Paraoxonase 2 (PON2) decreases high glucose-induced macrophage triglycerides (TG) accumulation, via inhibition of NADPH-oxidase and DGAT1 activity: studies in PON2-deficient mice.
OBJECTIVE
The present study investigates the role of paraoxonase 2 (PON2) in the attenuation of macrophage triglycerides (TG) biosynthesis, and oxidative stress, under diabetic conditions.


METHODS
Peritoneal macrophages (MPM) from PON2-deficient and from C57BL/6 control mice were harvested and cultured under normal (5mM) or high glucose concentration (30mM), and evaluated for cellular TG metabolism as well as for their oxidative stress.


RESULTS
In PON2-deficient MPM vs. control MPM, under diabetic conditions (high glucose concentration), we observed substantial increment in TG accumulation (3 fold), TG biosynthesis (2.6 fold) and microsomal diacylglycerol acyltransferase1 (DGAT1) activity (+60%). Furthermore, in these cells we have demonstrated increased oxidative stress, as expressed by significant increment in cellular oxidative stress (+25%), macrophage-mediated LDL oxidation (+41%) and expression of the receptor for advanced glycation end products - RAGE (+18%). Apocynin, an NADPH-oxidase inhibitor, abolished the increment in MPM TG accumulation, MPM TG biosynthesis, and microsomal DGAT1 activity, as a result of PON2-deficiency, under diabetic conditions.


CONCLUSIONS
We conclude that PON2 has a significant protective role against macrophage triglyceride accumulation, macrophage TG biosynthesis, microsomal DGAT1 activity and macrophage oxidative stress, under high glucose concentrations. We suggest that this protective effect may be mediated by PON2 through the attenuation of NADPH-oxidase activity. The use of appropriate means to increase macrophage PON2 expression can lead to attenuation in macrophage TG accumulation and in cellular oxidative stress, under diabetic conditions, and thus may contribute to the decrement in macrophage atherogenicity and foam cell formation, attenuating the development of vascular complications in diabetes mellitus.
Meilin
Edna
E
The Lipid Research Laboratory, Technion, The Rappaport Family Institute for Research in the Medical Science, Rambam Medical Center, Haifa, Israel.
Aviram
Michael
M
Hayek
Tony
T
D000818:Animals; D043303:Aryldialkylphosphatase / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D002784:Cholesterol / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental; D051048:Diacylglycerol O-Acyltransferase / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008861:Microsomes / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress; D010100:Oxygen / Q000737:chemistry; D016133:Polymerase Chain Reaction; D014280:Triglycerides / Q000378:metabolism*
D014280:Triglycerides; D002784:Cholesterol; D019255:NADPH Oxidases; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase; D043303:Aryldialkylphosphatase; D005947:Glucose; D010100:Oxygen