on February 6, 2003
Published online before print February 6, 2003, doi: 10.1161/01.ATV.0000060462.35946.B3
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Submitted on November 20, 2002
Accepted on January 9, 2003
Human Serum Paraoxonase Decreases Macrophage Cholesterol Biosynthesis
Orit Rozenberg ;
From the Lipid Research Laboratory (O.R., M.A.), Technion Faculty of Medicine, The Rappaport Institute for Research in Medical Sciences, Rambam Medical Center, Haifa, Israel; and the Department of Medicine (D.M.S.), UCLA, Los Angeles, Calif.
* To whom correspondence should be addressed. E-mail: aviram{at}tx.technion.ac.il.
Objective--Human serum paraoxonase 1 (PON1) activity is inversely related to the risk of developing an atherosclerotic lesion, which contains cholesterol-loaded macrophage foam cells. To assess a possible mechanism for this relationship, we analyzed the effect of PON1 on cellular cholesterol biosynthesis.
Methods and Results--Mouse peritoneal macrophages (MPMs) were harvested from PON1-deficient mice (PON1° and PON1°/E° mice on the genetic background of C57BL/6J and E° mice, respectively). PON1°/E° mice exhibited a significantly 51% increased atherosclerotic lesion area and 35% increased macrophage cholesterol content compared with control E° mice. In parallel, macrophage cholesterol biosynthesis rates were increased in PON1-deficient mice MPMs by 50% compared with their controls. Incubation of macrophages with human PON1 revealed a dose-dependent inhibitory effect (up to 84%) on macrophage cholesterol biosynthesis. We demonstrated a PON1 phospholipase-A2-like activity on MPMs, evidenced by release of polyunsaturated fatty acids and formation of lysophosphatidylcholine. On incubation of macrophages with lysophosphatidylcholine, a dose-dependent inhibition (up to 40%) of cellular cholesterol biosynthesis was noted. The inhibitory effect of PON1 on macrophage cholesterol biosynthesis was shown to be downstream to mevalonate, probably at the lanosterol metabolic point.
Conclusions--PON1 inhibits macrophage cholesterol biosynthesis and atherogenesis probably through its phospholipase-A2-like activity.
Key words: paraoxonase • macrophage • cholesterol biosynthesis • phospholipase-A2 • lysophosphatidylcholine
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