VLDL triglycerides inhibit HDL-associated paraoxonase 1 (PON1) activity: in vitro and in vivo studies.
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 (0-660 μg 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.
The Lipid Research Laboratory, Technion Faculty of Medicine, the Rappaport Family Institute for Research in the Medical Sciences, Rambam Medical Center, Haifa, Israel.
Mira
M
Rosenblat
Sarah
S
Ward
Nina
N
Volkova
Tony
T
Hayek
Michael
M
Aviram
D000328:Adult; D000818:Animals; D043303:Aryldialkylphosphatase / Q000037:antagonists & inhibitors / Q000097:blood* / Q000737:chemistry; D001629:Bezafibrate / Q000494:pharmacology / Q000627:therapeutic use; D016022:Case-Control Studies; D002460:Cell Line; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D006801:Humans; D015228:Hypertriglyceridemia / Q000097:blood* / Q000201:enzymology; D000960:Hypolipidemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D008075:Lipoproteins, HDL / Q000097:blood*; D008079:Lipoproteins, VLDL / Q000097:blood* / Q000737:chemistry; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D014280:Triglycerides / Q000097:blood* / Q000737:chemistry; D014304:Triolein / Q000737:chemistry
D000960:Hypolipidemic Agents; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D014304:Triolein; D002784:Cholesterol; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; D001629:Bezafibrate