👤 Jose Luis Sánchez-Quesada

Small dense low-density lipoprotein (sdLDL) is a highly atherogenic LDL subclass associated with cardiovascular disease (CVD). While type 1 diabetes confers increased cardiovascular risk despite adequate glycemic control, the role of sdLDL and its regulators remains unclear. In this cross-sectional observational study, plasma from 69 individuals with long-standing type 1 diabetes and 24 healthy controls was analyzed. sdLDL-cholesterol (sdLDL-C) concentration, sdLDL-C/LDL-cholesterol ratio, LDL size and subclasses were assessed using homogeneous assays, NMR spectroscopy, and gradient gel electrophoresis. Apolipoprotein C3 (ApoC3), hepatic lipase (HL), endothelial lipase (EL), and cholesteryl ester transfer protein (CETP) activity were measured by immunoturbidimetric, ELISA and functional assays. Despite adequate glycemic control (mean HbA1c 7.6% [60 mmol/mol]) and near-normal lipid levels, individuals with type 1 diabetes had significantly higher sdLDL-C (0.56 ± 0.28 mmol/L vs 0.43 ± 0.26 mmol/L), increased sdLDL-C/LDL-cholesterol ratio (0.20 ± 0.08 vs 0.12 ± 0.06) and smaller LDL particle size (26.32 ± 1.08 nm vs 26.81 ± 0.68 nm) compared with controls. ApoC3 and HL mass/activity were significantly increased (8.67 ± 3.22 mg/dL vs 6.53 ± 2.42; 46.60 ± 16.12 ng/mL vs 15.45 ± 7.40 ng/mL and 1.03 ± 0.24 U/mL vs 0.89 ± 0.23 U/mL; respectively), CETP activity significantly reduced (808.8 ± 197.0 pmol/mL/h vs 929.7 ± 149.6 pmol/mL/h), and endothelial lipase levels unchanged. sdLDL-C positively correlated with ApoC3 (r = 0.7517) and inversely with CETP activity (r = -0.2682). Long-standing type 1 diabetes with adequate glycemic control is associated with an atherogenic sdLDL profile despite near-normal conventional lipid levels. This first multi-method characterization study of sdLDL in type 1 diabetes highlights the contribution of ApoC3, CETP and HL to sdLDL-C enrichment and suggests that direct assessment of sdLDL may improve cardiovascular risk stratification. Show less

Atherosclerotic cardiovascular disease (ASCVD), including coronary heart disease and cerebrovascular disease, is caused by the accumulation of plaque on artery walls. Elevated levels of low-density lipoprotein (LDL) cholesterol significantly contribute to the development and progression of ASCVD. Multiple studies have provided evidence of a correlation between individual LDL subpopulations and the development of atherosclerosis (AS); among these, small, dense low-density lipoprotein (sdLDL) and lipoprotein(a) [Lp(a)] have been particularly implicated. There are multiple considerations of why sdLDL may cause AS including their low affinity for the LDL receptor, their ability to diffuse into the artery wall and remain there for a long time, and their tendency to become excessively oxidized. Oxidized LDL (oxLDL), generated under oxidative stress, drives AS by impairing endothelial function, promoting foam cell formation, and triggering vascular inflammation. Lp(a) contributes to the development and progression of AS by causing inflammation of the arterial wall. Studies conducted in recent years have found that electronegative LDL [L5/LDL(-)] may also be an important factor in the development and progression of AS. L5/LDL(-) causes atherosclerotic changes in the vascular wall by triggering apoptosis in endothelial cells via the lectin-like oxLDL receptor-1. This article offers an updated overview of ASCVD and briefly examines the classifications of atherogenic LDL subfractions and their roles in atherogenesis. Show less

Hydrolysis of VLDL triacylglycerol (TG) by lipoprotein lipase (LpL) is a major step in energy metabolism and VLDL-to-LDL maturation. Most functional LpL is anchored to the vascular endothelium, yet a small amount circulates on TG-rich lipoproteins. As circulating LpL has low catalytic activity, its role in VLDL remodeling is unclear. We use pre-heparin plasma and heparin-sepharose affinity chromatography to isolate VLDL fractions from normolipidemic, hypertriglyceridemic, or type-2 diabetic subjects. LpL is detected only in the heparin-bound fraction. Transient binding to heparin activates this VLDL-associated LpL, which hydrolyses TG, leading to gradual VLDL remodeling into IDL/LDL and HDL-size particles. The products and the timeframe of this remodeling closely resemble VLDL-to-LDL maturation in vivo. Importantly, the VLDL fraction that does not bind heparin is not remodeled. This relatively inert LpL-free VLDL is rich in TG and apoC-III, poor in apoE and apoC-II, shows impaired functionality as a substrate for the exogenous LpL or CETP, and likely has prolonged residence time in blood, which is expected to promote atherogenesis. This non-bound VLDL fraction increases in hypertriglyceridemia and in type-2 diabetes but decreases upon diabetes treatment that restores the glycemic control. In stark contrast, heparin binding by LDL increases in type-2 diabetes triggering pro-atherogenic LDL modifications. Therefore, the effects of heparin binding are associated negatively with atherogenesis for VLDL but positively for LDL. Collectively, the results reveal that binding to glycosaminoglycans initiates VLDL remodeling by circulating LpL, and suggest heparin binding as a marker of VLDL functionality and a readout for treatment of metabolic disorders. Show less