Cholesterol reduction and macrophage function: role of paraoxonases

Abstract

Purpose of review Unregulated uptake of oxidized LDL by macrophages to form foam cells is the hallmark for atherosclerosis. The paraoxonase (PON) family of enzymes play a critical role in attenuating atherosclerotic lesion formation by hydrolyzing lipid peroxides (LOOHs) and preventing the oxidation of LDL particles and by enhancing HDL-mediated cholesterol efflux. Findings in recent years suggest novel mechanisms by which PON isoforms interact with macrophages to regulate cholesterol metabolism and cellular function. Recent findings The association of PON with HDL particles facilitates binding of the particle to macrophages and ABCA1-dependent cholesterol efflux. The hydrolysis of membrane phospholipids by PON generates lysophosphatidylcholine which is shown to regulate expression of cholesterol transport proteins. The PON family also regulates multiple aspects of macrophage function. PON attenuates inflammation and prevents induction of apoptosis via activation of an SR-B1-dependent signaling mechanism. PON limits macrophage-dependent oxidant formation by preventing activation of the membrane-associated NADPH oxidase and by stabilizing mitochondria. PON also promotes the differentiation of macrophages to an anti-inflammatory phenotype. This function appears to be independent of PON enzymatic activity and, rather, is dependent on the ability of endogenous sulfhydryls to neutralize pro-inflammatory peroxides. Summary In recent years, the therapeutic efficacy of HDL-based therapies has been subject to dispute. Pharmacological approaches that target an increase in the expression and/or activity of PON may facilitate macrophage cholesterol metabolism and attenuate inflammatory injury.

Current Understanding of the Immunomodulatory Activities of High-Density Lipoproteins

“…HDL particles carry important enzymes, such as paraoxonase, which can exert a protective effect against oxidative damage of circulating lipoproteins and cells [ 43 ]. Among the enzymes of the paraoxonase family, paraoxonase 1 (PON1) and paraoxonase 3 (PON3) are mainly associated with HDL and exhibit paraoxonase, lactonase and esterase activities [ 44 ]. PON1 protects HDL and low-density lipoprotein (LDL) against oxidation, reduces macrophage and aortic oxidative status associated with decreased superoxide anion production, and enhances the reverse cholesterol transport by facilitating the binding of HDL particles to macrophages [ 45 , 46 , 47 , 48 ].…”

“…M1 macrophages are regarded as pro-inflammatory and are induced by T helper type 1 (Th1) cytokines, including interferon γ, tumor necrosis factor (TNF) α (TNF-α), IL-2, and LPS. M2 macrophages are implicated in the resolution of inflammation via suppression of cytokine secretion and promotion of wound healing and tissue remodeling [ 44 , 108 ]. Several humoral factors may modify the balance between M1 and M2 phenotypes.…”

“…Among the paraoxonase family of enzymes, PON1 and PON3 are mainly associated with HDL [ 44 ]. PON1 was shown to directly impact inflammation via attenuation of inflammatory cytokine release of macrophages, such as TNF-α and IL-6 [ 171 ].…”

On the Role of Paraoxonase-1, Chemokine (C-C motif) Ligand 2 and Metabolism in Oxidation, Inflammation and Disease. A 2021 Update

“…Further, PON1 inhibits the formation of free radical species in macrophages by preventing the activation of NADPH oxidase and by stabilizing mitochondria. PON1 also promotes the differentiation of macrophages into an anti-inflammatory phenotype [146]. A recent study of note [147] showed that genetically reduced PON1 concentration induces proatherogenic changes in plasma proteomes in humans and mice.…”

Paraoxonases Activities and Polymorphisms in Elderly and Old-Age Diseases: An Overview

“…As stated before, HDL is described as having the antioxidant ability to prevent or delay the oxidation of LDL due to proteins associated with its surface, such as PON-1, which can prevent the oxidation of HDL, as well as LDL [125][126][127][128][129][130][131][132][133][134][135][136][137]. Again, it is important to note that both PON-1 and PON-3 are components of HDL and that they reduce the atherogenicity of lipoproteins through of hydrolyzing of lipolactones [138,139]. As a result, the uptake of atherogenic lipoproteins by macrophages and the formation of foam cells is reduced [140].…”