Lysolecithin reprogramming via LPCAT1 modulation restores endothelial function and prevents diabetes-associated dysmetabolism

TL;DR

This study shows that a peptide from Spirulina can prevent diabetes-related metabolic issues by restoring lipid balance and endothelial function.

Contribution

A novel orally administered peptide (SP6) is proposed to target lysolecithin reprogramming and LPCAT1 modulation in T2DM.

Findings

SP6 preserves LPCAT1 levels and modulates lysolecithin remodeling in multiple organs of diabetic mice.

SP6 improves insulin secretion and glycemic control by enhancing ATP production.

High glucose disrupts LPC/PC balance and endothelial function via LPCAT1 downregulation.

Abstract

Dysregulation of lysophosphatidylcholines (LPCs) and phosphatidylcholines (PCs) is linked to endothelial dysfunction and impaired tissue repair. Nevertheless, the organ-specific modulation of lysolecithin remodeling in T2DM remains unexplored. Here, we investigate the LPC/PC remodeling dynamics in a T2DM model and propose a novel therapeutic approach using an orally bioavailable peptide (SP6) derived from Spirulina platensis.

LPC/PC levels were analyzed by UHPLC-HRMS. Membrane fluidity, VEGF/API5, LPCAT1, VE-cadherin, and GLUT1 were evaluated by merocyanine assay, qPCR, immunoblotting, and immunofluorescence. In vivo, T2DM was induced by a high-fat diet and streptozotocin, and SP6 was orally administered. Tissue lipidomics, GLUTs expression, and insulin secretion were assessed, with the latter also spatially characterized in pancreatic tissue by MALDI-MS imaging.

High glucose induced LPC/PC imbalance, enhanced membrane fluidity, impaired VEGF/API5 expression, and hindered wound healing and VE-cadherin localization via LPCAT1 downregulation and subsequent impact on GLUT1 translocation. In vivo analysis of diabetic mice revealed a multi-organ influence of SP6 preserving LPCAT1 mRNA levels in pancreas, liver, skeletal muscle, and adipose tissue and a specific pattern of lysolecithin remodeling, with selective modulation of LPC 16:0, 18:0, and 20:4 in plasma. Finally, its effects in T2DM are mediated by preserving insulin secretion and glycemic control through increased ATP production.

These findings reveal tissue-specific lysolecithin reprogramming in T2DM development and identify LPCAT1-mediated lysolecithin remodeling as a mechanism involved in T2DM-related endothelial and metabolic dysfunction. SP6 modulates lipid metabolism, vascular integrity, and glucose regulation at the transcript level, suggesting its potential as a new preventive treatment for T2DM and its complications.

The online version contains supplementary material available at 10.1186/s12933-025-03053-4.

What is currently known about this topic?
Lipidomic studies in type 2 diabetes reveal disrupted phospholipid metabolism, however conflicting trends, especially in lysophosphatidylcholines (LPCs) and phosphatidylcholines (PCs) are reported
What is the key research question?
Can modulation of lysolecithin reprogramming machinery reduce diabetes onset and progression?
What is new?
T2DM is markedly affected by the impairment of lysolecithin machinery homeostasis. SP6 shows promise as a preventive strategy targeting both endothelial integrity and lysolecithin reprogramming machinery in T2DM acting on aberrant LPCAT1 modulation
How might this study influence clinical practice?
SP6 emerges as a promising preventive candidate for targeting aberrant lysolecithin remodeling pathways in diabetic patients

What is currently known about this topic?

Lipidomic studies in type 2 diabetes reveal disrupted phospholipid metabolism, however conflicting trends, especially in lysophosphatidylcholines (LPCs) and phosphatidylcholines (PCs) are reported

What is the key research question?

Can modulation of lysolecithin reprogramming machinery reduce diabetes onset and progression?

What is new?

T2DM is markedly affected by the impairment of lysolecithin machinery homeostasis. SP6 shows promise as a preventive strategy targeting both endothelial integrity and lysolecithin reprogramming machinery in T2DM acting on aberrant LPCAT1 modulation

How might this study influence clinical practice?

SP6 emerges as a promising preventive candidate for targeting aberrant lysolecithin remodeling pathways in diabetic patients

The online version contains supplementary material available at 10.1186/s12933-025-03053-4.

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