Interaction of Lipoproteins with Heparan Sulfate Proteoglycans and with Lipoprotein Lipase. Studies by Surface Plasmon Resonance Technique

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.

Section: Discussionmentioning

confidence: 99%

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

Loeffler

Heeren

Blaeser

et al. 2007

“…This may either assist the LRP-dependent pathway (52)(53)(54) or mediate non-LRPdependent HSPG uptake (55). Heparinase injection into the liver (56) eliminates remnant removal but disrupts hepatic architecture.…”

Section: Discussionmentioning

confidence: 99%

Chylomicron remnant uptake in the livers of mice expressing human apolipoproteins E3, E2 (Arg158→Cys), and E3-Leiden

Lee

Grosskopf

Choi

et al. 2004

Apolipoprotein E2 (apoE2) and apoE3-Leiden cause chylomicron remnant accumulation (type III hyperlipidemia). However, the degree of dyslipidemia and its penetrance are different in humans and mice. Remnant uptake by isolated liver from apoE ؊ / ؊ mice transgenic for human apoE2, apoE3-Leiden, or apoE3 was measured. In the presence of both LDL receptor (LDLR) and LDL receptor-related protein (LRP), remnant uptake was apoE3 Ͼ E3-Leiden Ͼ E2 mice. Absence of LDLR reduced uptake in apoE3 and apoE3-Leiden-secreting livers but not in apoE2-secreting livers. LRP inhibition with receptor-associated protein reduced uptake in apoE3-and apoE2-secreting livers, but not in apoE3-Leiden-secreting livers, regardless of the presence of LDLR. Fluorescently labeled remnants clustered with LRP in apoE3-secreting livers only in the absence of LDLR, but clustered in livers that expressed apoE2 even in the presence of LDLR, and did not cluster with LRP in livers of apoE3-Leiden even in the absence of LDLR. Remnants were reconstituted with the three human apoE isoforms. Removal by liver of mApoe ؊ / ؊ / mldlr ؊ / ؊ mice expressing the human LDLR was slightly greater than removal in the previous experiments with apoE3 Ͼ E2 Ͼ E3-Leiden. Thus, in vivo, human apoE2 is cleared primarily by LRP, apoE3-Leiden is cleared only by the LDLR, and apoE3 is cleared by both. -Lee, S-J., I. Grosskopf, S. Y. Choi, and A. D. Cooper. Chylomicron remnant uptake in the livers of mice expressing human apoE3, apoE2 (Arg158 → Cys), and apoE3-Leiden.

“…LPL has been shown to anchor lipoproteins and increase their uptake into peripheral tissue, an action that is independent of its lipolytic activity (46,47). To demonstrate that the measured label is truly the lipolytic product of LPL and that ASP and insulin affect in situ LPL activity and not the uptake of whole particles, we used THL to inhibit LPL activity.…”

Section: Inhibition Of In Situ Lpl Activity In Adipocytes By Thl and mentioning

confidence: 99%

ASP enhances in situ lipoprotein lipase activity by increasing fatty acid trapping in adipocytes

Faraj

Sniderman

Cianflone

2004

Dietary fat circulates in the blood in the form of triglyceride (TG)-rich lipoproteins (chylomicrons), which contain an inner core of 80-95% TG (1). Postprandially, plasma TG increases 2-2.5 times above fasting levels (2, 3) and is rapidly cleared from the plasma by the efficient coupling of two events. The first involves hydrolysis by lipoprotein lipase (LPL), and the second involves uptake and metabolic disposition by local tissue. LPL is situated principally in skeletal muscle and white adipose tissue (WAT). In skeletal muscle, the great majority of nonesterified fatty acids (NEFAs) are oxidized, whereas in WAT, they are esterified to form TG [for review, see ref. (4)].LPL exerts its lipolytic action while attached to the endothelial glycocalyx (5). LPL is synthesized and secreted from underlying parenchymal cells, mainly adipose and muscle tissue, and is then translocated to the endothelial apical surface (6). Studies of factors affecting LPL activity in WAT have focused primarily on the synthesis and secretion of LPL from the adipocytes. Insulin is a major promoter of LPL activity in that it causes both synthesis and secretion to increase. In vitro studies of murine 3T3-L1 cells have shown that insulin increases LPL activity through an increase in protein synthesis, dimerization, cellular secretion, and increased cell surface-associated mass (7-10). The effects of insulin are both time-and concentrationdependent (9, 10). Furthermore, the release of LPL from adipocytes is enhanced by an endothelial cell-secreted factor that is in turn insulin-dependent (10).The conventional view is that LPL activity in WAT is the rate-limiting step in the hydrolysis of TG-rich lipoproteins and the uptake of derived NEFAs (11). In fact, this has not always been supported by in vivo findings. In a study examining the effect of epinephrine on LPL activity in humans, the extraction of plasma TG across a subcutaneous WAT bed was increased with epinephrine infusion, indicating an increase in WAT LPL activity. However, LPLderived NEFAs were not taken up into WAT but released into the circulation (12). The authors concluded that the coordinated reciprocal regulation of NEFA influx and NEFA efflux (resulting from the activation of hormone sensitive lipase (HSL) by epinephrine) is an essential de-