VLDL triglycerides inhibit HDL-associated paraoxonase 1 (PON1) activity: in vitro and in vivo studies

• Published in: BioFactors (Oxford) Vol. 38; no. 4; pp. 292 - 299
• Main Authors: Rosenblat, Mira, Ward, Sarah, Volkova, Nina, Hayek, Tony, Aviram, Michael
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.07.2012
• Subjects: Adult; Animals; Aryldialkylphosphatase - antagonists & inhibitors; Aryldialkylphosphatase - blood; Aryldialkylphosphatase - chemistry; bezafibrate; Bezafibrate - pharmacology; Bezafibrate - therapeutic use; Case-Control Studies; Cell Line; Cholesterol - blood; Cholesterol - secretion; HDL; Humans; Hypertriglyceridemia - blood; Hypertriglyceridemia - enzymology; hypertriglyceridemic patients; Hypolipidemic Agents - pharmacology; Hypolipidemic Agents - therapeutic use; Lipoproteins, HDL - blood; Lipoproteins, VLDL - blood; Lipoproteins, VLDL - chemistry; Macrophages - drug effects; Macrophages - secretion; Mice; Middle Aged; Paraoxonase 1 (PON1); triglyceride; Triglycerides - blood; Triglycerides - chemistry; Triolein - chemistry; VLDL
• ISSN: 0951-6433; 1872-8081; 1872-8081
• DOI: 10.1002/biof.1021

We analyzed, for the first time, both in vitro and in vivo, the effect of very low density lipoprotein (VLDL), or of pure triglycerides, on high‐density lipoprotein (HDL)‐associated paraoxonase1 (PON1) catalytic activities. Incubation of serum or HDL from healthy subjects with VLDL (0–330 μg protein/mL) significantly decreased serum PON1 lactonase or arylesterase activities by up to 11% or 24%, and HDL‐associated PON1 lactonase or arylesterase activities by up to 32% or 46%, respectively, in a VLDL dose‐dependent manner. VLDL (0–660μg protein/mL) also inhibited recombinant PON1 (rePON1) lactonase or arylesterase activities by up to 20% or 42%, respectively. Similar inhibitory effect was noted upon rePON1 incubation with pure triglyceride emulsion. Bezafibrate therapy to three hypertriglyceridemic patients (400 mg/day, for one month) significantly decreased serum triglyceride concentration by 67%, and increased serum HDL cholesterol levels by 48%. PON1 arylesterase or paraoxonase activities in the patients' HDL fractions after drug therapy were significantly increased by 86–88%, as compared to PON1 activities before treatment. Similarly, HDL‐PON1 protein levels significantly increased after bezafibrate therapy. Finally, bezafibrate therapy improved HDL biological activity, as HDL obtained after drug therapy showed increased ability to induce cholesterol efflux from J774A.1 macrophages, by 19%, as compared to HDL derived before therapy. We thus conclude that VLDL triglycerides inhibit PON1 catalytic activities, and bezafibrate therapy significantly improved HDL‐PON1 catalytic and biological activities. © 2012 International Union of Biochemistry and Molecular Biology, Inc.