Chylomicron- and VLDL-derived Lipids Enter the Heart through Different Pathways IN VIVO EVIDENCE FOR RECEPTOR- AND NON-RECEPTOR-MEDIATED FATTY ACID UPTAKE

Lipids circulate in the blood in association with plasma lipoproteins and enter the tissues either after hydrolysis or as non-hydrolyzable lipid esters. We studied cardiac lipids, lipoprotein lipid uptake, and gene expression in heart-specific lipoprotein lipase (LpL) knock-out (hLpL0), CD36 knock-out (Cd36(-/-)), and double knock-out (hLpL0/Cd36(-/-)-DKO) mice. Loss of either LpL or CD36 led to a significant reduction in heart total fatty acyl-CoA (control, 99.5 +/- 3.8; hLpL0, 36.2 +/- 3.5; Cd36(-/-), 57.7 +/- 5.5 nmol/g, p < 0.05) and an additive effect was observed in the DKO (20.2 +/- 1.4 nmol/g, p < 0.05). Myocardial VLDL-triglyceride (TG) uptake was reduced in the hLpL0 (31 +/- 6%) and Cd36(-/-) (47 +/- 4%) mice with an additive reduction in the DKO (64 +/- 5%) compared with control. However, LpL but not CD36 deficiency decreased VLDL-cholesteryl ester uptake. Endogenously labeled mouse chylomicrons were produced by tamoxifen treatment of beta-actin-MerCreMer/LpL(flox/flox) mice. Induced loss of LpL increased TG levels > 10-fold and reduced HDL by > 50%. After injection of these labeled chylomicrons in the different mice, chylomicron TG uptake was reduced by similar to 70% and retinyl ester by similar to 50% in hLpL0 hearts. Loss of CD36 did not alter either chylomicron TG or retinyl ester uptake. LpL loss did not affect uptake of remnant lipoproteins from ApoE knock-out mice. Our data are consistent with two pathways for fatty acid uptake; a CD36 process for VLDL-derived fatty acid and a non-CD36 process for chylomicron-derived fatty acid uptake. In addition, our data show that lipolysis is involved in uptake of core lipids from TG-rich lipoproteins.