Lipoprotein(a) and Effects of Diet: Time for Reassessment

Abstract

Dietary modification is a critical tool in the prevention of cardiovascular disease (CVD). While the role of saturated fat (SFA) intake is well established in affecting LDL cholesterol concentrations, diet impacts on lipoprotein(a) (Lp(a)) have been less studied. Lp(a) is a prevalent, strong, and highly heritable risk factor for CVD and a therapeutic target for CVD risk management. While significant insights have been made into the genetic regulation of Lp(a), our understanding of any metabolic impact on Lp(a) by other factors, including diets, is limited. For many years, Lp(a) was not considered to be subject to dietary regulation, but there is now clear evidence of a dietary impact, in particular variability in SFA intake, on Lp(a) concentrations. The present narrative review aims to provide an updated view on dietary regulation of Lp(a), moving beyond studies testing the effect of reducing SFA intake, to include new evidence from clinical trials on the impact of an increased sugar intake and ketogenic diets. In addition to describing an opposite effect of SFA on Lp(a) and LDL cholesterol concentrations, with a rise in Lp(a) during a reduced SFA intake, this review also provides new data on the role of apolipoprotein(a) size polymorphism, a major genetic regulator of Lp(a) concentrations. Beyond an impact on Lp(a) concentrations, the extent to which diet might impact Lp(a)'s molecular and metabolic properties including its lipidomic composition remains unknown. Taken together, evidence shows the presence of a dietary modulation of Lp(a) beyond its genetic control and points to the need to better understand Lp(a)'s cardiovascular risk factor properties, including metabolomics/lipidomics characteristics. This also raises the issue whether diet should be a component of elevated Lp(a) management, and this needs to be addressed in future studies.

Keywords: LDL-C; Lp(a); ketogenic diet; metabolic effect; saturated fat; simple sugar.

Figure 1

Lipoprotein(a) structure and molecular properties. Lp(a) contains a lipid core and one molecule of each of the two major apolipoproteins, apoB-100 and apo(a). Apo(a) is unique to Lp(a) with a repeated loop structure termed Kringle (K), where its K4 type 2 is present in a hypervariable copy number, resulting in an extensive apo(a) size variability. In general, smaller apo(a) sizes are associated with higher plasma Lp(a) concentrations. A set of other apolipoproteins involved in lipid metabolism as well as additional proteins linked to a variety of different functions and pathways have also been identified. The lipid core of Lp(a) consists of neutral lipids and phospholipids (PLs). While the main neutral lipids are cholesteryl esters (CEs) and triglycerides (TGs), PLs are mainly represented by choline-containing phospholipids (PCs), ethanolamine-containing phospholipids (PEs), and sphingomyelins (SMs).

Figure 2

A hypothetical overview of mechanisms underlying the impact of diet interventions on Lp(a) concentrations. On one hand, the genetic regulation of Lp(a) concentrations through a copy number variation in the LPA gene (i.e., the apo(a) size polymorphism) is well established. Hence, apo(a) hepatic production is under strong genetic control (panel (A)). On the other hand, evidence clearly suggests a presence of metabolic regulation of Lp(a) concentration through diet changes, including reducing dietary saturated fat intake and consuming a ketogenic diet or dietary simple sugars. We suggest the possibility of a potential impact (marked with “?”) of dietary changes on: (1) Lp(a) formation, (2) Lp(a) metabolism, and/or (3) Lp(a) clearance (panels (B–D)). It is important to differentiate apo(a) synthesis, clearly genetically regulated (panel (A)), from Lp(a) synthesis that involves the formation of the lipid portion (panel (B)). This concept has been somewhat underappreciated and deserves more attention. It is also possible that dietary changes might impact membrane composition and therefore potentially any receptor-mediated clearance through the kidney and/or liver (panel (D)). More studies are needed to better understand the exact location(s)/phase(s) of the impact and metabolites that play roles (panel (C)) in diet-mediated effects on Lp(a) concentrations.