FEEL-1 and FEEL-2 Are Endocytic Receptors for Advanced Glycation End Products

Tamura, Yoshiaki; Adachi, Hideki; Osuga, Jun-ichi; Ohashi, Ken; Yahagi, Naoya; Sekiya, Motohiro; Okazaki, Hiroaki; Tomita, Sachiko; Ikoma, Yoko; Shimano, Hitoshi; Nagai, Ryozo; Kimura, Satoshi; Tsujimoto, Masafumi; Ishibashi, Shun

doi:10.1074/jbc.m210211200

Cited by 185 publications

(139 citation statements)

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“…Stabilin-2 has been identified as a multifunctional scavenger receptor that endocytoses modified LDL and glycation end products and also evidences Gram-negative and Gram-positive bacterial-binding activities. 19,20 However, the possibility that stabilin-2 might participate in the phagocytosis of PS-exposed cell corpses remained an open question until now. In an effort to assess the potential involvement of stabilin-2 in the recognition and engulfing of apoptotic and aged cells, stabilin-2 was stably transfected into mouse fibroblast L cells, which evidence no phagocytic activity under normal conditions.…”

Section: Resultsmentioning

confidence: 99%

“…It has been reported in previous studies that stabilin-2 is only barely detectable in monocytes/macrophages. 20 However, we have determined, via RT-PCR, that stabilin-2 is expressed in HMDMs, HAMs, and several macrophage cell lines, including PMA-treated THP-1 and P388D1. Stabilin-2 was also detected in HMDMs via flow cytometry using mAb 5G3, and its expression was specifically downregulated by shRNA against stabilin-2.…”

Section: Discussionmentioning

confidence: 95%

“…19,21 Stabilin-1 and stabilin-2 have similar domain structures and expression patterns, and also operate as scavenger receptors. 17,19,20 In this point, stabilin-1 may be also involved in the clearance of apoptotic cells in macrophages. It remains to be determined whether two proteins are functionally linked.…”

Section: Discussionmentioning

confidence: 99%

“…Stabilin-2 was initially identified as the endocytic hyaluronan receptor on rat liver sinusoidal endothelial cells 17,18 and has also been reported to function as a scavenger receptor, which effects the endocytosis of modified LDL and glycation end products. 19,20 Stabilin-2 also has been shown to bind to Gram-negative and Gram-positive bacteria, thereby suggesting the potential involvement of stabilin-2 in the immune response. It is expressed at high levels in the sinusoidal endothelial cells of the spleen, lymph nodes, and liver.…”

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confidence: 99%

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Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor

et al. 2007

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Rapid phagocytic clearance of apoptotic cells is crucial for the prevention of both inflammation and autoimmune responses. Phosphatidylserine (PS) at the external surface of the plasma membrane has been proposed to function as a general 'eat me' signal for apoptotic cells. Although several soluble bridging molecules have been suggested for the recognition of PS, the PS-specific membrane receptor that binds directly to the exposed PS and provides a tickling signal has yet to be definitively identified. In this study, we provide evidence that stabilin-2 is a novel PS receptor, which performs a key function in the rapid clearance of cell corpses. It recognizes PS on aged red blood cells and apoptotic cells, and mediates their engulfment. The downregulation of stabilin-2 expression in macrophages significantly inhibits phagocytosis, and anti-stabilin-2 monoclonal antibody provokes the release of the anti-inflammatory cytokine, transforming growth factor-b. Furthermore, the results of timelapse video analyses indicate that stabilin-2 performs a crucial function in the rapid clearance of aged and apoptotic cells. These data indicate that stabilin-2 is the first of the membrane PS receptors to provide tethering and tickling signals, and may also be involved in the resolution of inflammation and the prevention of autoimmunity.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor

et al. 2007

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“…The gene encodes a 2551-amino acid glycoprotein with a molecular mass of ϳ315 kDa in SDS-PAGE. A primary function of this receptor is to bind and internalize HA for turnover, although other GAGs, such as the CSs (20, 34 -37) (this report) are also internalized by this receptor, and advanced glycation end products appear to be ligands as well (38,39). The internalized receptor traffics through the early endocytic pathway and is recycled to the cell surface (21,29,37,39).…”

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confidence: 99%

Expression, Processing, and Glycosaminoglycan Binding Activity of the Recombinant Human 315-kDa Hyaluronic Acid Receptor for Endocytosis (HARE)

Harris

Kyosseva

Weigel

et al. 2007

Journal of Biological Chemistry

120

156

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The hyaluronic acid (HA) receptor for endocytosis (HARE; also designated stabilin-2 and FEEL-2) mediates systemic clearance of glycosaminoglycans from the circulatory and lymphatic systems via coated pit-mediated uptake. HARE is primarily found as two isoforms ( The glycosaminoglycan (GAG)2 hyaluronic acid (HA) is a protein-free polymer of disaccharide units containing glucuronic acid and N-acetylglucosamine (1, 2). HA is involved in many physiological processes (3), such as wound healing, development, and metastasis of some cancers (4 -8). The typical molecular mass of the polysaccharide ranges from just a few thousand Da (tens of sugars) that are thought to be important in cellular signaling (6) to several million Da (tens of thousands of sugars). These larger forms of HA are present throughout the body and are particularly concentrated within the bursa of major joints, such as the knee, where they help to provide shock absorbance in cartilage or lubrication in synovial fluid (9, 10), and the eye, where HA maintains structural integrity of the vitreous humor (11). The adult human body contains ϳ15 g of HA, of which about 5 g are turned over daily (12). Partially degraded HA perfuses from extracellular matrices (ECMs) and enters the lymphatic and vascular circulation systems, where it is catabolized to shorter fragments. This active maintenance of HA turnover must be efficient in order to maintain homeostatic conditions for total body HA.All of the other GAGs, including the chondroitin sulfates (CSs), heparan sulfate (HS), and keratan sulfate, are linked to core proteins (as proteoglycans) that help to form ECMs, such as the basement membranes of tissues, or structural components of organs, such as the vitreous humor. There are over 30 known core proteins that are essential for a diverse array of functions, such as neural development, growth factor signaling, and pathogen recognition (13). These core proteins are found as prevalent components of tissue ECMs or as specialized components needed for the development of microenvironments that interface a specialized tissue cell type with the ECM. Both the proteoglycans and their attached GAG chains may combinatorially interact with ligands and contribute to modulation of the functional aspects of a particular microenvironment (e.g. CS interacting with apolipoprotein E for uptake of ␤-very low density lipoprotein in hippocampal neurons) (14). Although numerous studies have focused on how the inhibition of some CS proteoglycans enhances neural development, especially in injured spinal cord models, there is very little information on how CS and HS are catabolized. The current model is that extracellular chondroitinases, heparinases, and proteases initially break down these GAGs and proteoglycans, and their final digestion can then take place intracellularly at the local tissue * This research was supported by NIGMS, National Institutes of Health, Grant GM69961. The costs of publication of this article were defrayed in part by the payment of page charges. This article ...

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Lipid and Lipoprotein Metabolism

Ruotolo

Howard

2004

International Textbook of Diabetes Mellitus

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The three major components of the dyslipidemia associated with insulin resistance are increased fasting and postprandial triglyceride‐rich lipoproteins (TRLs), decreased high‐density lipoprotein (HDL), and increased small, dense low‐density lipoprotein (LDL) particles. The insulin resistance and compensatory hyperinsulinemia lead to overproduction of VLDL particles, an early abnormality of insulin resistance. A relative defective lipoprotein lipase (LPL)‐mediated lipolysis has also an important role in the dyslipidemia, since largely contributes to the decreased clearance of fasting and postprandial TRLs and to the decreased production of HDL particles. The resulting increased concentration of cholesteryl ester‐rich fasting and postprandial TRLs [intermediate‐density lipoprotein (IDL) and chylomicron remnants, respectively] is a central lipoprotein abnormality of insulin resistance. The increase of small, dense LDL particles, and decrease of large, buoyant HDL particles seem to be consequential events of the delayed metabolism of TRLs. The dyslipidemia associated with insulin resistance plays a major role in the development of atherosclerosis, and contributes largely to the increased cardiovascular disease risk in individuals with insulin resistance. Peroxisome proliferator‐activated receptors (PPARs) (α, γ, and δ) are ligand‐activated transcription factors belonging to the nuclear receptor family. PPARs agonists seem to improve the dyslipidemia of insulin resistance, by regulating the expression of important genes involved in the deranged lipoprotein metabolism associated with insulin resistance. New compounds with multiple PPAR‐agonist activity are currently under investigation, and could represent a possible solution to the radical treatment of the dyslipidemia of insulin resistance.

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FEEL-1 and FEEL-2 Are Endocytic Receptors for Advanced Glycation End Products

Cited by 185 publications

References 30 publications

Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor

Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor

Expression, Processing, and Glycosaminoglycan Binding Activity of the Recombinant Human 315-kDa Hyaluronic Acid Receptor for Endocytosis (HARE)

Lipid and Lipoprotein Metabolism

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