Heparin binding triggers human VLDL remodeling by circulating lipoprotein lipase: Relevance to VLDL functionality in health and disease
Por:
Jayaraman, S, Perez, A, Minambres, I, Sanchez-Quesada, JL, Gursky, O
Publicada:
1 ene 2022
Ahead of Print:
1 oct 2021
Resumen:
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 heparinbound 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.
Filiaciones:
Jayaraman, S:
Boston Univ, Dept Physiol & Biophys, Sch Med, Boston, MA 02118 USA
Perez, A:
Hosp Santa Creu & Sant Pau, Endocrinol Dept, Barcelona, Spain
CIBER Diabet & Metab Dis CIBERDEM, Barcelona, Spain
Minambres, I:
Hosp Santa Creu & Sant Pau, Endocrinol Dept, Barcelona, Spain
Sanchez-Quesada, JL:
CIBER Diabet & Metab Dis CIBERDEM, Barcelona, Spain
Hosp Santa Creu & Sant Pau, Cardiovasc Biochem Grp, Res Inst, CIBERDEM, Barcelona, Spain
Gursky, O:
Boston Univ, Dept Physiol & Biophys, Sch Med, Boston, MA 02118 USA
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