CD36 is involved in high-affinity peripheral FFA uptake. CD36-deficient (cd36^−/−) mice exhibit increased plasma FFA and triglyceride (TG) levels. The aim of the present study was to elucidate the cause of the increased plasma TG levels in cd36^−/− mice. cd36^−/− mice showed no differences in hepatic VLDL-TG production or intestinal [³H]TG uptake compared with wild-type littermates. cd36^−/− mice showed a 2-fold enhanced postprandial TG response upon an intragastric fat load (P < 0.05), with a concomitant 2.5-fold increased FFA response (P < 0.05), suggesting that the increased FFA in cd36^−/− mice may impair LPL-mediated TG hydrolysis. Postheparin LPL levels were not affected. However, the in vitro LPL-mediated TG hydrolysis rate as induced by postheparin plasma of cd36^−/− mice in the absence of excess FFA-free BSA was reduced 2-fold compared with wild-type plasma (P < 0.05). This inhibition was relieved upon the addition of excess FFA-free BSA. Likewise, increasing plasma FFA in wild-type mice to the levels observed in cd36^−/− mice by infusion prolonged the plasma half-life of glycerol tri[³H]oleate-labeled VLDL-like emulsion particles by 2.5-fold (P < 0.05).

We conclude that the increased plasma TG levels observed in cd36^−/− mice are caused by decreased LPL-mediated hydrolysis of TG-rich lipoproteins resulting from FFA-induced product inhibition of LPL.