Omega-3 Triglycerides Modify Blood Clearance and Tissue Targeting Pathways of Lipid Emulsions

Abstract

Omega-3-rich (n-3) triglycerides (TG) are increasingly recognized as having modulating roles in many physiological and pathological conditions. We questioned whether the catabolism of lipid emulsions would be changed after enrichment with fish oil (n-3) TG as compared to enrichment with omega-6-rich soy oil (n-6) TG. Phospholipid-stabilized emulsions of n-3 TG and n-6 TG were labeled with [(3)H]cholesteryl oleoyl ether and administered by bolus injection to wild-type (WT) mice, mice lacking the low-density lipoprotein receptor (LDL-R) (LDL-R -/-), and apolipoprotein E (apoE) knockout mice (apoE -/-). The effects of exogenous apoE, heparin, Triton WR 1339, and lactoferrin on catabolism of emulsions were also assayed. n-3 TG emulsions were cleared faster from blood and had different extrahepatic tissue targeting compared to n-6 TG emulsions. In apoE -/- and LDL-R -/- mice, blood clearance of n-6 TG emulsions slowed with decreased liver uptake, but no changes were observed in n-3 TG emulsion clearance and tissue uptake compared to WT mice. In WT mice, addition of exogenous apoE to the emulsion increased liver uptake of n-6 TG emulsions but had no impact on n-3 TG emulsions. Pre-injection of heparin increased and Triton WR 1339 and lactoferrin decreased blood clearance of n-6 TG emulsions with little or no effect on n-3 TG emulsions. Liver uptake of n-6 TG emulsions increased after heparin injection and decreased after Triton WR 1339 injection, but uptake of n-3 TG emulsions was not changed. These data show that the catabolism of n-3 TG emulsions and the catabolism of n-6 TG emulsions occur via very different mechanisms. Removal of chylomicron-sized n-6 TG emulsions is modulated by lipoprotein lipase (LPL), apoE, LDL-R, and lactoferrin-sensitive pathways. In contrast, clearance of chylomicron-sized n-3 TG emulsions relies on LPL to a very minor extent and is independent of apoE, LDL-R, and lactoferrin-sensitive pathways.

Lipoprotein lipase

“…Using labeled chylomicrons and emulsions, Hultin et al (81) found a large amount of uptake of core lipids into peripheral tissues. A similar observation was recently made by Qi et al (82), who noted that uptake of cholesteryl esters was modified by the lipid composition of emulsions. How does this occur?…”

Effects of triacylglycerol and diacylglycerol oils on blood clearance, tissue uptake, and hepatic apolipoprotein B secretion in mice

“…A large body of studies has been conducted to investigate the roles of specific core lipid FAs in blood clearance and tissue delivery (12)(13)(14)(15)(16). However, the metabolism of intravenous lipid emulsions primarily composed of different AG structures has been poorly defined.…”

“…For example, lipid emulsions rich in mediumchain TAG were demonstrated to be more efficiently hydrolyzed by LPL or HL than emulsions with long-chain TAG, resulting in rapid clearance of medium-chain TAG emulsions from blood (12,13). On the other hand, lipid emulsions rich in v-3 FAs from fish oil are less efficiently hydrolyzed by LPL but cleared more efficiently as whole particles compared with v-6 emulsion (14)(15)(16).…”

Saturated fat–rich diet enhances selective uptake of LDL cholesteryl esters in the arterial wall

“…After 24 hours incubation at 37°C, LDL was re-isolated by sequential gradient ultracentrifugation, and apoB was then labeled with the ALEXA fluorophore according to the manufacturer's method. Isolated LDL was applied to a Sepharose CL-2B gel filtration column (Sigma-Aldrich) (28) to ensure that BODIPY-C12 and ALEXA fluorescence labeling did not alter LDL homogeneity and co-eluted with the LDL fraction (as determined by fluorometry). In separate experiments, fluorescent-labeled LDL cell binding and uptake and LDL-CE SU were compared with those of radiolabeled [ 125 I]LDL in vitro in cultured fibroblasts and showed similar results in both LDL binding and cell association (data not shown).…”