Friday, April 19, 2024
4/19/2024
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.
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