Paraoxonase 1 and atherosclerosis

Abstract

Paraoxonase 1 (PON1), residing almost exclusively on HDL, was discovered because of its hydrolytic activity towards organophosphates. Subsequently, it was also found to hydrolyse a wide range of substrates, including lactones and lipid hydroperoxides. PON1 is critical for the capacity of HDL to protect LDL and outer cell membranes against harmful oxidative modification, but this activity depends on its location within the hydrophobic lipid domains of HDL. It does not prevent conjugated diene formation, but directs lipid peroxidation products derived from these to become harmless carboxylic acids rather than aldehydes which might adduct to apolipoprotein B. Serum PON1 is inversely related to the incidence of new atherosclerotic cardiovascular disease (ASCVD) events, particularly in diabetes and established ASCVD. Its serum activity is frequently discordant with that of HDL cholesterol. PON1 activity is diminished in dyslipidaemia, diabetes, and inflammatory disease. Polymorphisms, most notably Q192R, can affect activity towards some substrates, but not towards phenyl acetate. Gene ablation or over-expression of human PON1 in rodent models is associated with increased and decreased atherosclerosis susceptibility respectively. PON1 antioxidant activity is enhanced by apolipoprotein AI and lecithin:cholesterol acyl transferase and diminished by apolipoprotein AII, serum amyloid A, and myeloperoxidase. PON1 loses this activity when separated from its lipid environment. Information about its structure has been obtained from water soluble mutants created by directed evolution. Such recombinant PON1 may, however, lose the capacity to hydrolyse non-polar substrates. Whilst nutrition and pre-existing lipid modifying drugs can influence PON1 activity there is a cogent need for more specific PON1-raising medication to be developed.

The Role of Polyphenols in Modulating PON1 Activity Regarding Endothelial Dysfunction and Atherosclerosis

“…In those with severe sepsis, PON1 can be used as a marker serum suggestive of a worse prognosis. Another advantage is that PON1 can fight against endotoxins from Gram-negative bacteria [ 33 , 34 ]…”

Established and potential cardiovascular risk factors in metabolic syndrome: Effect of bariatric surgery

“…CEC in metabolic syndrome is reduced as a function of the number of metabolic syndrome components [31 ▪ ]. Alterations in the HDL proteome with metabolic syndrome include changes in ApoA1, ApoA2, PON1, ApoC3, ApoJ [24,32,33] and glutathione peroxidase. There are also shifts in myeloperoxidase [34,35], lipoprotein-associated phospholipase A2 (Lp-PLA2) [36], microRNA (miRNA) [37 ▪ ], SAA [27 ▪▪ ] and ceruloplasmin [38].…”

Alteration of the intestinal microbiota and serum metabolites in a mouse model of Pon1 gene ablation

“…Several studies have elucidated the potential of Paraoxonase 1( Pon1 ) in the development of diseases. Hitherto, critical roles of Pon1 have been identified in atherosclerosis‐related diseases, 1,2 obstructive sleep apnea, 3 cancer, 4 diabetes, 5 neurological diseases, 6 and inflammatory diseases 7 . Some studies have shown that disrupted Pon1 is associated with an increased risk of atherosclerosis and cardiovascular disease, 8 and impaired gene function increases lipoprotein oxidation and causes advanced atherosclerotic lesions 9,10 .…”