Paraoxonase 2 attenuates macrophage triglyceride accumulation via inhibition of diacylglycerol acyltransferase 1

Abstract

This study questioned the role of paraoxonase 2 (PON2) in attenuation of macrophage lipids accumulation. Mouse peritoneal macrophages (MPMs) harvested from PON2-deficient mice versus control C57BL/6 mice, look like foam cells and were larger in size and filled with lipid droplets. Macrophage triglyceride (but not cholesterol) content, biosynthesis rate, and microsomal acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) activity (not mRNA and protein) in PON2-deficient versus control MPM were all significantly increased by 4.6-, 3.6-, and 4.4-fold, respectively. Similarly, microsomal DGAT1 activity and cellular triglyceride content were significantly decreased in human PON2-transfected cells as well as upon incubation of PON2-deficient MPM with recombinant PON2. In all the above experimental systems, PON2 also decreased macrophage oxidative state. Incubation of PON2-deficient MPM with the free radicals generator 2,2′-amidinopropane hydrochloride increased cellular oxidative stress and DGAT1 activity by 2.2-and 3.4-fold, respectively, whereas incubation of microsomes from PON2-deficient MPM with superoxide dismutase decreased DGAT1 activity by 40%. We thus conclude that PON2 attenuates macrophage triglyceride accumulation and foam cell formation via inhibition of microsomal DGAT1 activity, which appears to be sensitive to oxidative state.-Rosenblat, M., R. Coleman, S. T. Reddy, and M. Aviram. Paraoxonase 2 attenuates macrophage triglyceride accumulation via inhibition of diacylglycerol acyltransferase 1. J. Lipid Res. 2009. 50: 870-879.

Increased expression of interleukin-1β in triglyceride-induced macrophage cell death is mediated by p38 MAP kinase

“…The uptake of oxidized low density lipoprotein (oxLDL) and accumulation of triglyceride (TG) by macrophages are important contributing factors during the development of atherosclerosis (7). TG accumulation in macrophages causes oxidative stress and further contributes to the formation of the foam cell phenotype (8)(9)(10). Death of foam cells in atherosclerotic lesions can be triggered under a variety of conditions such as hypoxia, ATP depletion, a high concentration of oxLDL, and intracellular accumulation of unesterified or free cholesterol (11,12).…”

Triglyceride-Induced Macrophage Cell Death Is Triggered by Caspase-1

“…These foam cells subsequently die and promote further inflammation, plaque development, and rupture in atherosclerosis. [10][11][12][13][14][15] Based on these observations, studies have focused on understanding the molecular mechanism of TG on macrophages, especially in cell death. TG has been reported to promote necrotic macrophage cell death by inducing mitochondria-mediated oxidative stress.…”

Association of Human Monocytic Paraoxonse 2 (Pon 2) and Serum Nitric Oxide Levels in Preeclampsia Patients

“…However, its antioxidant functions at the cellular level, joining the host of intracellular antioxidant enzymes that protect cells from oxidative stress (19) . PON2 represents an endogenous defense mechanism against vascular oxidative stress and unfolded protein response-induced cell death, thereby contributing to the prevention of atherosclerosis (20) .…”