Hepatic low-density lipoprotein receptor–related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol

Santo, Sonia M. S. Espirito; Pires, Nuno; Boesten, Lianne S.M.; Gerritsen, Gery; Bovenschen, Niels; Dijk, Ko Willems van; Jukema, J. Wouter; Princen, H.M.G.; Bensadoun, André; Li, Wei Ping; Herz, Joachim; Havekes, Louis M.; Vlijmen, Bart J.M. van

doi:10.1182/blood-2003-11-4051

Cited by 33 publications

(21 citation statements)

References 29 publications

(46 reference statements)

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“…By promoting accumulation of highly atherogenic CM remnants and IDL in the plasma, hepatic LRP deficiency can contribute to the atherogenic diathesis in CRF. In addition, hepatic LRP deficiency has been shown to promote atherosclerosis in LRP knockout mice, independent of its action on lipoprotein metabolism [30]. This phenomenon has been attributed to the accumulation of other proatherogenic ligands of LRP.…”

Section: Discussionmentioning

confidence: 98%

Down-regulation of hepatic LDL receptor-related protein (LRP) in chronic renal failure

Kim¹,

Vaziri²

2005

Kidney International

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Section: Discussionmentioning

confidence: 98%

Down-regulation of hepatic LDL receptor-related protein (LRP) in chronic renal failure

Kim¹,

Vaziri²

2005

Kidney International

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“…However, atherosclerotic development has been determined in cell-specific LRP1 depletion in macrophages, SMCs, and hepatocytes. Each of these cell-specific deficiencies of LRP1 increased lesion size in hypercholesterolemic mice [9-13]. Despite the many associations of RAP with LRP1 expression, the effects of RAP deficiency on atherosclerosis contrast those of LRP1 deficiency.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, effects of LRP1 in atherosclerosis have been extensively studied in mouse models. There is compelling evidence that cell-specific LRP1 deficiency in hepatocytes, macrophages, or smooth muscle cells (SMCs) augments atherosclerosis in hypercholesterolemic mice [9-13]. …”

Section: Introductionmentioning

confidence: 99%

Deficiency of receptor-associated protein attenuates angiotensin II-induced atherosclerosis in hypercholesterolemic mice without influencing abdominal aortic aneurysms

Wang¹,

Subramanian²,

Lü³

et al. 2012

Atherosclerosis

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Objective Receptor-associated protein (RAP) was initially described as a regulator of low density lipoprotein receptor-related protein 1 (LRP1), but is now known to regulate many proteins. Since the direct effects of RAP on vascular pathologies have not been studied, this study determined whether RAP deficiency influenced angiotensin II (AngII)-induced atherosclerosis and abdominal aortic aneurysms (AAAs) in hypercholesterolemic mice. Methods and results Male LDL receptor -/- mice that were either RAP +/+ or -/- were infused with AngII (500 ng/kg/min) for 4 weeks while consuming a saturated fat-enriched diet. RAP deficiency had no effects on body weight or AngII-induced increases of systolic blood pressure. Despite increased plasma cholesterol concentrations, RAP deficiency reduced atherosclerotic lesion size in aortic arches, while having no effect on AngII-induced AAAs. RAP deficiency profoundly reduced LRP1 protein abundance in macrophages, but did not change its abundance in aortic smooth muscle cells. Also, RAP deficiency had no effects on mRNA abundance of LRP1 or lipoprotein lipase in macrophages. To determine whether RAP deficiency in leukocytes influenced AngII-induced atherosclerosis, irradiated male LDL receptor -/- mice were repopulated with bone marrow-derived cells from either RAP +/+ or -/- male mice. The chimeric mice were infused with AngII (500 ng/kg/min) for 4 weeks while fed the saturated fat-enriched diet. RAP deficiency in bone marrow-derived cells did not influence either plasma cholesterol concentrations or atherosclerotic lesion size. Conclusions Whole body RAP deficiency attenuated atherosclerosis without influencing AAAs in hypercholesterolemic mice infused with AngII. The anti-atherogenic effect was not attributable to RAP deficiency in bone marrow-derived cells.

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“…With time the immunofluorescence shifted to a granular pattern, indicating that the enzyme had been internalized. The internalization may have occurred with lipase bound to HSPG, as demonstrated with cultured fibroblasts and with hepatocytes [32,35,36] and/or with lipase bound to LRP as suggested by several authors [24,25,35,37]. In fibroblasts, both these pathways contribute to LPL internalization [38].…”

Section: Discussionmentioning

confidence: 99%

“…The rapid extraction of LPL by the liver in the presence of heparin implies that some other type of binding site must be present there. Members of the LDL receptor (LDL-R) family bind both the active and the inactive form of the lipase [23] and two recent studies indicate that LRP is involved in hepatic uptake of LPL [24,25]. The binding of active LPL to LRP is, however, strongly impeded by heparin [26].…”

Section: Discussionmentioning

confidence: 99%

Effects of heparin on the uptake of lipoprotein lipase in rat liver

et al. 2004

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BackgroundLipoprotein lipase (LPL) is anchored at the vascular endothelium through interaction with heparan sulfate. It is not known how this enzyme is turned over but it has been suggested that it is slowly released into blood and then taken up and degraded in the liver. Heparin releases the enzyme into the circulating blood. Several lines of evidence indicate that this leads to accelerated flux of LPL to the liver and a temporary depletion of the enzyme in peripheral tissues.ResultsRat livers were found to contain substantial amounts of LPL, most of which was catalytically inactive. After injection of heparin, LPL mass in liver increased for at least an hour. LPL activity also increased, but not in proportion to mass, indicating that the lipase soon lost its activity after being bound/taken up in the liver. To further study the uptake, bovine LPL was labeled with 125I and injected. Already two min after injection about 33 % of the injected lipase was in the liver where it initially located along sinusoids. With time the immunostaining shifted to the hepatocytes, became granular and then faded, indicating internalization and degradation. When heparin was injected before the lipase, the initial immunostaining along sinusoids was weaker, whereas staining over Kupffer cells was enhanced. When the lipase was converted to inactive before injection, the fraction taken up in the liver increased and the lipase located mainly to the Kupffer cells.ConclusionsThis study shows that there are heparin-insensitive binding sites for LPL on both hepatocytes and Kupffer cells. The latter may be the same sites as those that mediate uptake of inactive LPL. The results support the hypothesis that turnover of endothelial LPL occurs in part by transport to and degradation in the liver, and that this transport is accelerated after injection of heparin.

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Hepatic low-density lipoprotein receptor–related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol

Cited by 33 publications

References 29 publications

Down-regulation of hepatic LDL receptor-related protein (LRP) in chronic renal failure

Down-regulation of hepatic LDL receptor-related protein (LRP) in chronic renal failure

Deficiency of receptor-associated protein attenuates angiotensin II-induced atherosclerosis in hypercholesterolemic mice without influencing abdominal aortic aneurysms

Effects of heparin on the uptake of lipoprotein lipase in rat liver

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