The human asialoglycoprotein receptor is a possible binding site for low-density lipoproteins and chylomicron remnants

Windler, E.; Greeve, Jobst; Levkau, Bodo; Kolb-Bachofen, Victoria; Daerr, W; Greten, H.

doi:10.1042/bj2760079

Cited by 58 publications

(33 citation statements)

References 52 publications

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“…It is generally accepted, however, that for the initial liver recognition of remnants, the so-called "capture step," additional systems are needed. The initial sequestration step was suggested to involve heparan sulfate proteoglycans (5,12), the lipolysis-stimulated receptor (13)(14)(15), a TG-rich lipoprotein receptor (16,17), the asialoglycoprotein receptor (18), LPL (19), and/or hepatic lipase (20), while we also provided evidence for a specific remnant receptor (21)(22)(23) to function as an initial recognition site for remnants. However, the removal pathways of chylomicrons and their remnants remain complex, and the precise mechanism of recognition is still unclear and under debate (1-3).…”

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confidence: 56%

Scavenger Receptor BI Plays a Role in Facilitating Chylomicron Metabolism

Out¹,

Kruijt²,

Rensen³

et al. 2004

Journal of Biological Chemistry

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The function of scavenger receptor class B type I (SR-BI) in mediating the selective uptake of high density lipoprotein (HDL) cholesterol esters is well established. However, the potential role of SR-BI in chylomicron and chylomicron remnant metabolism is largely unknown. In the present investigation, we report that the cell association of 160 nm-sized triglyceride-rich chylomicronlike emulsion particles to freshly isolated hepatocytes from SR-BI-deficient mice is greatly reduced (>70%), as compared with wild-type littermate mice. Competition experiments show that the association of emulsion particles with isolated hepatocytes is efficiently competed for (>70%) by the well established SR-BI ligands, HDL and oxidized low density lipoprotein (LDL), whereas LDL is ineffective. Upon injection into SR-BI-deficient mice the hepatic association of emulsion particles is markedly decreased (ϳ80%) as compared with wild-type mice. The relevance of these findings for in vivo chylomicron (remnant) metabolism was further evaluated by studying the effect of SR-BI deficiency on the intragastric fat load-induced postprandial triglyceride response. The postprandial triglyceride response is 2-fold higher in SR-BI-deficient mice as compared with wild-type littermates (area-under-the-curve 39.6 ؎ 1.2 versus 21.1 ؎ 3.6; p < 0.005), with a 4-fold increased accumulation of chylomicron (remnant)-associated triglycerides in plasma at 6 h after intragastric fat load. We conclude that SR-BI is important in facilitating chylomicron (remnant) metabolism and might function as an initial recognition site for chylomicron remnants whereby the subsequent internalization can be exerted by additional receptor systems like the LDL receptor and LDL receptor-related protein. Chylomicrons are triglyceride (TG)1 -rich lipoproteins that transport dietary lipids from the intestine to the liver. Upon entering the circulation, chylomicrons are converted to remnants by the TG-hydrolyzing action of lipoprotein lipase (LPL) and the acquisition of apolipoproteins (apo) such as apoE. Chylomicron remnants are subsequently taken up by the liver by an apoE-mediated process (reviewed in Refs. 1-3). The essential role of apoE in remnant clearance was indicated by the accumulation of remnants in apoE-deficient mice (4). It has been suggested that several apoE-dependent recognition sites contribute to the removal of remnants, including the low-density lipoprotein (apoB and -E) receptor (LDLr) (4 -9), and the LDLr-related protein/␣ 2 -macroglobulin receptor (LRP) (8, 10, 11). It is generally accepted, however, that for the initial liver recognition of remnants, the so-called "capture step," additional systems are needed. The initial sequestration step was suggested to involve heparan sulfate proteoglycans (5, 12), the lipolysis-stimulated receptor (13-15), a TG-rich lipoprotein receptor (16, 17), the asialoglycoprotein receptor (18), LPL (19), and/or hepatic lipase (20), while we also provided evidence for a specific remnant receptor (21-23) to function as an initial re...

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mentioning

confidence: 56%

Scavenger Receptor BI Plays a Role in Facilitating Chylomicron Metabolism

Out¹,

Kruijt²,

Rensen³

et al. 2004

Journal of Biological Chemistry

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“…Lactoferrin binds to both LRP and HSPG (57). Because LRP knockout status in mice is lethal (22), we tested the role of HSPG as a potential receptor for Ad infection in vivo.…”

Section: Ad-blood Factor Complexes Enter Liver Cells Via Heparan Sulfmentioning

confidence: 99%

Adenovirus Binding to Blood Factors Results in Liver Cell Infection and Hepatotoxicity

Shayakhmetov

Gaggar

et al. 2005

J Virol

373

422

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Adenoviruses (Ad) are efficient vehicles for gene delivery in vitro and in vivo. Therefore, they are a promising tool in gene therapy, particularly in the treatment of cancer and cardiovascular diseases. However, preclinical and clinical studies undertaken during the last decade have revealed a series of problems that limit both the safety and efficacy of Ad vectors, specifically after intravenous application. Major obstacles to clinical use include innate toxicity and Ad sequestration by nontarget tissues. The factors and mechanisms underlying these processes are poorly understood. The majority of intravenously injected Ad particles are sequestered by the liver, which in turn causes an inflammatory response characterized by acute transaminitis and vascular damage. Here, we describe a novel pathway that is used by Ad for infection of hepatocytes and Kupffer cells upon intravenous virus application in mice. We found that blood factors play a major role in targeting Ad vectors to hepatic cells. We demonstrated that coagulation factor IX and complement component C4-binding protein can bind the Ad fiber knob domain and provide a bridge for virus uptake through cell surface heparan sulfate proteoglycans and low-density lipoprotein receptor-related protein. An Ad vector, Ad5mut, which contained mutations in the fiber knob domain ablating blood factor binding, demonstrated significantly reduced infection of liver cells and liver toxicity in vivo. This study contributes to a better understanding of adenovirus-host interactions for intravenously applied vectors. It also provides a rationale for novel strategies to target adenovirus vector to specific tissues and to reduce virus-associated toxicity after systemic application.

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“…However, it is generally accepted that for the initial liver recognition of remnants, the so-called "capture step," additional systems are needed. The initial sequestration step was suggested to involve heparan sulfate proteoglycans (26,33), the lipolysis-stimulated receptor (34)(35)(36), a TGrich lipoprotein receptor (37,38), the asialoglycoprotein receptor (39), LPL (40) and/or HL (41), and a specific remnant receptor (42)(43)(44). We recently observed a reduced recognition of 160 nm TG-rich CM-like emulsion particles to freshly isolated hepatocytes from SR-BI-deficient mice (45).…”

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confidence: 99%