Isolation and Characterization of Low Sulfated Heparan Sulfate Sequences with Affinity for Lipoprotein Lipase

Spillmann, Dorothe; Lóokene, Aivar; Olivecrona, Gunilla

doi:10.1074/jbc.m604702200

Cited by 22 publications

(9 citation statements)

References 53 publications

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“…We suspect that the preferential binding of LPL to endothelial cells could reflect higher levels of HSPG sulfation in capillary endothelial cells. HSPG composition is known to vary among different organs and tissues (29)(30)(31), and this could influence LPL binding (32,33). To pursue the idea that different levels of HSPG sulfation could affect the tran-sitioning of LPL to GPIHBP1, we tested the ability of different heparin preparations (with defined length but variable sulfation patterns) to interfere with GPIHBP1-LPL interactions.…”

Section: Resultsmentioning

confidence: 99%

A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase

Kristensen

Midtgaard

Mysling

et al. 2018

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

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140

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The intravascular processing of triglyceride-rich lipoproteins depends on lipoprotein lipase (LPL) and GPIHBP1, a membrane protein of endothelial cells that binds LPL within the subendothelial spaces and shuttles it to the capillary lumen. In the absence of GPIHBP1, LPL remains mislocalized within the subendothelial spaces, causing severe hypertriglyceridemia (chylomicronemia). The N-terminal domain of GPIHBP1, an intrinsically disordered region (IDR) rich in acidic residues, is important for stabilizing LPL's catalytic domain against spontaneous and ANGPTL4-catalyzed unfolding. Here, we define several important properties of GPIHBP1's IDR. First, a conserved tyrosine in the middle of the IDR is posttranslationally modified by O-sulfation; this modification increases both the affinity of GPIHBP1-LPL interactions and the ability of GPIHBP1 to protect LPL against ANGPTL4-catalyzed unfolding. Second, the acidic IDR of GPIHBP1 increases the probability of a GPIHBP1-LPL encounter via electrostatic steering, increasing the association rate constant () for LPL binding by >250-fold. Third, we show that LPL accumulates near capillary endothelial cells even in the absence of GPIHBP1. In wild-type mice, we expect that the accumulation of LPL in close proximity to capillaries would increase interactions with GPIHBP1. Fourth, we found that GPIHBP1's IDR is not a key factor in the pathogenicity of chylomicronemia in patients with the GPIHBP1 autoimmune syndrome. Finally, based on biophysical studies, we propose that the negatively charged IDR of GPIHBP1 traverses a vast space, facilitating capture of LPL by capillary endothelial cells and simultaneously contributing to GPIHBP1's ability to preserve LPL structure and activity.

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Section: Resultsmentioning

confidence: 99%

A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase

Kristensen

Midtgaard

Mysling

et al. 2018

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

Self Cite

140

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“…The binding of TRLs to the heparan sulfate chains presumably occurs through electrostatic interactions between negatively charged sulfate and carboxyl groups with complementary positively charged domains in the apolipoproteins (apoB and apoE) or lipases (LPL or hepatic lipase) associated with the particles. In general, only 8-12 monosaccharide residues are needed to bind to many proteins, including LPL and apoE (52)(53)(54)(55), but the pattern of sulfate groups and uronic acids that mediate TRL binding is unknown. Liver heparan sulfate is unusual in that it is more highly sulfated than heparan sulfate in other tissues (54,56,57).…”

Section: Discussionmentioning

confidence: 99%

Syndecan-1 is the primary heparan sulfate proteoglycan mediating hepatic clearance of triglyceride-rich lipoproteins in mice

Stanford¹,

Bishop²,

Foley³

et al. 2009

J. Clin. Invest.

158

183

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Elevated plasma triglyceride levels represent a risk factor for premature atherosclerosis. In mice, accumulation of triglyceride-rich lipoproteins can occur if sulfation of heparan sulfate in hepatocytes is diminished, as this alters hepatic lipoprotein clearance via heparan sulfate proteoglycans (HSPGs). However, the relevant HSPG has not been determined. In this study, we found by RT-PCR analysis that mouse hepatocytes expressed the membrane proteoglycans syndecan-1, -2, and -4 and glypican-1 and -4. Analysis of available proteoglycandeficient mice showed that only syndecan-1 mutants (Sdc1 -/-mice) accumulated plasma triglycerides. Sdc1 -/-mice also exhibited prolonged circulation of injected human VLDL and intestinally derived chylomicrons. We found that mice lacking both syndecan-1 and hepatocyte heparan sulfate did not display accentuated triglyceride accumulation compared with single mutants, suggesting that syndecan-1 is the primary HSPG mediating hepatic triglyceride clearance. Immunoelectron microscopy showed that syndecan-1 was expressed specifically on the microvilli of hepatocyte basal membranes, facing the space of Disse, where lipoprotein uptake occurs. Abundant syndecan-1 on wild-type murine hepatocytes exhibited saturable binding of VLDL and inhibition by heparin and facilitated degradation of VLDL. Furthermore, adenovirus-encoded syndecan-1 restored binding, uptake, and degradation of VLDL in isolated Sdc1 -/-hepatocytes and the lipoprotein clearance defect in Sdc1 -/-mice. These findings provide the first in vivo genetic evidence that syndecan-1 is the primary hepatocyte HSPG receptor mediating the clearance of both hepatic and intestinally derived triglyceride-rich lipoproteins.

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“…We, therefore, performed chromatography on heparin-sepharose, as was previously done to study the effect of ANGPTL4 on LPL (9). It is well established that monomers and dimers of LPL interact with heparin with a different affinity (25)(26)(27). Therefore, LPL can be separated on a heparin-sepharose column into inactive LPL monomers and active LPL dimers (Fig.…”

Section: Dissociation Of Lpl Dimers By Angptl Proteins and Their Compmentioning

confidence: 99%

On the mechanism of angiopoietin-like protein 8 for control of lipoprotein lipase activity

Kovrov

Kristensen

Larsson

et al. 2019

Journal of Lipid Research

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102

148

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ANGPTL3, ANGPTL4, and ANGPTL8, are known to function as negative regulators of LPL activity in white adipose tissue (WAT), brown adipose tissue, and oxidative tissues (1-7). ANGPTL4, the most-studied family member, is expressed at various sites in the body (8). ANGPTL4 consists of an N-terminal coiled-coil domain (ccd) and a C-terminal, fibrinogen-like domain. The N-terminal ccd of ANGPTL4 inactivates LPL by promoting dissociation of the active LPL dimer into inactive monomers (9, 10). In this way, ANGPTL4 acts as a potent energy homeostasis switch causing reduced uptake of FAs from TG-rich lipoproteins in WAT during fasting (11,12). During physical activity or exercise, ANGPTL4 is upregulated in resting muscles, where it lowers LPL activity and thereby helps to direct FAs toward the contracting muscle tissue for energy production (13). In contrast to ANGPTL4, ANGPTL3 is mainly produced in the liver. It was previously demonstrated that the N-terminal ccd of ANGPTL3 reduces the activity of LPL in oxidative tissues in the fed state, thus directing the flow of lipoprotein-derived FAs to WAT for storage (14). In molar terms, ANGPTL3 is a relatively weak regulator of LPL in comparison to ANGPTL4 (10,15,16). Recent studies have shown, however, that the effect of ANGPTL3 on LPL is greatly enhanced by ANGPTL8 (15,17,18). ANGPTL8 is mostly produced in the liver and WAT and consists of a ccd, which is similar to those of ANGPTL3 and ANGPTL4, but ANGPTL8 is lacking a C-terminal, fibrinogen-like domain (6, 7). By itself, ANGPTL8 has no detectable effect on the activity of LPL. Reduction of LPL activity by ANGPTL8 occurs only in the presence of ANGPTL3 (15,18). It was recently demonstrated that ANGPTL8 needs to be coexpressed with ANGPTL3, by the same host cell, in order to have an effect on LPL activity (18).In this report, we show that recombinant ANGPTL8 produced in Escherichia coli has to be refolded together with Abstract Angiopoietin-like (ANGPTL) 8 is a secreted inhibitor of LPL, a key enzyme in plasma triglyceride metabolism. It was previously reported that ANGPTL8 requires another member of the ANGPTL family, ANGPTL3, to act on LPL. ANGPTL3, much like ANGPTL4, is a physiologically relevant regulator of LPL activity, which causes irreversible inactivation of the enzyme. Here, we show that ANGPTL8 can form complexes with either ANGPTL3 or ANGPTL4 when the proteins are refolded together from their denatured states. In contrast to the augmented inhibitory effect of the ANGPTL3/ ANGPTL8 complex on LPL activity, the ANGPTL4/ANGPTL8 complex is less active compared with ANGPTL4 alone. In our experiments, all three members of the ANGPTL family use the same mechanism to inactivate LPL, which involves dissociation of active dimeric LPL to monomers. This inactivation can be counteracted by the presence of glycosylphosphatidylinositol-anchored HDL binding protein 1, the endothelial LPL transport protein previously known to protect LPL from spontaneous and ANGPTL4-catalyzed inactivation. Our data demonstrate that ANGPTL8 may funct...

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Isolation and Characterization of Low Sulfated Heparan Sulfate Sequences with Affinity for Lipoprotein Lipase

Cited by 22 publications

References 53 publications

A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase

A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase

Syndecan-1 is the primary heparan sulfate proteoglycan mediating hepatic clearance of triglyceride-rich lipoproteins in mice

On the mechanism of angiopoietin-like protein 8 for control of lipoprotein lipase activity

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