Triacylglycerol-rich lipoproteins protect lipoprotein lipase from inactivation by ANGPTL3 and ANGPTL4.
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Triacylglycerol-rich lipoproteins protect lipoprotein lipase from inactivation by ANGPTL3 and ANGPTL4. / Nilsson, Stefan K; Anderson, Fredrick; Ericsson, Madelene; Larsson, Mikael; Makoveichuk, Elena; Lookene, Aivar; Heeren, Jörg; Olivecrona, Gunilla.
in: Biochim Biophys Acta, Jahrgang 1821, Nr. 10, 10, 2012, S. 1370-1378.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Triacylglycerol-rich lipoproteins protect lipoprotein lipase from inactivation by ANGPTL3 and ANGPTL4.
AU - Nilsson, Stefan K
AU - Anderson, Fredrick
AU - Ericsson, Madelene
AU - Larsson, Mikael
AU - Makoveichuk, Elena
AU - Lookene, Aivar
AU - Heeren, Jörg
AU - Olivecrona, Gunilla
PY - 2012
Y1 - 2012
N2 - Lipoprotein lipase (LPL) is important for clearance of triacylglycerols (TG) from plasma both as an enzyme and as a bridging factor between lipoproteins and receptors for endocytosis. The amount of LPL at the luminal side of the capillary endothelium determines to what extent lipids are taken up. Mechanisms to control both the activity of LPL and its transport to the endothelial sites are regulated, but poorly understood. Angiopoietin-like proteins (ANGPTLs) 3 and 4 are potential control proteins for LPL, but plasma concentrations of ANGPTLs do not correlate with plasma TG levels. We investigated the effects of recombinant human N-terminal (NT) ANGPTLs3 and 4 on LPL-mediated bridging of TG-rich lipoproteins to primary mouse hepatocytes and found that the NT-ANGPTLs, in concentrations sufficient to cause inactivation of LPL in vitro, were unable to prevent LPL-mediated lipoprotein uptake. We therefore investigated the effects of lipoproteins (chylomicrons, VLDL and LDL) on the inactivation of LPL in vitro by NT-ANGPTLs3 and 4 and found that LPL activity was protected by TG-rich lipoproteins. In vivo, postprandial TG protected LPL from inactivation by recombinant NT-ANGPTL4 injected to mice. We conclude that lipoprotein-bound LPL is stabilized against inactivation by ANGPTLs. The levels of ANGPTLs found in blood may not be sufficient to overcome this stabilization. Therefore it is likely that the prime site of action of ANGPTLs on LPL is in subendothelial compartments where TG-rich lipoprotein concentration is lower than in blood. This could explain why the plasma levels of TG and ANGPTLs do not correlate.
AB - Lipoprotein lipase (LPL) is important for clearance of triacylglycerols (TG) from plasma both as an enzyme and as a bridging factor between lipoproteins and receptors for endocytosis. The amount of LPL at the luminal side of the capillary endothelium determines to what extent lipids are taken up. Mechanisms to control both the activity of LPL and its transport to the endothelial sites are regulated, but poorly understood. Angiopoietin-like proteins (ANGPTLs) 3 and 4 are potential control proteins for LPL, but plasma concentrations of ANGPTLs do not correlate with plasma TG levels. We investigated the effects of recombinant human N-terminal (NT) ANGPTLs3 and 4 on LPL-mediated bridging of TG-rich lipoproteins to primary mouse hepatocytes and found that the NT-ANGPTLs, in concentrations sufficient to cause inactivation of LPL in vitro, were unable to prevent LPL-mediated lipoprotein uptake. We therefore investigated the effects of lipoproteins (chylomicrons, VLDL and LDL) on the inactivation of LPL in vitro by NT-ANGPTLs3 and 4 and found that LPL activity was protected by TG-rich lipoproteins. In vivo, postprandial TG protected LPL from inactivation by recombinant NT-ANGPTL4 injected to mice. We conclude that lipoprotein-bound LPL is stabilized against inactivation by ANGPTLs. The levels of ANGPTLs found in blood may not be sufficient to overcome this stabilization. Therefore it is likely that the prime site of action of ANGPTLs on LPL is in subendothelial compartments where TG-rich lipoprotein concentration is lower than in blood. This could explain why the plasma levels of TG and ANGPTLs do not correlate.
KW - Animals
KW - Humans
KW - Mice
KW - Enzyme Activation
KW - Hepatocytes/metabolism
KW - Angiopoietins/pharmacology
KW - Chylomicrons/physiology
KW - Lipoprotein Lipase/metabolism
KW - Lipoproteins/physiology
KW - Lipoproteins, LDL/physiology
KW - Lipoproteins, VLDL/physiology
KW - Triglycerides/physiology
KW - Animals
KW - Humans
KW - Mice
KW - Enzyme Activation
KW - Hepatocytes/metabolism
KW - Angiopoietins/pharmacology
KW - Chylomicrons/physiology
KW - Lipoprotein Lipase/metabolism
KW - Lipoproteins/physiology
KW - Lipoproteins, LDL/physiology
KW - Lipoproteins, VLDL/physiology
KW - Triglycerides/physiology
M3 - SCORING: Journal article
VL - 1821
SP - 1370
EP - 1378
JO - Biochim Biophys Acta
JF - Biochim Biophys Acta
SN - 0006-3002
IS - 10
M1 - 10
ER -
