GPIHBP1 Is Responsible for the Entry of Lipoprotein Lipase into Capillaries

Davies, Brandon S.J.; Beigneux, Anne P.; Barnes, Richard H.; Tu, Yiping; Gin, Peter; Weinstein, Michael M.; Nobumori, Chika; Nyrén, Rakel; Goldberg, Ira J.; Olivecrona, Gunilla; Bensadoun, André; Young, Stephen G.; Fong, Loren G.

doi:10.1016/j.cmet.2010.04.016

Cited by 316 publications

(440 citation statements)

References 23 publications

(42 reference statements)

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“…The protein GPIHBP1 binds to the endothelium of capillary cells where it provides a platform for LPL to process triglycerides from lipoproteins (41). GPIHBP1 also helps transport LPL across the endothelial cells, and a recent study has shown that this transport is bidirectional (25,42). ANGPTL4 could thus inhibit LPL in either the subendothelial space or on the surface of the capillary endothelium, and a number of recent studies support the former option.…”

Section: Discussionmentioning

confidence: 85%

Angiopoietin-like Protein 4 Inhibition of Lipoprotein Lipase

Lafferty

Bradford

Erie

et al. 2013

Journal of Biological Chemistry

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Background: Lipoprotein lipase (LPL) clears triglycerides from the blood, and angiopoietin-like protein 4 (ANGPTL4) inhibits LPL activity. Results: Inhibited LPL is in a complex with ANGPTL4, and upon dissociation LPL regains activity. Conclusion: ANGPTL4 is a reversible, noncompetitive inhibitor of LPL, not an unfolding molecular chaperone as reported previously. Significance: Understanding the mechanism of LPL inhibition supports efforts to develop new therapies for hypertriglyceridemia.

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Section: Discussionmentioning

confidence: 85%

Angiopoietin-like Protein 4 Inhibition of Lipoprotein Lipase

Lafferty

Bradford

Erie

et al. 2013

Journal of Biological Chemistry

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“…To stain blood vessels, FITC-labeled tomato lectin (Vector Laboratories) was injected i.v. into mice as described (17). Epifluorescence microscopy images were obtained with an Axiovert 200MOT microscope equipped with an ApoTome, and processed with Axiovert 4.6 software (all from Zeiss).…”

Section: Methodsmentioning

confidence: 99%

Regulation of prelamin A but not lamin C by miR-9, a brain-specific microRNA

Jung¹,

Coffinier²,

Choe

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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192

217

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Lamins A and C, alternatively spliced products of the LMNA gene, are key components of the nuclear lamina. The two isoforms are found in similar amounts in most tissues, but we observed an unexpected pattern of expression in the brain. Western blot and immunohistochemistry studies showed that lamin C is abundant in the mouse brain, whereas lamin A and its precursor prelamin A are restricted to endothelial cells and meningeal cells and are absent in neurons and glia. Prelamin A transcript levels were low in the brain, but this finding could not be explained by alternative splicing. In lamin Aonly knockin mice, where alternative splicing is absent and all the output of the gene is channeled into prelamin A transcripts, large amounts of lamin A were found in peripheral tissues, but there was very little lamin A in the brain. Also, in knockin mice expressing exclusively progerin (a toxic form of prelamin A found in Hutchinson-Gilford progeria syndrome), the levels of progerin in the brain were extremely low. Further studies showed that prelamin A expression, but not lamin C expression, is down-regulated by a brain-specific microRNA, miR-9. Expression of miR-9 in cultured cells reduced lamin A expression, and this effect was abolished when the miR-9-binding site in the prelamin A 3′ UTR was mutated. The down-regulation of prelamin A expression in the brain could explain why mouse models of Hutchinson-Gilford progeria syndrome are free of central nervous system pathology.

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“…Rat heart microvascular endothelial cells transduced with a GPIHBP1 lentivirus were grown on fibronectin-coated Millicell filters (polyethylene terephthalate, 1.1 cm 2 filtration area, 1 μm pore size; Millipore) until they formed tight monolayers (11). After adding V5-tagged LPL to the basolateral chamber and PBS solution to the apical chamber, the cells were incubated at 37°C for 1 h. The LPL transported to the apical surface of cells was released with heparin (100 U/mL for 5 min) and quantified as described previously (11). Transport was also assessed by microscopy.…”

Section: Methodsmentioning

confidence: 99%

“…LPL is synthesized by myocytes and adipocytes and secreted into the interstitial spaces, but is then transported to the capillary lumen by GPIHBP1, a GPI-anchored protein of endothelial cells (10,11). An absence of GPIHBP1 abolishes the entry of LPL into capillaries, causing severe chylomicronemia and an accumulation of catalytically active LPL in the interstitial spaces (11).…”

mentioning

confidence: 99%

Mutations in lipoprotein lipase that block binding to the endothelial cell transporter GPIHBP1

Voss

Davies

Tat

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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GPIHBP1, a glycosylphosphatidylinositol-anchored protein of capillary endothelial cells, shuttles lipoprotein lipase (LPL) from subendothelial spaces to the capillary lumen. An absence of GPIHBP1 prevents the entry of LPL into capillaries, blocking LPL-mediated triglyceride hydrolysis and leading to markedly elevated triglyceride levels in the plasma (i.e., chylomicronemia). Earlier studies have established that chylomicronemia can be caused by LPL mutations that interfere with catalytic activity. We hypothesized that some cases of chylomicronemia might be caused by LPL mutations that interfere with LPL's ability to bind to GPIHBP1. Any such mutation would provide insights into LPL sequences required for GPIHBP1 binding. Here, we report that two LPL missense mutations initially identified in patients with chylomicronemia, C418Y and E421K, abolish LPL's ability to bind to GPIHBP1 without interfering with LPL catalytic activity or binding to heparin. Both mutations abolish LPL transport across endothelial cells by GPIHBP1. These findings suggest that sequences downstream from LPL's principal heparin-binding domain (amino acids 403–407) are important for GPIHBP1 binding. In support of this idea, a chicken LPL (cLPL)–specific monoclonal antibody, xCAL 1–11 (epitope, cLPL amino acids 416–435), blocks cLPL binding to GPIHBP1 but not to heparin. Also, changing cLPL residues 421 to 425, 426 to 430, and 431 to 435 to alanine blocks cLPL binding to GPIHBP1 without inhibiting catalytic activity. Together, these data define a mechanism by which LPL mutations could elicit disease and provide insights into LPL sequences required for binding to GPIHBP1.

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GPIHBP1 Is Responsible for the Entry of Lipoprotein Lipase into Capillaries

Cited by 316 publications

References 23 publications

Angiopoietin-like Protein 4 Inhibition of Lipoprotein Lipase

Angiopoietin-like Protein 4 Inhibition of Lipoprotein Lipase

Regulation of prelamin A but not lamin C by miR-9, a brain-specific microRNA

Mutations in lipoprotein lipase that block binding to the endothelial cell transporter GPIHBP1

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