Chylomicron- and VLDL-derived Lipids Enter the Heart through Different Pathways

Abstract

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 ␤-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 ϳ70% and retinyl ester by ϳ50% 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 VLDLderived 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.Under normal physiological conditions, myocardial energy demands are predominantly met by fatty acid (FA) 3 oxidation (Ͼ70%) with the remaining energy provided by glucose, lactate, and ketones. The majority of the lipid entering cardiac cells is diverted toward FA utilization (1) with some being stored or used for structural requirements. FAs are delivered to the heart from two sources: (a) FAs esterified as triglyceride (TG) contained in circulating lipoproteins and liberated by lipoprotein lipase (LpL)-mediated lipolysis, and (b) non-esterified FA, referred to as free FAs (FFAs), bound to serum albumin. The mechanisms responsible for the uptake of FAs by the heart, or any organ, are incompletely understood. Specifically, the importance of receptor-mediated uptake versus diffusion of FAs across membranes is under debate. Studies in cardiomyocytes (2-4) and other cells (5, 6) have suggested that uptake of FAs by cultured cells can occur via two pathways (7,8). A low capacity but high affinity uptake pathway thought to represent receptormediated uptake is operative at FFA/albumin ratios normally found in the plasma (5). At higher FFA concentrations, uptake occurs via a lower affinity non-saturable process (9, 10); this has been studied in synthetic membranes and thought to represent non-receptor uptake also referred to as "flip-flop" (11-13). Several proteins including fatty acid translocase (FAT/ ...

Uptake of Dietary Retinoids at the Maternal-Fetal Barrier

“…We speculate that the LPL bridging function, supposedly still present only in the placenta of WT mice treated with P-407, could play a predominant role in the uptake of the whole nascent chylomicrons. In agreement with previous studies showing that steady state retinoid content of adult tissues was not different between WT and ML0 mice despite reduced chylomicron remnant uptake (15,17), steady state placental retinoid levels were not statistically different between WT and ML0 mice in our study (Table 2). Hence, in the absence of placental LPL expression, alternative pathways may exist to facilitate the uptake of postprandial retinoids by the placenta.…”

“…The fatty acid transporter, CD36, and the HDL receptor, scavenger receptor class B-1, are also expressed in human and mouse placenta (45)(46)(47)(48) and have been implicated in the uptake of lipoproteins. In agreement with Bharadwaj et al (17), who showed that the cardiac uptake of chylomicrons containing retinyl esters was not different from control in mice lacking CD36, we found no difference in CD36 mRNA expression levels between ML0 and WT mice regardless of the dietary regimen. We show that only when ML0 were fed the vitamin A-excess diet, scavenger receptor class B-1 expression was up-regulated in placenta (Fig.…”

“…within the placenta) catalytic function of this enzyme contribute to this process. We also provided evidence that the placenta can take up not only chylomicron remnants but also nascent chylomicrons, likely through the bridging function of LPL, which involves facilitating the interaction of these particles with lipoprotein receptors or their uptake via recycling of the cell membrane (proteoglycan components) (17,24). Finally, the placenta may also acquire dietary retinoids via the maternal circulating complex RBP-retinol.…”

“…LPL is a major enzyme in lipid metabolism responsible for the hydrolysis of the core triglycerides in chylomicrons and very low density lipoprotein and subsequent release of free fatty acids (13). LPL has also been shown in vitro and in vivo to mediate the uptake of chylomicrons and their remnants containing retinyl esters in adipocytes, skeletal muscle (14 -16), heart (17), and mammary gland (18), not only by facilitating the formation of chylomicron remnants but also by directly hydrolyzing retinyl ester within these particles (14). LPL is present in both human and mouse placental tissues (19 -21).…”

Ectopic Fat Depots and Left Ventricular Function in Nondiabetic Men With Nonalcoholic Fatty Liver Disease

“…Other potential sources for free fatty acids are lipolysis of circulating lipoproteins by lipoprotein lipase, hydrolysis of intramyocardial triglyceride by adipose triglyceride lipase, and uptake of lipids via very low-density lipoprotein receptors. [20][21][22] In this context, it is interesting that the expression of both sterol-regulatory element-binding protein-1c and peroxisome proliferator activated receptor-γ were reported to be increased in heart biopsies of subjects with the MetS, reflecting adaptation to metabolic derangements. 23 Recently, dynamic positron emission tomographic imaging of both heart and liver was used to follow-up the fate of dietary fatty acids in humans.…”