Objective - The Hyplip2 congenic mouse strain contains part of chromosome 15 from MRL/MpJ on BALB/cJ (B/c) background. Hyplip2 mice show elevated plasma levels of cholesterol and predominantly triglycerides (TG), and are susceptible to diet-induced atherosclerosis. This study aimed at elucidation of the mechanism(s) explaining the hypertriglyceridemia. Methods and Results - Hypertriglyceridemia can result from an increased intestinal or hepatic TG production and/or by a decreased LPL-mediated TG clearance. The intestinal TG absorption and chylomicron formation was studied after i.v. injection of Triton WR1339 and intragastric load of olive oil containing glycerol tri[3H]oleate. No difference was found in intestinal TG absorption. Moreover, the hepatic VLDL-TG production rate and VLDL particle production, after injection of Triton WR1339, were also not affected. To investigate the LPL-mediated TG clearance, mice were injected i.v. with glycerol tri[3H]oleate-labeled VLDL-like emulsion particles. In Hyplip2 mice, the particles were cleared at a decreased rate (t(1/2) 25+/-6 vs 11+/-2 min, p<0.05) concomitant with decreased uptake of emulsion-TG derived 3H-labeled fatty acids by the liver and white adipose tissue. Conclusion - The increased plasma TG levels in Hyplip2 mice do not result from an enhanced intestinal absorption or increased hepatic VLDL-production, but are caused by decreased LPL-mediated TG clearance.