The Carboxy‐Terminal Domain of Lipoprotein Lipase Induces Cellular Catabolism of Normal Very Low Density Lipoproteins via the Low Density Lipoprotein Receptor—Related Protein/α<sub>2</sub>‐Macroglobulin Receptor

Chappell, David; Inoue, Ituro; Fry, Glenna L.; Pladet, M W; Iverius, Per-Henrik; Lalouel, Jean-Marc; Strickland, Dudley K.

doi:10.1111/j.1749-6632.1994.tb44333.x

Cited by 24 publications

(45 citation statements)

References 14 publications

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“…For several reasons, a2MR/LRP could contribute to the formation of foam cells: (a) the present results show that a2MR/LRP is expressed in lesion macrophages and SMC; (b) a2MR/LRP can bind and internalize apo E-enriched remnant lipoproteins (22,23) and LPL-triglyceride-rich lipoprotein complexes (25,26); (c) a2MR/LRP is not downregulated by an increased cellular cholesterol content (23), which could allow the formation of foam cells; (d) human aortic intima contains as much as 5-15% of the total lipoprotein particles as the VLDL and intermediate density lipoproteins (41). These remnantlike particles also contain significant quantities of apo E (41) and could be potential ligands for a2MR/LRP; and (e) apo E and LPL can mediate the binding to a2MR/LRP of f3-VLDL and triglyceride-rich lipoproteins.…”

Section: Discussionmentioning

confidence: 95%

“…Recent results also demonstrate that receptor-active a2-macroglobulin markedly enhances the TGF-,B-induced growth response of cultured rat aortic SMC and that this effect is dependent upon the binding of the complex to a2MR/LRP (21). a2MR/LRP can also bind apo E-enriched chylomicron and VLDL remnants (22,23), lipoprotein lipase (LPL) (24), and LPL-triglyceride-rich lipoprotein complexes (25,26 In situ hybridization. In situ hybridizations were done using either oligonucleotide probes or riboprobes as described (6,27,28).…”

Section: Introductionmentioning

confidence: 99%

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Expression of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein and scavenger receptor in human atherosclerotic lesions.

Luoma¹,

Hiltunen²,

Särkioja³

et al. 1994

J. Clin. Invest.

136

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Macrophage-and smooth muscle cell (SMC)-derived foam cells are typical constituents of human atherosclerotic lesions. At least three receptor systems have been characterized that could be involved in the development of foam cells: a2-macroglobulin receptor/LDL receptor-related protein (a2MR/LRP), scavenger receptor, and LDL receptor.We studied the expression of these receptors in human atherosclerotic lesions with in situ hybridization and immunocytochemistry. An abundant expression of a2MR/LRP mRNA and protein was found in SMC and macrophages in both early and advanced lesions in human aortas. a2MR/LRP was also present in SMC in normal aortas. Scavenger receptor mRNA and protein were expressed in lesion macrophages but no expression was found in lesion SMC. LDL receptor was absent from the lesion area but was expressed in some aortas in medial SMC located near the adventitial border. The results demonstrate that (a) a2MR/LRP is, so far, the only lipoprotein receptor expressed in lesion SMC in vivo; (b) scavenger receptors are expressed only in lesion macrophages; and (c) both receptors may play important roles in the development of human atherosclerotic lesions. (J. Clin.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Expression of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein and scavenger receptor in human atherosclerotic lesions.

Luoma¹,

Hiltunen²,

Särkioja³

et al. 1994

J. Clin. Invest.

136

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“…In contrast, LRP1 prefers to interact with apoE-enriched chylomicron and VLDL remnants (15,16). The latter receptor is also responsible for LpL-mediated endocytosis of whole lipoprotein particles (17)(18)(19). Thus, whereas VLDL receptor expression in high-energy metabolism tissues may modulate sensitivity to diet-induced obesity and diabetes via LpL-catalyzed fatty acid uptake (14,20), the high level of LRP1 expression in adipocytes (21) suggests that LRP1 may partner with apoE and/or LpL in mediating the effects of TGRL in diet-induced obesity.…”

Section: Introductionmentioning

confidence: 99%

Adipocyte LDL receptor–related protein–1 expression modulates postprandial lipid transport and glucose homeostasis in mice

Hofmann¹,

Zhou²,

et al. 2007

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Diet-induced obesity and its serious consequences such as diabetes, cardiovascular disease, and cancer are rapidly becoming a major global health threat. Therefore, understanding the cellular and molecular mechanisms by which dietary fat causes obesity and diabetes is of paramount importance in order to identify preventive and therapeutic strategies. Increased dietary fat intake results in high plasma levels of triglyceride-rich lipoproteins (TGRL). Tissue uptake of TGRL has been shown to promote glucose intolerance. We generated mice with an adipocyte-specific inactivation of the multifunctional receptor LDL receptor-related protein-1 (LRP1) to determine its role in mediating the effects of TGRL on diet-induced obesity and diabetes. Knockout mice displayed delayed postprandial lipid clearance, reduced body weight, smaller fat stores, lipid-depleted brown adipocytes, improved glucose tolerance, and elevated energy expenditure due to enhanced muscle thermogenesis. We further demonstrated that inactivation of adipocyte LRP1 resulted in resistance to dietary fat-induced obesity and glucose intolerance. These findings identify LRP1 as a critical regulator of adipocyte energy homeostasis, where functional disruption leads to reduced lipid transport, increased insulin sensitivity, and muscular energy expenditure. IntroductionThe chronic consumption of meals rich in fat and carbohydrates is a major causative factor of obesity and diabetes. The prevailing view on the mechanism by which these dietary factors contribute to obesity and diabetes is that when energy intake surpasses expenditure, the excess calories are deposited as fat in adipose tissues and its subsequent mobilization to nonadipose tissues causes insulin resistance that ultimately leads to type 2 diabetes (1-3). High fat and carbohydrate intake also leads to plasma lipid abnormalities, including high plasma levels of nonesterified fatty acids (NEFAs) and triglyceride-rich lipoproteins (TGRL) as well as reduced plasma levels of HDL (2, 3). Numerous past studies have shown that elevated plasma NEFA levels directly induce insulin resistance and thus play a causative role in the pathogenesis of obesity-related diabetes (1,4,5). However, only sporadic attention has been paid to the role of TGRL in obesity and diabetes. The TGRL are generally thought of primarily as triglyceride carriers in the circulation, delivering substrates to tissues where lipoprotein lipase-catalyzed (LpL-catalyzed) hydrolysis liberates NEFAs prior to their uptake by cells through CD36 and other pathways (6). It is important to note that TGRL as well as lipase-hydrolyzed TGRL remnants can also be internalized by cells directly via whole-particle uptake and provide triglyceride-derived fatty acids via mechanisms mediated by LDL receptor family member proteins (7). Results showing

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“…23 After synthesis, LRP is cleaved into 515-kDa (␣-chain) and 85-kDa (␤-chain) subunits. 24 LRP has been shown to act as an endocytosis-mediating receptor for several ligands, including lactoferrin, 25,26 thrombospondin, 27 protease-anti-protease complexes, 28 plasma lipoproteins such as apoE-enriched VLDL, 29,30 lipoprotein lipase and lipoprotein lipase-triglyceride-rich lipoprotein complexes, [31][32][33]. 34 Therefore, the aim of the present study was to demonstrate whether LRP was responsible for the binding and internalization of agLDLs in VSMCs.…”

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confidence: 99%

LDL Receptor–Related Protein Mediates Uptake of Aggregated LDL in Human Vascular Smooth Muscle Cells

Llorente‐Cortés

Martínez-González

Badimon

2000

ATVB

135

154

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Abstract-Foam cell formation is a key event in the onset and progression of atherosclerotic lesions. We have previously reported that internalization of aggregated low density lipoproteins (agLDLs) by vascular smooth muscle cells (VSMCs) produces cholesteryl ester (CE) accumulation in these cells. The aim of this study was to analyze whether the low density lipoprotein receptor-related protein (LRP) mediates the uptake of agLDL by VSMCs. First, immunocytochemistry and fluorescence microscopic analysis with the use of anti-LRP antibodies indicated that there was a high expression of LRP in VSMCs. Confocal microscopic analysis with the use of agLDLs labeled with fluorochrome 1,1Ј-dioctadecyl-3,3,3Ј,3Ј-tetramethylindocarbocyanine and anti-LRP antibodies showed the colocalization of agLDL and LRP.The second approach was to analyze the effect of LRP ligands on agLDL internalization; lactoferrin strongly inhibited CE accumulation from agLDLs (85.0Ϯ5.7% at 25 g/mL) by impairing agLDL binding. Coincubation of agLDL with anti-LRP antibodies decreased in a dose-dependent manner agLDL-derived CE accumulation (from 20% at 12.5 g/mL to 80% at 50 g/mL). The third approach was to evaluate whether antisense LRP oligodeoxynucleotides were able to block agLDL internalization. Treatment of VSMCs with 5 mol/L antisense LRP oligodeoxynucleotides reduced agLDL-derived CE accumulation by 84Ϯ2%. In conclusion, these results from immunologic, biochemical, and molecular interventions demonstrate that LRP mediates the binding and internalization of agLDL in human VSMCs. Because LRP is highly expressed in VSMCs and the uptake of 1 LDL aggregate amounts to the deposition of several hundreds of LDL particles, the uptake of agLDL through LRP could have a crucial role for lipid deposition in VSMCs. O ne of the main events in the atherogenic process is the accumulation of lipids, mainly cholesteryl esters (CEs). 1,2 Vascular smooth muscle cells (VSMCs) synthesize proteoglycans, extracellular matrix components involved in the focal deposition of cholesterol-rich particles. 3,4 The uptake of matrix-retained lipoproteins by VSMCs and macrophages produces CE accumulation and leads to foam cell formation. Macrophages become foam cells through the uptake of diversely modified LDLs, whereas the aggregation of LDLs seems to be a key condition for lipid accumulation in VSMCs. [5][6][7] Recently, we have shown that accumulation of CEs in VSMCs from in vitro-aggregated LDL (agLDL) is dependent on agLDL concentration and the degree of aggregation. 8 AgLDLs obtained by vortexing LDL in vitro share structural characteristics with LDL aggregates present in atherosclerotic lesions. 9 -11 In macrophages, phagocytosis and/or scavenger receptors mediate cholesterol accumulation from different types of modified LDL. [12][13][14][15][16] In human lesions, scavenger receptors are present at high levels in macrophages but not in VSMCs. 17,18 VSMCs express scavenger receptors only after stimulation with certain growth factors, 19,20 and a direct involvement of these...

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The Carboxy‐Terminal Domain of Lipoprotein Lipase Induces Cellular Catabolism of Normal Very Low Density Lipoproteins via the Low Density Lipoprotein Receptor—Related Protein/α₂‐Macroglobulin Receptor

Cited by 24 publications

References 14 publications

Expression of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein and scavenger receptor in human atherosclerotic lesions.

Expression of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein and scavenger receptor in human atherosclerotic lesions.

Adipocyte LDL receptor–related protein–1 expression modulates postprandial lipid transport and glucose homeostasis in mice

LDL Receptor–Related Protein Mediates Uptake of Aggregated LDL in Human Vascular Smooth Muscle Cells

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The Carboxy‐Terminal Domain of Lipoprotein Lipase Induces Cellular Catabolism of Normal Very Low Density Lipoproteins via the Low Density Lipoprotein Receptor—Related Protein/α2‐Macroglobulin Receptor

Cited by 24 publications

References 14 publications

Expression of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein and scavenger receptor in human atherosclerotic lesions.

Expression of alpha 2-macroglobulin receptor/low density lipoprotein receptor-related protein and scavenger receptor in human atherosclerotic lesions.

Adipocyte LDL receptor–related protein–1 expression modulates postprandial lipid transport and glucose homeostasis in mice

LDL Receptor–Related Protein Mediates Uptake of Aggregated LDL in Human Vascular Smooth Muscle Cells

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Resources

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The Carboxy‐Terminal Domain of Lipoprotein Lipase Induces Cellular Catabolism of Normal Very Low Density Lipoproteins via the Low Density Lipoprotein Receptor—Related Protein/α₂‐Macroglobulin Receptor