Lipidomic profiling of plasma triglyceride species reveals distinct signatures and dietary associations in drug-refractory hypertriglyceridemia.

Abstract

Background & aims: Hypertriglyceridemia (HTG) is a common metabolic disorder associated with acute pancreatitis and cardiovascular events. Although lifestyle modification and medications usually reduce triglycerides (TG), some patients develop drug-refractory HTG (r-HTG), where TG levels remain high despite treatment. Lipidomics has emerged as a powerful tool for elucidating disease mechanisms and nutritional effects. This study aimed to characterize plasma TG species composition in r-HTG using lipidomics and to explore potential genetic and dietary influences.

Methods: We recruited 140 participants: 40 normal TG (NTG) controls and 100 HTG patients. HTG patients were subdivided into non-refractory (nr-HTG, n = 26) and refractory (r-HTG, n = 74) groups based on post-treatment TG levels. Plasma TG composition was profiled by LC-MS and analyzed using analysis of covariance and logistic regression. Dietary questionnaires and genotyping of HTG-related genes were also conducted.

Results: Proportional TG species patterns were similar in NTG and nr-HTG but distinct in r-HTG, a difference not reflected by total TG concentration. Of 251 TG species, 117 (46.6%) differed significantly between nr-HTG and r-HTG groups, with r-HTG enriched in TG species containing fewer double bonds and lower carbon numbers. A four-species TG panel plus drug use for identifying r-HTG achieved an AUROC of 0.953, increasing to 0.963 with genetic data, outperforming the drug-only model (0.717). Dietary analysis revealed r-HTG patients consumed fried breakfasts more often (64.9% vs. 42.3%, P = 0.044) and less vegetarian food (1.4% vs. 15.4%, P = 0.016), which may suggest a tendency toward higher intake of animal-derived saturated fatty acids.

Conclusions: This study demonstrates that the proportional composition of TG species is an important independent factor for r-HTG. The enrichment of saturated and monounsaturated fatty acids within TG compositions of r-HTG patients may be influenced by dietary patterns, highlighting the potential relevance of dietary management. Future studies should assess tailored dietary strategies or targeted modulation of fatty acid composition for treating r-HTG.