Lipoprotein lipase-facilitated uptake of LDL is mediated by the LDL receptor

Abstract

LPL mediates the uptake of lipoproteins into different cell types independent of its catalytic activity. The mechanism of this process and its physiological relevance are not clear. Taking into account the importance of the endothelial barrier for lipoprotein uptake, in vitro studies with primary aortic endothelial cells from wild-type and low density lipoprotein receptor (LDLR)-deficient (LDLR 2/2 ) mice were performed. Addition of LPL almost doubled the uptake of LDL into wild-type cells. However, there was virtually no LPL-mediated change of LDL uptake into LDLR 2/2 cells. Upregulation of LDLR by lipoproteindeficient serum/lovastatin in wild-type cells resulted in a 7-fold increase of LPL-mediated LDL uptake. Uptake of chylomicron remnants was not affected by LDLR expression. In proteoglycan-deficient cells, LPL did not increase the uptake of lipoproteins. The physiological relevance of this pathway was studied in mice that were both LDLR 2/2 and transgenic for catalytically inactive LPL in muscle. In the presence of LDLR, inactive LPL reduced LDL cholesterol significantly (13-24%). In the absence of LDLR, LDL cholesterol was not affected by transgenic LPL. Metabolic studies showed that in the presence of LDLR, LPL increased the muscular uptake of LDL by 77%. In the absence of LDLR, transgenic LPL did not augment LDL uptake. Chylomicron uptake was not affected by the LDLR genotype.We conclude that LPL-mediated cellular uptake of LDL, but not of chylomicrons, is dependent on the presence of both LDLR and proteoglycans.

Endothelial lipase enhances low density lipoprotein binding and cell association in THP-1 macrophages

“…A similar relationship between the LDLR and LPL-mediated lipid uptake was reported indicating a 2-fold increased uptake of native LDL in LPL-treated aortic endothelial and HepG2 cells whereas virtually no increase in uptake was observed in LDLR-deficient cells [35,36]. Unlike LPL, which can interact with LRP to facilitate lipoprotein metabolism [37][38][39][40], LRP does not appear to be required for the EL-mediated lipoprotein removal.…”

Biochemical Analysis of the Lipoprotein Lipase Truncation Variant, LPLS447X, Reveals Increased Lipoprotein Uptake

“…LPL enhances the binding, uptake and degradation of triglyceride-rich and remnant lipoproteins mediated by the LRP 18, 19 . LPL also enhances the LDL receptor-mediated uptake of LDL particles 36 , and enhances TRL uptake through the VLDL receptor (VLDLR) 41 . Previous reports demonstrate that the C-terminal domain of LPL is responsible for the interaction with LRP 16, 42–45 .…”

LRP6 Protein Regulates Low Density Lipoprotein (LDL) Receptor-mediated LDL Uptake

“…These findings indicated impaired function of LDLR in the absence of LRP6 and strongly implicated LRP6 in LDLR-dependent LDL uptake. The LPL-facilitated LDL uptake has shown to be a LDLR-dependent process (13). The effect of LRP6 on LPL-facilitated LDL uptake was examined in CHO-k1 cells.…”

“…Non-vesicular LDL uptake is a clathrin-independent process (15) that is associated with up-regulation of large network of invaginations originating from the plasma membrane (13). Cav-1 promotes formation of tubular invaginations (16,17) and has been implicated in LDL trafficking within cells (18,19).…”