Lp(a) and Oxidized Phospholipids - Impact of Diets

PROJECT SUMMARY/ABSTRACT
An elevated level of plasma lipoprotein(a) [Lp(a)] is an independent causal risk factor for cardiovascular
disease (CVD). Lifestyle modifications, including dietary changes, are recommended as first line therapy to
reduce CVD risk. Dietary guidelines to lower saturated fatty acids (SFA) and replace them with unsaturated
fats or complex carbohydrates target primarily low-density lipoprotein cholesterol (LDL-C). In the small number
of dietary studies that assessed Lp(a) level, a consistent increase was found in response to reduction in SFA
intake. As LPA gene controls Lp(a) level and very few non-genetic factors impact Lp(a), this diet-mediated
effect is notable. Importantly, the increase in Lp(a) level is a counter observation to the effect of SFA reduction
on LDL-C. The mechanism(s) underlying this paradoxical finding and furthermore how SFA reduction affects
Lp(a) atherogenic properties beyond its plasma level remains unknown. Lp(a) carries the majority of circulating
proinflammatory and proatherogenic oxidized phospholipids (OxPL) and Lp(a) atherogenicity is mediated by its
OxPL content. Despite this, little is known about what happens to OxPL when dietary SFA is reduced and its
major lipoprotein carrier is increased. This proposal will bridge these knowledge gaps and obtain a more
complete picture of CVD risk manipulation through SFA reduction consistent with current dietary guidelines.
The central hypothesis—Lp(a)-OxPL content is increased with dietary SFA replacement diminishing the
beneficial effect of LDL-C lowering on CVD risk—will be tested through a comprehensive research in the
largest and most diverse platform consisting of three NIH-funded well-controlled metabolic feeding trials
(DELTA 1, DELTA 2, and GET-READI). Specifically, the dynamics of changes in Lp(a)-OxPL in response to
SFA reduction will be assessed using quantitative (total concentration) (Aim 1) and qualitative (subspecies
composition) (Aim 3) approaches in both healthy and metabolically challenged individuals. Replacement
strategies for SFA reduction (unsaturated fats vs. complex carbohydrate) and genetic variability modelled via
the apolipoprotein(a) size polymorphism will be tested as response modulators. Specific subgroups (e.g.,
ethnic/racial, those with and without metabolic burden) who may benefit the least (or the most) from the
generalized dietary guidelines to reduce SFA intake will be identified (Aim 2). As clinical laboratory values for
LDL-C include Lp(a) cholesterol, the opposing effect of SFA reduction on these two lipoproteins, therefore,
likely results in an inaccurate estimation of the true LDL-C response. This critical issue will be mapped in more
detail. The findings originating in the largest and most diverse compilation of data will improve the
understanding of a common non-pharmacological therapy that may enhance the atherogenic potential of Lp(a)
beyond its plasma level. Ultimately, this will assist in adopting precision nutrition as part of a heart-healthy
lifestyle for an improved CVD risk prevention and management.

Grant Number: 5R01HL157535-04
NIH Institute/Center: NIH
Principal Investigator: Enkhmaa Byambaa