Lipoprotein lipase (LPL) has a central role in lipoprotein metabolism to maintain normal lipoprotein levels in blood and, through tissue specific regulation of its activity, to determine when and in what tissues triglycerides are unloaded. Recent data indicate that angiopoietin-like protein (Angptl)-4 inhibits LPL and retards lipoprotein catabolism. We demonstrate here that the N-terminal coiledcoil domain of Angptl-4 binds transiently to LPL and that the interaction results in conversion of the enzyme from catalytically active dimers to inactive, but still folded, monomers with decreased affinity for heparin. Inactivation occurred with less than equimolar ratios of Angptl-4 to LPL, was strongly temperaturedependent, and did not consume the Angptl-4. Furthermore, we show that Angptl-4 mRNA in rat adipose tissue turns over rapidly and that changes in the Angptl-4 mRNA abundance are inversely correlated to LPL activity, both during the fed-to-fasted and fastedto-fed transitions. We conclude that Angptl-4 is a fasting-induced controller of LPL in adipose tissue, acting extracellularly on the native conformation in an unusual fashion, like an unfolding molecular chaperone.chaperone ͉ heparin affinity ͉ protein folding ͉ surface plasmon resonance
The metabolism of chylomicron remnants and VLDL was studied in healthy controls and normo-(NTG) and hypertriglyceridemic (HTG) patients with coronary artery disease after intake of an oral fat load. Specific determination of apo B-48 and B-100 enabled separation of the respective contribution of the two lipoprotein species. The postprandial plasma levels of small (Sf 20-60) and large (Sf 60-400) chylomicron remnants increased in controls and NTG patients. In contrast, only large chylomicron remnants increased in the HTG patients. An increase of large VLDL was seen in response to the oral fat load in all groups, whereas small VLDL were either unchanged in the controls and the NTG patients, or decreased in the HTG patient group. The whole plasma concentration of C apolipoproteins was essentially uninfluenced by the oral fat load, whereas the content in large triglyceride-rich lipoproteins paralleled the apo B elevations in controls and NTG patients. An even more prominent increase of apo B in large triglyceriderich lipoproteins in the HTG group was not accompanied by an increase of C apolipoproteins. These findings indicate that chylomicrons compete with VLDL for removal of triglycerides by lipoprotein lipase and that the postprandial metabolism of triglyceride-rich lipoproteins is severely defective in hypertriglyceridemia. (J. Clin. Invest. 1993.91:748-758.) Key words: chylomicron remnants * very low density lipoprotein -apolipoprotein B-48 * apolipoprotein B-100 * apolipoprotein C-I1
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...
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