Human PON3, Effects Beyond the HDL

Abstract

T he article by Shih et al 1 in this issue of CirculationResearch is the first report of transgenic expression of human Paraoxonase 3 (PON3) in mice and its ability to decrease significantly atherosclerotic lesion formation and adiposity. These effects were, interestingly, observed only in male but not in female mice on either C57BL/6J or LDLR KO backgrounds. Noteworthy, no human or mouse PON3 were detected in mouse HDL and plasma and therefore the effects of human PON3 were derived from PON3 in the tissues, not in the blood.PON3 is a member of the PON gene family that includes PON1, PON2, and PON3. 2 PON enzymes are well conserved in mammals: at the amino acid level, the orthologs share 79% to 95% and the paralogs Ϸ65% identity. 2,3 PON1, PON2 and PON3, have different cell and tissue distribution as well as different regulation of expression, suggesting distinct physiological roles for each of them. These roles, however, remain largely unknown. Phylogenetic, structural and biochemical data demonstrate that all three PONs are primarily lactone hydrolyzing enzymes, albeit with different substrate specificity. [3][4][5] PON1 is by far the most studied member of the family, and much of our understanding of the PON enzymes is derived primarily from studies involving PON1 protein. PON1 is synthesized in the liver and secreted in the blood where it associates almost exclusively with the HDL fraction. There is ample evidence from in vitro, animal and epidemiological studies that PON1 protects against atherosclerosis 6,7 ; however, the exact mechanisms are still elusive.When PON3 proteins were detected in rabbit and human serum associated with the HDL fraction, 8,9 they were first tested in systems in which PON1 had demonstrated an effect: purified rabbit PON3 protected LDL against copper induced oxidation in vitro 8 ; stably transfected cells overexpressing human PON3 oxidized LDL to a less extent than control cells and were able to retard biological effects of preformed mildly oxidized LDL. 9 Thus, PON3 became well thought-out like another HDL protein with antioxidant/antiatherogenic properties 10 despite the fact that in rabbit and human sera PON3 is at least 2 orders of magnitude less abundant than PON1. 8,9 So, is the HDL indeed the place where PON3 acts physiologically, at least for all mammalian species?Here is a brief review of the interspecies differences in PON3 expression and tissue distribution. PON3 protein has been isolated from and/or detected in the livers or liverderived cell lines from rabbit, rat, mouse and human. 1,9,11,12 Human PON3 is expressed throughout the entire gastrointestinal tract, with highest message and protein levels in the esophagus and stomach. 13 In mouse gastro-intestinal tract, PON3 has highest expression in jejunum and ileum and was not detected in colon. 13 PON3 cDNA was detected in cultured airway epithelial from wild type and at even higher levels from PON1-knockout mice. 14 PON3 is expressed in murine, but not in human macrophages. 15 Shih and colleagues 1 report the presence ...

Protectors or Traitors: The Roles of PON2 and PON3 in Atherosclerosis and Cancer

“…Moreover, human PON3 is present on HDL particles and absent in macrophages while the opposite is true for mice [1, 27]. In general, it has been postulated that human PON3 exerts its (antiatherogenic) function rather inside than outside the cells [35, 73], similar to PON2 and likely different from PON1. Studies performed by Shih et al also revealed a role for PON3 in lipid metabolism that links to adiposity; intriguingly, this was gender-specific for yet unknown reasons [35].…”

Paraoxonase 3 inhibits cell proliferation and serves as a prognostic predictor in hepatocellular carcinoma

“…PON3 is mainly expressed in the liver, and exerts anti-inflammatory and anti-oxidative properties in cellular lever, namely in hepatocytes [9, 11, 12]. PON3 was reported as a more efficient inhibitor of oxidative stress than PON1 in rabbit serum [13].…”

“…PON1 is also synthesized in the liver and is secreted into the serum where it performs antioxidant and anti-inflammatory activities [10]. However, the similar protective activities of PON3 are thought to take place mainly at the cellular level, namely in hepatocytes [11, 12]. Moreover, rabbit serum PON3 has a significantly more pronounced antioxidant effect when compared with serum PON1 [13], and serum PON3 concentration is also associated with the severity of hepatic impairment in patients with chronic liver disease [14].…”

Modulation of paraoxonase 1 and 3 expression after moderate exercise training in the rat

“…Although this may suggest distinct physiological roles for each of them ( 19 ), much remains unknown. All members of the PON family display antioxidant properties ( 20 ) and are mainly synthesized by the liver; however, at least in rabbits and humans, only PON1 and PON3 are found in the serum in association with HDL, where they prevent the oxidative modifi cation of LDL.…”