerosis in apolipoprotein E knockout mice

“…9,13,14 PON1 and PON3 share similar potentials in protecting against atherogenesis, but their expression, protein localization and enzymatic activities are different, suggesting that their physiological functions are far from redundant. [14][15][16] Although transgenic expression of PON1 or PON3 offered a great potential for the treatment of atherosclerosis, there have been few studies that compared the effects of PON1 and PON3 on atherosclerosis in the same model. Moreover, despite their distinct physiological functions, it is not yet clear whether they can work in a synergistic or complementary way to protect against atherosclerosis.…”