Dietary cholesterol increases paraoxonase 1 enzyme activity

Abstract

This article is available online at http://www.jlr.org High density lipoprotein (HDL) levels have long believed to be cardioprotective ( 1 ) through a variety of processes, including reverse cholesterol transport in which excess cholesterol is taken to the liver for excretion ( 2 ). However, recent studies have highlighted the need to better understand the cardioprotective role of HDL. For example, two recent Mendelian randomization studies found that single nucleotide polymorphisms (SNP) that predict plasma HDL cholesterol (HDL-C) variance were not associated with myocardial infarction (MI) ( 3, 4 ). Moreover, a recent drug trial with torcetrapib, a cholesterol ester transport protein inhibitor, found that although torcetrapib increased levels of HDL and lowered deleterious low density lipoprotein (LDL) levels, it did not affect atherosclerotic measures and paradoxically led to an increase in adverse cardiovascular events ( 5 ). In addition, a recent large randomized clinical trial did not show a benefi t of niacin in preventing adverse cardiovascular outcomes, despite improved levels of HDL-C and triglycerides in the treatment group ( 6 ). These results refocus attention on the many aspects of HDL biology that are not captured by serum measurements of HDL, such as its paraoxonase 1 (PON1) activity, which itself is inversely associated with cardiovascular and other human diseases.The activity of PON1 , a liver-produced glycoprotein enzyme bound to the surface of HDL, is consistently correlated with atherosclerotic vascular disease and end-organ damage ( 7-9 ). PON1 is at least partially responsible for the cardioprotective inhibitory effects of HDL on LDL peroxidation ( 10-12 ), and it also has been demonstrated to hydrolyze oxidized lipid or lipid hydroperoxides in LDL ( 13 ). Inactivation of PON1 reduced the ability of HDL to Abstract HDL-associated paraoxonase 1 (PON1) activity has been consistently associated with cardiovascular and other diseases. Vitamins C and E intake have previously been positively associated with PON1 in a subset of the Carotid Lesion Epidemiology and Risk (CLEAR) cohort. The goal of this study was to replicate these fi ndings and determine whether other nutrient intake affected PON1 activity. To predict nutrient and mineral intake values, 1,402 subjects completed a standardized food frequency survey of their dietary habits over the past year. Stepwise regression was used to evaluate dietary and covariate effects on PON1 arylesterase activity. Five dietary components, cholesterol ( P < 2.0 × 10 ؊ 16 ), alcohol ( P = 8.51 × 10 ؊ 8 ), vitamin C ( P = 7.97 × 10 ؊ 5 ), iron ( P = 0.0026), and folic acid (0.037) were independently predictive of PON1 activity. Dietary cholesterol was positively associated and predicted 5.5% of PON1 activity, second in variance explained. This study presents a novel fi nding of dietary cholesterol, iron, and folic acid predicting PON1 activity in humans and confi rms prior reported associations, including that with vitamin C. Identifying and understanding en...

Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project

“…First, although the ESP data contained two coding PON1 functional SNVs ( PON1 Q192 and PON1 L55M ), PON1 -108C/T was not captured by the exome sequencing methods. PON1 -108C/T is a major determinant of PON1 activity, accounting for ‫ف‬ 14% of PON1 activity variance ( 7,20 ). However, as PON1 -108C/T has not been associated with heart disease in meta-analyses ( 8,9 ) or carotid artery disease in smaller cohorts ( 3,6,7 ), and that is found more frequently in AA subjects.…”

“…One of these hypotheses is that geneby-environment interactions among common SNVs comprise a large portion of heritability ( 18,19 ). Given the wide variety of pharmacologic and dietary determinants on PON1 expression and enzyme activity ( 20 ), the potential interaction of these environmental factors with PON1 variants could represent another important source of trait heritability.…”

PLTP activity inversely correlates with CAAD: effects of PON1 enzyme activity and genetic variants on PLTP activity

“…The study population is a subset (n = 1,115) of the previously described CLEAR study ( 8,(10)(11)(12)(40)(41)(42)(43)(44)(45)(46)(47) PLTP region SNP associations with PLTPa. SNPs with у 1% frequency identifi ed in the PLTP region between 50 kb upstream of the fi rst codon or downstream of the last (n = 124 SNPs) were included in our analyses of the genetic predictors of PLTPa.…”

The contribution of paraoxonase 1 and myeloperoxidase to HDL-cholesterol functionality

“…On the contrary, in a cohort-based analysis of 1548 humans, Kim et al [38] confirmed that dietary saturated myristic acid and monounsaturated gadoleic acid can positively affect the circulating PON1 activity. It has been also indicated that other dietary compounds such as extra-virgin olive oil, virgin coconut oil, vitamin C, iron and folic acid and dietary cholesterol are positive predictors of the circulating PON1 activity and the possible HDL-C functionality [6,37,44]. Moreover, a significant elevation in the plasma PON1 activity and the HDL-C level has been observed in hypercholesterolemic subjects, in response to anthocyanins at a dose of 160 mg two times daily [97].…”