Triacylglycerol-rich lipoproteins protect lipoprotein lipase from inactivation by ANGPTL3 and ANGPTL4.
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.
Department of Medical Biosciences/Physiological Chemistry, Umeå University, SE-901 87 Umeå, Sweden. Stefan.nilsson@medbio.umu.se
Stefan K
SK
Nilsson
Fredrick
F
Anderson
Madelene
M
Ericsson
Mikael
M
Larsson
Elena
E
Makoveichuk
Aivar
A
Lookene
Joerg
J
Heeren
Gunilla
G
Olivecrona
D000091303:Angiopoietin-Like Protein 3; D000075803:Angiopoietin-Like Protein 4; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000494:pharmacology*; D000818:Animals; D002914:Chylomicrons / Q000502:physiology; D004789:Enzyme Activation; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008074:Lipoproteins / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000502:physiology; D008079:Lipoproteins, VLDL / Q000502:physiology; D051379:Mice; D014280:Triglycerides / Q000502:physiology*
C479896:ANGPTL3 protein, human; C474772:ANGPTL4 protein, human; D000091303:Angiopoietin-Like Protein 3; D000075803:Angiopoietin-Like Protein 4; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; D002914:Chylomicrons; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D014280:Triglycerides; D008071:Lipoprotein Lipase