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. 2025 Aug 26;26(17):8284.
doi: 10.3390/ijms26178284.

Triglycerides as Determinants of Global Lipoprotein Derangement: Implications for Cardiovascular Prevention

Núria Amigó  1   2   3 , Pol Torné  3 , Liv T Nordestgaard  4   5 , Francesco Di Giacomo-Barbagallo  6   7 , Carla Merino  3 , Paolo Magni  8   9 , Ana González-Lleó  6   10   11 , Natalia Andreychuk  10   11 , Alberico L Catapano  8   9 , Lluís Masana  10   11 , Daiana Ibarretxe  10   11
Affiliations

Triglycerides as Determinants of Global Lipoprotein Derangement: Implications for Cardiovascular Prevention

Núria Amigó et al. Int J Mol Sci. .

Abstract

Plasma triglyceride levels are a strong cardiovascular risk marker. However, triglyceride-lowering therapies have not demonstrated a reduction in cardiovascular events, suggesting that triglycerides may serve as surrogate markers for other atherogenic mechanisms. The aim is to investigate the role of triglycerides in derangements of the global lipoprotein profile, as assessed by 1H-NMR spectroscopy. Serum lipoprotein profiles were analyzed in patients with metabolic alterations attending the Lipid Unit of a University hospital (n = 822). Lipoprotein particle number, size, and composition were evaluated and visualized through a graphic representation of a lipoprotein network analysis referred to lipid silhouette in patients sorted by triglyceride quartiles. Profound alterations in lipoprotein quantity and composition were associated with incremental triglyceride concentrations independently on the presence of diabetes or obesity, including a significantly increased number of VLDL and smaller LDL particles, and higher remnant cholesterol, representing up to 30% of all cholesterol in quartile 4. It was also a significant triglyceride enrichment of LDL and HDL particles. Triglycerides are not merely components of atherogenic dyslipidemia; they are a key driver of the overall changes and are strongly associated with a proatherogenic plasma lipoprotein profile. Visualization of these alterations provides supplementary insights to support cardiovascular prevention strategies.

Keywords: advanced lipoprotein profile; cardiovascular prevention; cholesterol; nuclear magnetic resonance; residual cardiovascular risk; triglycerides.

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Conflict of interest statement

CM and PT were employed by the company BiosferTeslab. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
(a) Absolute values of total cholesterol concentrations and its distribution between triglyceride-rich lipoproteins (remnant cholesterol—Rm C), low-density lipoproteins (LDL), and high-density lipoproteins (HDL) sorted by quartiles of triglyceride concentrations based on NMR analysis. (b) Remnant cholesterol and LDL–C distribution. Percentage distribution of cholesterol across all atherogenic, apolipoprotein B containing, lipoproteins.
Figure 2
Figure 2
Mean lipid silhouettes derived from ten lipoprotein parameters measured by nuclear magnetic resonance (1H–NMR) in patients categorized by triglyceride concentration quartiles. Alteration of parameters are represented as a contraction of the silhouette towards its center, with the extent of contraction proportional to the variance of the respective parameter. LDL–Z: LDL diameter size; S–LDL–P: smaller LDL particles; LDL–C: LDL cholesterol; LDL–TG: LDL triglycerides; Rem C: Remnant cholesterol; VLDL–TG: VLDL triglycerides; HDL–Z: HDL diameter size; M–HDL–P: number of medium-size HDL particles; HDL–C: HDL cholesterol; HDL–TG/HDL–C: HDL triglycerides/cholesterol ratio. The shadow represents the confidence interval.
Figure 3
Figure 3
Schematic representation of triglyceride metabolism. (a) In individuals with low triglyceride (TG) levels, hepatic production of very low-density lipoprotein (VLDL) particles via microsomal triglyceride transfer protein (MTP) is lower. Once in circulation, triglyceride-rich lipoproteins (TRLs) undergo efficient delipidation, facilitating normal lipid exchange with low-density lipoproteins (LDL) and high-density lipoproteins (HDL) mediated by cholesteryl ester transfer protein (CETP). (b) In individuals with high intrahepatic triglyceride content (e.g., due to obesity, diabetes, unhealthy diet, or alcohol consumption) hepatic secretion of VLDL increases, enlarging the pool of atherogenic lipoproteins. The excessive TRL burden overwhelms lipoprotein lipase (LPL) and hepatic lipase (HL) activity, leading to partially delipidated TRLs (remnant lipoproteins). Elevated circulating triglyceride levels disrupt lipid exchange processes mediated by cholesteryl ester transfer protein (CETP), leading to triglyceride enrichment and cholesterol depletion in LDL and HDL particles. This results in the formation of smaller, denser LDL and HDL particles. Concurrently, TRLs transport more cholesterol, increasing levels of remnant cholesterol, which could significantly contribute to atherogenesis.
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