Abstract
Aim: Elevated plasma TG and low HDL-cholesterol are part of CVD residual risk. Lipoprotein lipase (LPL) is the central enzyme controlling plasma TG hydrolysis and affecting de novo HDL formation. Thus LPL is an attractive target for correcting dyslipidemia and reduction of CVD residual risk. We have identified a novel first-in-class small molecule LPL activator - LP071. The objective with this study was to characterize the plasma lipid metabolism in LPL activator treated mice. Methods: ApoE3L:CETP mice were treated week with LP071. Plasma lipid profiles were analyzed using FPLC fractioning. LPL activity was investigated systemically and in specific tissue. Using triton WR1339 blockade chylomicron and VLDL secretion were assessed. Functional lipid clearance test were performed by oral fat tolerance tests. Results: Fasting plasma TG levels decreased with 97 % in apoE3L:CETP mice treated with LP071; HDL-c were increased by 116 % and (V)LDL-c were decreased with 91 %. Plasma free glycerol and NEFA were significantly lowered, 26 % and 22 % respectively. After an oral lipid load the plasma lipid response was significantly blunted in LP071 treated mice compared to controls. LPL activity in subcutaneous adipose tissue was increased 1500 % and in BAT LPL was increased by 100% at 3 h after a lipid gavage in WT mice treated with LP071. Conclusions: LP071 is a potent compound that can improve plasma lipid levels to a less atherogenic profile. The LP-class LPL activators can potentially help battle CVD residual risk in the future.
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