Fatty acid control of lipoprotein lipase: a link between energy metabolism and lipid transport.

Abstract

Lipoprotein lipase (LPL) catalyzes the fluxgenerating step in transport of fatty acids from lipoprotein triacylglycerols into tissues for use in metabolic reactions. In viro studies have shown that fatty acids can bind to the enzyme and impede its other interactions. In this study we have searched for evidence of fatty acid control of LPL in vivo by rapid infusion of a triacylglycerol emulsion to healthy volunteers. During infusion the activity of LPL but not of hepatic lipase increased in plasma, but to different degrees in different individuals. The time course for the increase in LPL activity differed from that for triacylglycerols but followed the plasma levels of free fatty acids. This was true during infusions and when the emulsion was given as a bolus iijection. In particular there were several instances when plasma triacylglycerol levels were very high but free fatty acids and LPL activity remained low. Model studies with bovine LPL showed that fatty acids displace the enzyme from heparin-agarose. We suggest that in situations when fatty acids are generated more rapidly by LPL than they are used by the local tissue, they cause dissociation of the enzyme from its binding to endothelial heparan sulfate and are themselves released into circulation.Triacylglycerol (TG) transport is a major pathway in energy metabolism and handles more than 100 g of lipid per day in individuals on a typical Western diet. The TGs are unloaded from the lipoproteins through hydrolysis by lipoprotein lipase (LPL) at the vascular endothelium in extrahepatic tissues (for review, see refs. 1 and 2). It is generally assumed that the rate-limiting factor is the amount of LPL available at the endothelium (3). In support of this, studies in animals have shown a correlation between the activity of LPL in a tissue and its uptake of fatty acids from chylomicra (1,2,4). Inherent in this view is the assumption that the tissue can assimilate the fatty acids at the rate that the enzyme provides them. The possibility that fatty acid assimilation can be rate-limiting has been raised (5) but has received little attention. In vitro studies have, however, shown that LPL has a built-in mechanism for product control. The enzyme can bind fatty acids, which reduces its affinity for lipid droplets (6, 7) as well as for heparin-like polysaccharides (8) and abolishes the activation by apolipoprotein C-II (9). This suggests that accumulation of fatty acids at the endothelium might inhibit further lipolysis and disrupt the binding of LPL to heparan sulfate. Whether this mechanism ever comes into play in vivo is not known. To demonstrate it one would need a condition in which the clearing capacity was overloaded. In this study we have tried to create such a situation by rapid infusion of a lipid emulsion. Analyses. Blood samples (5 ml) were collected in EDTA and immediately put in ice water. Plasma was rapidly separated by centrifugation for 5 min at 1000 x g using a Beckman refrigerated centrifuge. Plasma lipids were determined by the following enzy...

Age-related relationships between muscle fat content and metabolic traits in growing rabbits

“…In agreement, transgenic mice that overexpressed LPL specifically in the skeletal muscle, show a dose-dependent induction of oxidative enzymes [44]. Taken together, it is tempting to speculate that decreased FA oxidation from 10 to 20 wk of age resulted in high levels of intracellular FA-derived molecules, thus causing a decrease in LPL activity in a "product control" mechanism [45]. The exact role of LPL in muscle fat deposition remains to be investigated in further experiments, including other dietary (high fat diet), physiological (fasted) and physical (exercised animals) conditions.…”

Short-Time Infusion of Fish Oil-Based Lipid Emulsions, Approved for Parenteral Nutrition, Reduces Monocyte Proinflammatory Cytokine Generation and Adhesive Interaction with Endothelium in Humans

“…This is consistent with the notion that synthetic lipid aggregates activate endothelial lipoprotein lipases, including translocation of the enzyme from its cellular binding sites into the vascular compartment. Activation and translocation result in an increase in plasma free fatty acids due to escape from local cellular uptake mechanisms (21,22). Kinetics and extent of plasma -3 lipid increase thus exceed corresponding alterations in response to conventional dietary fish oil uptake by order of magnitude (23,24).…”

ASP stimulates glucose transport in cultured human adipocytes

“…15 There is direct evidence in humans that the rate of fatty acid uptake from triglyceride-rich particles is limited. 19 A major portion of the fatty acids released from chylomicrons are not immediately taken up by adipocytes 20 but rather continue to circulate. Thus, the rate of chylomicron triglyceride hydrolysis by lipoprotein lipase is not a direct function of the mass of this enzyme present on the endothelial surface, but the increase in ambient circulating fatty acids can also result in product inhibition of lipoprotein lipase and in¯uence triglyceride clearance.…”