Apolipoprotein E content of VLDL limits LPL-mediated triglyceride hydrolysis

• Published in: Journal of lipid research 2022-01, Vol.63 (1), p.100157, Article 100157
• Main Authors: Whitacre, Brynne E., Howles, Philip, Street, Scott, Morris, Jamie, Swertfeger, Debi, Davidson, W. Sean
• Format: Article
• Language: English
• Subjects: Adult; apolipoprotein E; apolipoprotein(s); Apolipoproteins E - metabolism; chylomicrons; Female; Humans; Hydrolysis; lipolysis; Lipoprotein Lipase - metabolism; lipoprotein metabolism; lipoproteins; Lipoproteins, VLDL - metabolism; LPL; Male; metabolic disease; TG-rich lipoproteins; Triglycerides - blood; Triglycerides - metabolism; VLDL
• ISSN: 0022-2275; 1539-7262; 1539-7262
• DOI: 10.1016/j.jlr.2021.100157

High levels of circulating triglycerides (TGs), or hypertriglyceridemia, are key components of metabolic diseases, such as type 2 diabetes, metabolic syndrome, and CVD. As TGs are carried by lipoproteins in plasma, hypertriglyceridemia can result from overproduction or lack of clearance of TG-rich lipoproteins (TRLs) such as VLDLs. The primary driver of TRL clearance is TG hydrolysis mediated by LPL. LPL is regulated by numerous TRL protein components, including the cofactor apolipoprotein C-II, but it is not clear how their effects combine to impact TRL hydrolysis across individuals. Using a novel assay designed to mimic human plasma conditions in vitro, we tested the ability of VLDL from 15 normolipidemic donors to act as substrates for human LPL. We found a striking 10-fold difference in hydrolysis rates across individuals when the particles were compared on a protein or a TG basis. While VLDL TG contents moderately correlated with hydrolysis rate, we noticed substantial variations in non-apoB proteins within these particles by MS. The ability of LPL to hydrolyze VLDL TGs did not correlate with apolipoprotein C-II content, but it was strongly inversely correlated with apolipoprotein E (APOE) and, to a lesser extent, apolipoprotein A-II. Addition of exogenous APOE inhibited LPL lipolysis in a dose-dependent manner. The APOE3 and (particularly) APOE4 isoforms were effective at limiting LPL hydrolysis, whereas APOE2 was not. We conclude that APOE on VLDL modulates LPL activity and could be a relevant factor in the pathogenesis of metabolic disease.