Surface lipids in lipoproteins interact with proteins and receptors at the surface of cell membranes, mediating lipoprotein-cell signaling and trafficking events. Despite this, little is known about lipoproteins' surface lipid composition and any changes introduced by type-2 diabetes mellitus (T2DM). Herein, we investigate the surface lipid composition in purified VLDL, LDL and HDL populations isolated from patients with poor (PC, HbA1c>8.5%) and good glycemic control (GC, HbA1c<6.5%) using high-performance thin-layer chromatography (HPTLC) and targeted liquid chromatography-mass spectrometry (LC-MRM-MS) approaches, which were complemented with biophysical measurements. Composed largely of free cholesterol (Chol), phosphatidylcholine (PC), and sphingomyelin (SM), the surface of lipoproteins contains minor quantities of phosphatidylethanolamine (PE), phosphatidylinositol (PI), monoglycerides (MG), ceramides (Cer) and glucosyl-ceramides (GlcCer). Our findings show that PE levels are altered in VLDL and LDL in T2DM. Screening of predominant Chol and PC lipids derivatives, cholesterol sulfate (CholS) and oxidized phosphatidylcholines (oxPC), revealed pronounced changes in LDL. At the biophysical level, T2DM impacted VLDL and HDL surface properties but not those of LDL. The distinct behavior of lipoproteins’ composition and biophysical parameters in T2DM patients and in response to medication, diet, and physical exercise, may contribute to particle-membrane interactions. • Composition of surface lipids changes in lipoproteins from T2DM; • In glucotoxic conditions, PE levels are altered in VLDL and LDL; • Cholesterol sulfate is increased in ApoB-100-containing lipoproteins; • At biophysical level, LDL is not responsive to hypoglycemic therapy
Reis et al. (2026) studied this question.