The hepatic uptake of VLDL in lrp-ldlr-/-vldlr-/- mice is regulated by LPL activity and involves proteoglycans and SR-BI.
LPL activity plays an important role in preceding the VLDL remnant clearance via the three major apolipoprotein E (apoE)-recognizing receptors: the LDL receptor (LDLr), LDL receptor-related protein (LRP), and VLDL receptor (VLDLr). The aim of this study was to determine whether LPL activity is also important for VLDL remnant clearance irrespective of these receptors and to determine the mechanisms involved in the hepatic remnant uptake. Administration of an adenovirus expressing LPL (AdLPL) into lrp(-)ldlr(-/-)vldlr(-/-) mice reduced both VLDL-triglyceride (TG) and VLDL-total cholesterol (TC) levels. Conversely, inhibition of LPL by AdAPOC1 increased plasma VLDL-TG and VLDL-TC levels. Metabolic studies with radiolabeled VLDL-like emulsion particles showed that the clearance and hepatic association of their remnants positively correlated with LPL activity. This hepatic association was independent of the bridging function of LPL and HL, since heparin did not reduce the liver association. In vitro studies demonstrated that VLDL-like emulsion particles avidly bound to the cell surface of primary hepatocytes from lrp(-)ldlr(-/-)vldlr(-/-) mice, followed by slow internalization, and involved heparin-releaseable cell surface proteins as well as scavenger receptor class B type I (SR-BI). Collectively, we conclude that hepatic VLDL remnant uptake in the absence of the three classical apoE-recognizing receptors is regulated by LPL activity and involves heparan sulfate proteoglycans and SR-BI.
Hu
Lihui
L
Netherlands Organization for Applied Scientific Research-Quality of Life, Gaubius Laboratory, 2301 CE Leiden, The Netherlands.
van der Hoogt
Caroline C
CC
Espirito Santo
Sonia M S
SM
Out
Ruud
R
Kypreos
Kyriakos E
KE
van Vlijmen
Bart J M
BJ
Van Berkel
Theo J C
TJ
Romijn
Johannes A
JA
Havekes
Louis M
LM
van Dijk
Ko Willems
KW
Rensen
Patrick C N
PC
D000818:Animals; D018955:CD36 Antigens / Q000378:metabolism*; D015243:Cholesterol, VLDL / Q000097:blood; D004655:Emulsions; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011509:Proteoglycans / Q000378:metabolism*; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D018955:CD36 Antigens; D015243:Cholesterol, VLDL; D004655:Emulsions; D026502:LDL-Receptor Related Proteins; D008024:Ligands; D011509:Proteoglycans; D011973:Receptors, LDL; C036053:VLDL receptor; D008071:Lipoprotein Lipase