lipoprotein lipase experiment

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• Published: 23 August 2024

A negatively charged cluster in the disordered acidic domain of GPIHBP1 provides selectivity in the interaction with lipoprotein lipase

• Robert Risti 1 ,
• Mart Reimund 1 ,
• Natjan-Naatan Seeba 1 &
• Aivar Lõokene 1  

Scientific Reports volume  14 , Article number:  19639 ( 2024 ) Cite this article

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• Enzyme mechanisms
• Lipoproteins

GPIHBP1 is a membrane protein of endothelial cells that transports lipoprotein lipase (LPL), the key enzyme in plasma triglyceride metabolism, from the interstitial space to its site of action on the capillary lumen. An intrinsically disordered highly negatively charged N-terminal domain of GPIHBP1 contributes to the interaction with LPL. In this work, we investigated whether the plethora of heparin-binding proteins with positively charged regions found in human plasma affect this interaction. We also wanted to know whether the role of the N-terminal domain is purely non-specific and supportive for the interaction between LPL and full-length GPIHBP1, or whether it participates in the specific recognition mechanism. Using surface plasmon resonance, affinity chromatography, and FRET, we were unable to identify any plasma component, besides LPL, that bound the N-terminus with detectable affinity or affected its interaction with LPL. By examining different synthetic peptides, we show that the high affinity of the LPL/N-terminal domain interaction is ensured by at least ten negatively charged residues, among which at least six must sequentially arranged. We conclude that the association of LPL with the N-terminal domain of GPIHBP1 is highly specific and human plasma does not contain components that significantly affect this complex.

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Introduction.

GPIHBP1 is a capillary endothelial cell protein that transports lipoprotein lipase (LPL), the main enzyme in hydrolytic degradation of blood triglycerides, across endothelial cells to the capillary lumen. Biallelic loss-of-function mutations in GPIHBP1 cause LPL to be retained in the interstitial space, resulting in severe hypertriglyceridemia, which in turn can lead to life-threatening acute pancreatitis 1 . According to a recent study by Song et al. 2 , part of the GPIHBP1 transported LPL relocates to heparan sulfate proteoglycans (HSPGs) in the glycocalyx. At this site, LPL acts on triglyceride-rich lipoproteins, breaking down their triglycerides into fatty acids and monoglycerides that are usable components for cells. It is not known whether the displacement of LPL from GPIHBP1 to the glycocalyx is entirely spontaneous or is influenced by some plasma component. Understanding this mechanism may be important because its misregulation can lead to elevations in plasma triglyceride levels, which are correlated with an increased risk of cardiovascular disease and other metabolic disorders.

Two distinct regions of GPIHBP1—an intrinsically disordered N-terminal acidic domain with a long stretch of aspartate and glutamate residues, and a cysteine-rich Ly6 domain with a three-finger structure – are involved in the interaction with LPL. Both GPIHBP1 domains are also required for its transport function 3 . Surface plasmon resonance (SPR) studies show that while the interaction of the N-terminal domain with LPL is characterized by a high on–off rate, the complex with Ly6 forms and also dissociates at a slower rate 4 , 5 , 6 . While the sequence of the Ly6 domain is highly conserved between species, the N-terminal domains differ in length, distribution, and number of negative charges 7 . For example, human N-terminal domain of GPIHBP1 contains 21 negatively charged residues, but mouse or opossum have 17 or 32 acidic residues, respectively. X-ray structures of the LPL/GPIHBP1 complex reveal that the Ly6 domain binds to the C-terminal domain of LPL and that this association is mainly hydrophobic in nature 8 , 9 . Although the binding region of LPL involved in the interaction with the N-terminal domain was not identified in the X-ray structures, it is probable that the highly positively charged region of LPL plays a crucial role in its formation. This region is also likely to be involved in LPL’s interaction with other polyanions such as the polysaccharides heparin and heparan sulfates 10 . Comparison of affinities of synthetic peptides corresponding to the sequence of the N-terminal domain of mouse, bovine or human GPIHBP1 suggested that the number of negatively charged residues in the N-terminal domain might be important 4 . The GPIHBP1 N-terminal domain of several species also contains a tyrosine whose sulfation may play a role in affinity for LPL 6 . However, the structural motifs of the N-terminal domain of GPIHBP1 that confer its high affinity to LPL remain largely unclear.

Previous studies have shown that LPL binds strongly to heparin and heparan sulfates and, like the N-terminal domain, this interaction is transient and characterized by high on- and off-rates 11 . Furthermore, the interaction seems to not be highly specific, LPL prefers HS sequences with high negative charge density 12 , 13 . These observations raise a question of specificity for the binding of the N-terminal domain to LPL. Is it completely non-specific, having only an additional role in the interaction with full-length GPIHBP1 or does it play a specific role? It is noteworthy to bear in mind that many heparin-binding proteins have been identified in human plasma 14 , 15 , 16 , the common feature of which is the presence of a positively charged region in their folded structure 17 . Considering that the interaction of some proteins with heparin is primarily non-specific and ionic, depending mainly on the charge density, it is reasonable to ask whether the N-terminal domain of GPIHBP1 could be a potential ligand for them.

Here, we investigated whether human plasma contains components that bind to the N-terminal domain of GPIHBP1 or affect its interaction with LPL. Using SPR, affinity chromatography, and fluorescence techniques, we were unable to identify any plasma component, other than LPL, that bound the N-terminus with detectable affinity or affected its interaction with LPL. In contrast, we ascertain several plasma proteins that bound avidly to heparan sulfate or heparin. Based on these observations, we conclude that the association of LPL with the N-terminal domain of GPIHBP1 is highly specific and human plasma does not contain components that substantially affect this complex. By combining binding and stabilization studies of different synthetic peptides, we show that the high affinity of the LPL/N-terminal domain interaction is ensured by at least ten negatively charged residues, among which at least six must be in a sequentially arranged cluster.

Materials and methods

LPL was purified from bovine milk as previously described 18 . Aliquoted stock solutions of LPL were stored at −80 °C in a buffer containing 10 mMBis-Tris, pH 6.5, 1.5 M NaCl. Samples were used immediately after thawing and only used once. Synthetic peptides (Table 1 ) were purchased from GeneCust (Luxembourg). Some peptides contained an extra cysteine residue at the C-terminal end. The synthetic peptides were biotinylated and labeled by DyLight 488 dye (Pierce) at cysteines as previously described 4 . Heparan sulfate was biotinylated at amino groups as previously described 11 . Extinction coefficients at 280 nm for determination of peptide/protein concentrations were as follows: LPL—70,440 M −1 cm −1 ; human N-terminal peptide, bovine N-terminal peptide, peptide 1 and peptide 4–1480 M −1 cm −1 ; mouse N-terminal peptide—2960 M −1 cm −1 . The extinction coefficients were calculated according to Gill and Hippel 19 . Concentrations of LPL were calculated using its monomer molecular weight of 55 kDa. Heparin binding proteins, namely antithrombin III (#194,936) and fibroblast growth factor 2 (FGF-2) (#153,509) were purchased from ICN Biomedicals Inc., protamine (#P4005) was purchased from Sigma Aldrich. 1,2-Di-O-lauryl-rac-glycero3-glutaric acid 6-methylresorufin ester (DGGR) (#30,058) was purchased from Sigma Aldrich. Nonfasting human EDTA-plasmas were purchased from the Tallinn Blood Centrum. Lipoprotein deficient human plasma was obtained from plasma by using an ultracentrifuge as previously described 20 . Triglyceride and cholesterol concentrations were determined using Triglyceride Colorimetric Assay Kit (Cayman, USA) and Cholesterol Fluorometric Assay Kit (Cayman, USA).

Surface plasmon resonance experiments

SPR experiments were conducted on a Biacore 3000 (GE Healthcare Life Sciences) instrument. Neutravidin (Sigma) was covalently attached to the surface of CM5 (GE Healthcare Life Sciences) sensor chips using the amine coupling kit (GE Healthcare Life Sciences). To study the binding of human plasma components to different ligands, biotinylated N-terminal peptide of GPIHBP1 or biotinylated heparan sulfate were bound to the sensor chip surface via biotin-NeutrAvidin interaction. 578 RU of biotinylated N-terminal GPIHBP1 was bound to the surface of the sensor which corresponded to a surface density of 148.5 fmol/mm 2 .

Nonfasting pooled human plasma samples with a mean TG concentration of 1.08 mM ( n  = 8) or pooled lipoprotein deficient human plasma samples ( n  = 3) were diluted tenfold and injected over the surfaces (60 µl, 20 µl/min). In control experiments, 20 nM, 40 nM or 80 nM purified bovine LPL was added to the same tenfold diluted pooled lipoprotein deficient human plasma. Measurements were performed at 25 °C in a running buffer containing 20 mM HEPES, pH 7.4, 0.15 M NaCl. The same measurement conditions were also used in the control experiments with isolated heparin binding proteins (antithrombin III, protamine, FGF-2).

The affinity between various peptides and LPL was assessed using a SPR competition assay, following the experiments first described by Reimund et al. 4 . The sequences of the investigated peptides are presented in Table 1 . The experimental steps of the binding study were as follows: (1) Biotinylated N-terminal peptide of GPIHBP1 was immobilized to the sensor chip via NeutrAvidin. (2) LPL (800 nM) was mixed with different peptides at increasing concentrations at 4 °C. LPL or solutions of LPL/peptide complexes were injected over the sensor chip’s surface (30 µl, 5 µl/min). (3) Binding of LPL to the immobilized N-terminal peptide of GPIHBP1 was registered near the equilibrium at the end of each injection. Measurements were carried out at 4 °C. Running buffer contained 20 mM NaH 2 PO 4 , pH 7.4, 2 mg/ml BSA, 0.4 M NaCl. The affinity of the peptides for LPL, expressed as K D values, was calculated using Eq. ( 1 ).

where P 0 is the concentration of peptide in the injected solution, the K D is the equilibrium dissociation constant, Δ R is the change in SPR at equilibrium, and ‘ a ’ is the change in SPR for binding of LPL to the surface when the solution did not contain free peptide.

Direct binding studies were performed to investigate the interaction between peptide 6 and LPL (Table 1 ). Biotinylated peptide 6 was attached to the surface via NeutrAvidin and solutions of 1, 2 or 3 µM LPL were injected over this surface. Experimental conditions were the same as in competition experiments.

Affinity chromatography

Fasting human plasma (17 ml) was loaded to an 8 ml heparin column (Heparin Sepharose 6 Fast Flow affinity resin, GE Healthcare Life Sciences) in a buffer containing 100 mM TRIS, pH 7.4, 0.15 M NaCl. The column was washed with 80 ml of the same buffer. Heparin binding proteins (i.e. bound material) were eluted from the column using a buffer containing 100 mM TRIS, pH 7.4, 2 M NaCl. Eluted proteins were pooled together, dialyzed to buffer containing 100 mM TRIS, pH 7.4, 0.15 M NaCl and loaded to an affinity column containing immobilized N-terminal peptide of GPIHBP1. The latter was made by attaching biotinylated N-terminal peptide to HiTrap Streptavidin HP column (GE Healthcare Life Sciences). The column was washed with 100 mM TRIS, pH 7.4, 0.15 M NaCl buffer and elution was performed in a 0.15–2 M NaCl gradient. All steps were carried out at 10 °C. Identification of human plasma proteins that bound to the heparin column was obtained as a service from the Proteomics Core Facility at the Institute of Technology, University of Tartu (Tartu, Estonia).

Fluorescence anisotropy

Fluorescence anisotropy experiments were conducted on a Hitachi F-7000 (Hitachi High-Tech, Japan) fluorescence spectrophotometer. The excitation and emission wavelengths were 493 nm and 518 nm, respectively. Experiments were done either in phosphate buffer (20 mM phosphate, pH 7.4, 0.15 M NaCl), or in the same buffer with added 10 mg/ml BSA, 10 IU/ml heparin or 50% lipoprotein free human plasma. Dylight 488 maleimide labeled N-terminal peptide of GPIHBP1 at concentrations of 100 nM were mixed with increasing concentrations of LPL. Next, fluorescence was measured when excitation and emission polarizers both were oriented vertically, and when the excitation polarizer was oriented vertically, and the emission polarizer was oriented horizontally.

From the acquired data the fluorescence anisotropy was calculated using Eq. ( 2 ):

where r is fluorescence anisotropy, \({I}_{\parallel }\) is observed fluorescence intensity when the emission polarizer was oriented parallel to the direction of the polarized excitation, \({I}_{\perp }\) is the observed fluorescence intensity when the emission polarizer was oriented perpendicular to the direction of the polarized excitation.

Dependence between change of anisotropy and LPL concentration was fitted with Eq. ( 3 ) for calculation of the K D values for a 1:1 binding model:

where r is the change of fluorescence anisotropy, r max is the value of anisotropy of the complex of LPL with the N-terminal peptide, L 0 is the concentration of LPL, P 0 is the concentration of the peptide, K D is the equilibrium dissociation constant.

Determination of LPL activity with DGGR

Fluorescence spectroscopy was utilized to assess the effects of the N-terminal GPIHBP1 and synthetic peptides on the thermostability of LPL by monitoring LPL activity using the fluorogenic substrate DGGR. Experiments were conducted using a spectrofluorophotometer (Shimadzu RF-5301 PC, Shimadzu Corporation, Japan) at an excitation wavelength of 572 nm and an emission wavelength of 605 nm. 10 nM LPL was incubated at 37 °C in 20 mM HEPES, pH 7.4, 150 mM NaCl either alone, with 1 μM nGPIHBP1, or with 1 μM synthetic peptides. Initial LPL activity was measured at 37 °C immediately after mixing, and then at 10-min intervals.

Modeling of the predicted complex

The cryo-EM structure of LPL for the visualization of positively charged surfaces was obtained from the PDB entry 8ERL 21 . The structure of LPL in complex with either full-length GPIHBP1 or the N-terminal domain of GPIHBP1 was predicted using ColabFold 22 , which uses an optimized approach to accelerate protein–protein complex modeling by Alphafold2-Multimer 23 . The human LPL and GPIHBP1 sequences were obtained from Uniprot database entries Q6IAV0 and Q8IV16, respectively 24 . Five predicted structures were generated for each complex based on the chosen sequences and the model with the highest confidence score was chosen for visualization. ChimeraX was used to create the figures and calculate the Coulombic electrostatic potential of predicted structure surfaces 25 .

LPL is the only plasma component that binds the N-terminal domain of GPIHBP1 with high affinity

To investigate whether human plasma contains proteins in addition to LPL that bind to the N-terminal domain of GPIHBP1, we performed binding studies using SPR. Solutions of pooled human plasma samples ( n  = 8) or pooled lipoprotein-deficient human plasma samples ( n  = 3) were injected into sensor chip flow cells pre-immobilized with the N-terminal domain of GPIHBP1 (Fig.  1 ) or with heparan sulfate (Fig.  2 ). To assess the effect of nonspecific binding, the plasma solutions were injected into the flow cells that did not contain the N-terminal domain or heparan sulfate. The results of these experiments suggested that neither lipoprotein-deficient nor lipoprotein-containing human plasma contained components that bound to the N-terminal domain of GPIHBP1 with detectable affinity. In the case of lipoprotein-containing plasma, nonspecific binding to the sensor chip surface was even higher than to the N-terminal domain (Fig.  1 b). However, when 20 nM, 40 nM or 80 nM LPL was present in the lipoprotein deficient plasma samples, association with the N-terminal domain of GPIHBP1 was evident, and increased when the concentration of LPL was raised (Fig.  1 c–e). At the same time, injecting various heparin-binding proteins (antithrombin III, protamine, FGF-2) over the N-terminal domain of GPIHBP1 showed no binding, even at concentrations of 1 μM (Supplementary Fig. S1 ).

SPR studies assessing the binding of human plasma components to the N-terminal peptide of GPIHBP1. Solutions of tenfold diluted lipoprotein free human plasma ( a ), tenfold diluted whole plasma ( b ), or the same lipoprotein free plasma with added 20 nM LPL ( c ), 40 nM LPL ( d ) or 80 nM LPL ( e ) were injected to the flow cells with the immobilized N-terminal peptide of GPIHBP1. Solid line shows specific binding to the N-terminal peptide of GPIHBP1. Dashed line shows nonspecific binding to sensor chip matrix.

SPR studies assessing the binding of human plasma components to heparan sulfate. Solutions of tenfold diluted lipoprotein free human plasma ( a ), tenfold diluted whole plasma ( b ), or the same lipoprotein free plasma with added 20 nM LPL ( c ) were injected to the flow cells with the immobilized heparan sulfate. Solid line shows specific binding to heparan sulfate. Dashed line shows nonspecific binding to sensor chip matrix.

In contrast to the N-terminus of GPIHBP1, considerable binding of human plasma components to the immobilized heparan sulfate was observed (Fig.  2 a,b), consistent with previous studies showing that human plasma contains numerous heparin-binding proteins 14 , 15 , 16 . These experiments suggested that even though human plasma contains many heparin binding proteins, they either do not interact with the N-terminal domain of GPIHBP1, or their affinity to this domain is much lower than that of LPL.

In addition to SPR experiments, we used affinity chromatography to study the binding of plasma components to the N-terminal domain of GPIHPB1 and heparin. We used a streptavidin-Sepharose column onto which biotinylated N-terminal of GPIHBP1 was immobilized. Heparin was directly immobilized to CNBr activated agarose. Mass spectrometry identified a total of 76 plasma proteins, which were bound to heparin-agarose and subsequently eluted using a NaCl concentration gradient. The strongest proteolytic peptide intensity signals were given by antithrombin, kallikrein, thrombin, apolipoprotein E, histidine rich glycoprotein, alpha1 microglobulin, coagulation factor XI, complement factor D. However, these proteins did not bind to the N-terminal domain of the GPIHBP1 affinity column (Fig.  3 a)—all these proteins were present in the flow-through and no additional proteins were eluted in the NaCl gradient. The same was observed when whole plasma was injected over the affinity column (Fig.  3 b). In contrast, LPL in the presence of BSA bound to the column with immobilized N-terminal GPIHPB1 and eluted at NaCl concentration between 0.4 and 0.6 M (Fig.  3 c).

Testing the ability of heparin binding proteins purified from human plasma to bind to the N-terminal domain of GPIHBP1 using affinity chromatography. Biotinylated N-terminal peptide was attached to HiTrap Streptavidin HP column. ( a ) Plasma proteins eluted from heparin affinity column or ( b ) whole human plasma was loaded to the column. All proteins were in the flow-through. No additional proteins eluted in 0.15–2 M NaCl gradient. ( c ) LPL was loaded to the N-terminal peptide column and eluted in a 0.15–2 M NaCl gradient. Solid line shows optical density at 280 nm. Dashed line shows NaCl concentration.

Components of human plasma do not substantially interfere with the interaction between LPL and the N-terminal domain of GPIHBP1

To further investigate the interaction between LPL and the N-terminal domain of GPIHBP1, we used fluorescence anisotropy which allowed to conduct studies in undiluted blood plasma, i.e. the environment in which LPL functions in vivo. For comparison, measurements were performed under four different conditions: (1) in a standard phosphate buffer, (2) in the same buffer with added 10 mg/ml BSA, (3) in the same buffer with 10 IU/ml heparin, or (4) in the same buffer which contained lipoprotein free human plasma. As can be seen in Fig.  4 , the affinity of the interaction was the highest in phosphate buffer ( K D  = 60 nM). In buffers with BSA or lipoprotein free plasma the interaction was slightly weaker. Introducing heparin to the buffer completely blocked the interaction as heparin is known to disrupt the N-terminal GPIHBP1-LPL complex 4 . However, in these cases a simple binding model did not fit the data well and the K D value could not be reliably determined. This suggests a more complex binding mechanism. The comparable effect of BSA and plasma on the interaction suggests that albumin acted as an effector, whereas other components of human plasma did not appear to influence this interaction. The weak binding of BSA to LPL as shown in our recently published study would explain the slightly reduced affinity and the complex interaction mechanism 26 . These observations are in line with SPR findings in diluted human plasma (Fig.  1 ) showing the specificity and selectivity of this interaction and suggest that other plasma components do not compete with LPL to interact with the N-terminal domain of GPIHBP1.

Human plasma environment does not influence the affinity of the interaction between the N-terminal domain of GPIHBP1 and LPL. The change of fluorescence anisotropy of labeled N-terminal domain of GPIHBP1 was measured at different concentrations of LPL in standard phosphate buffer (black), in the buffer with 10 mg/ml BSA (white), or with 10 IU/ml heparin (blue), or in the buffer with 50% lipoprotein free human plasma (red).

A cluster of negatively charged residues drives specificity of the interaction between the N-terminal domain of GPIHBP1 and LPL

The observations that binding of LPL to the N-terminal domain of GPIHBP1 is specific prompted us to ask what structural features of the N-terminal domain ensure the high affinity of this interaction (Fig.  5 ). Firstly, we examined whether various regions of the domain may have different contributions to the total affinity. We chose peptides 1 and 2 (see Table 1 ), whose sequences partially overlapped but represented distinct regions within the human N-terminal domain of GPIHBP1. These peptides contained the same number (10) of negatively charged residues. Their affinities for LPL were compared to peptide 3 which also contained 10 negatively charged residues and whose affinity has been already previously determined 4 . Together the sequences of these three peptides make up the entire N-terminal domain sequence. All three peptides bound to LPL with affinities that did not differ greatly. However, peptide 3 had the highest affinity and peptide 1 had the lowest affinity. Their comparable affinities for LPL suggested that all parts of the N-terminal domain of GPIHBP1 contribute to the interaction with LPL.

The affinities for the interaction between LPL and different peptides as determined by SPR. Peptides 1–5 sequences correspond to the various regions of the human N-terminal domain of GPIHBP1. Peptides 6 and 7 sequences are partially based on the human N-terminal domain of GPIHBP1. Errors shown are S.D. of the fitting. K D values for human N-terminal peptide, peptide 3, peptide 4, peptide 5, peptide 7, mouse N-terminal peptide and bovine N-terminal peptide have been published previously 4 .

Next, we examined how important is the number and distribution of negatively charged groups. We designed peptide 6, the sequence of which was obtained by replacing several aspartate and glutamate residues with alanine in the sequence of the human N-terminal domain of GPIHBP1. As a result of such substitutions, there were no regions in peptide 6 with more than two adjacent negatively charged residues. The 21 amino acid sequence of peptide 6 contained 13 negatively charged groups, as did peptide 5, whose negatively charged residues were arranged compactly and formed a cluster of seven negatively charged residues in the middle of its 15 amino acid sequence. Peptide 5 exhibited a binding affinity to LPL comparable to that of the full-length N-terminus. Conversely, peptide 6 failed to demonstrate detectable binding under the experimental conditions employed. These observations suggest either considerably reduced affinity to LPL or a complete lack of interaction. Thus, the presence of only a certain number of negatively charged residues alone does not guarantee high affinity binding to LPL. Instead, the sequential arrangement of the negatively charged group in the sequence emerges as the critical factor. At the same time, the presence of negatively charged clusters was also not sufficient, because short cluster-containing peptides 4 and 8 did not interact with LPL. Summarizing the obtained results on Fig.  5 , our findings indicate that for robust binding to LPL, it is essential for a sequence to contain at least one negatively charged cluster of 6 residues, along with a minimum total of 10 negatively charged residues.

Clusters of negatively charged residues are crucial for LPL stabilization

As previous studies have shown, the N-terminal domain of GPIHBP1 stabilizes LPL from spontaneous thermal inactivation 5 , 27 . We therefore investigated whether the same peptides that were used in the interactions study could also prevent loss of catalytic activity of LPL at 37 °C (Fig.  6 and Supplementary Fig. S2 ). Peptide 4, which has the shortest sequence and no detectable affinity to LPL, could not stabilize LPL compared to plain buffer. Peptide 8, with two additional negatively charged residues compared to peptide 4, also failed to exert any effect on the stability of LPL. However, as the number of negatively charged residues increased further, so did the effect of the peptides on the stability of LPL. Peptide 3 conserved 60% of LPL activity. Peptide 5, and the human N-terminal peptide, which had a higher affinity to LPL compared to peptide 3, increased LPL stability even further. Interestingly, while peptide 6 has the same number of negatively charged residues as peptide 5, it failed to increase LPL stability compared to plain buffer. This demonstrates that, much like the binding affinity of peptides to LPL is not solely dependent on the number of negatively charged residues, neither is the effect of peptides on LPL stability.

Clusters of negatively charged residues are crucial for LPL stabilization. 10 nM LPL was incubated at 37°C with 1 μM nGPIHBP1 or peptides. LPL activity was determined with DGGR immediately, and after 10 min of incubation. Results are presented as a mean percentage of remaining initial activity ± SD of three independent measurements. LPL stability was highly dependent on the presence of negatively charged amino acid clusters, and their size.

Predicted models show interaction of the N-terminal domain of GPIHBP1 with the large positively charged region of LPL

LPL has a large positively charged region spanning from the C-terminal domain, across the hinge region, to the N-terminal domain as shown on Fig.  7 a. This patch is comprised of four distinct positive charge clusters of which three are important for binding to heparin 10 . We hypothesized that the same clusters might be important for the interaction with the N-terminal domain of GPIHBP1. While the binding of the Ly6 domain of GPIHBP1 has been elucidated 8 , 9 , the binding of the N-terminal domain has remained elusive, likely due to its disordered and dynamic nature. We therefore used ColabFold to predict the localization of the interaction interface between the N-terminal domain of GPIHBP1 and LPL (Fig.  7 b). All predicted models consistently demonstrated binding of the highly negatively charged N-terminal domain of GPIHBP1 to the basic patch of LPL. This was also true in the case of full-length GPIHBP1 (Fig.  7 c), where the Ly6 domain was simultaneously bound to the same C-terminal region of LPL as shown in crystal structures 8 , 9 . In both complexes shown in Fig.  7 , the C-terminal segment of the N-terminal domain, which contains a cluster of negatively charged groups (DEEDEDEVEEEE), directly interacts with the surface of LPL. The rest of the domain remains away and can support interactions with long-range electrostatic forces. However, it should be considered that the per-residue model confidence score (pLDDT) for the predicted structure of the complexes was very low (< 50), which means that interactions between other regions are also possible. It is also feasible that the low scores are a consequence of the inherent disorder of the N-terminal GPIHBP1 peptide and are a predictor of the dynamic nature of the peptide, rather than a sign of low prediction confidence 28 .

Predicted models showing how the N-terminal domain of GPIHBP1 interacts with the positively charged patch of LPL. ( a ) LPL has a wide polyanion binding region as visualized on an experimentally derived structure. Predicted complexes of LPL with the N-terminal domain of GPIHBP1 ( b ) or with full-length GPIHBP1 ( c ) demonstrate how the highly negatively charged region (red) of GPIHBP1 fits into the large positively charged patch (blue) of LPL. The N-terminus of GPIHBP1 is indicated.

In the present study, we show that although plasma contains numerous proteins that bind to the negatively charged polysaccharides heparin and heparan sulfate, we were unable to identify any that interacted with the highly negatively charged and disordered N-terminal domain of GPIHBP1 with detectable affinity. At the same time LPL binds to this domain with high affinity 4 , 6 . Furthermore, plasma proteins did not block the interaction between LPL and the N-terminal domain in tenfold diluted plasma as shown by SPR. This observation supports the speculation that movement of LPL from GPIHBP1 to HSPGs in the glycocalyx might occur spontaneously 2 . Fluorescence anisotropy measurements in undiluted human plasma suggested that only albumin, the major plasma protein, slightly reduced this interaction. Such a large difference between LPL and other heparin-binding proteins was somewhat unexpected because several of the plasma proteins interact with heparin with considerable affinity 17 . Moreover, the interaction of several of these proteins with heparin has been shown to be rather non-specific without favoring specific heparin sequences. In addition, plasma concentrations of some heparin-binding plasma proteins are relatively high. A prime illustration of this concept can be found in thrombin, which typically maintains a plasma concentration ranging between 5 and 10 mg/dl or 0.7–1.3 µM 29 and its interaction with heparin is predominantly nonspecific 30 . Thus, it is difficult to find an explanation for the large difference between LPL and other heparin-binding proteins. We speculate that the high affinity of LPL/N-terminal domain interaction is due to the large positively charged polyanion binding region in LPL ( ∼ 2400 Å 2 ) 8 , which includes the region in the C-terminal domain, the hinge region, and the N-terminal catalytic domain of the enzyme. In other heparin-binding proteins, the area of the corresponding regions is substantially smaller, ranging from 200 to 1150 Å 17 . The wide ( ∼ 60 × 40Å 2 ) 8 and positively charged region in LPL may allow the N-terminal domain to be positioned there in several different ways, leading to more degrees of freedom, an increase in binding entropy and thus a potential increase in the binding affinity 31 , 32 .

The results of the present study suggest that the high affinity of the N-terminal domain for LPL is ensured by the presence of at least 10 negatively charged residues, at least 6 of which are in a consecutive cluster. This conclusion is also supported by the knowledge that all known GPIHBP1 sequences from different species have both a cluster and a sufficient number of negative residues in their N-terminal domain. The important role of the cluster was particularly evident in the comparison of peptides 5 and 6 which had an equal number of negative charges but showed a considerable difference in their interaction with LPL. Only the cluster-containing peptide 5 bound to LPL with substantial affinity and stabilized its active conformation. According to the small-angle X-ray scattering (SAXS) analyses 6 , the chain length of the disordered N-terminal domain is 68 Å, most of which could fit into the highly positively charged polyanion-binding region in LPL. However, our results suggest that the high density of negative charge of the cluster region is a prerequisite for strong binding. Therefore, the cluster region is likely to be the "hot" region of the N-terminal domain in the interaction with LPL. Our data further indicates a strong correlation between the affinity of the examined peptides and their capacity to stabilize LPL. It is reasonable to infer that the stabilization of LPL necessitates a dense concentration of negatively charged sequences within the polypeptide chain, facilitating binding to regions of LPL characterized by a high density of positive charge. Electrostatic repulsion forces likely underlie LPL's instability, arising from positively charged residues within LPL's highly positively charged region.

Our modeling findings align with the SPR experiments and stabilization studies: the cluster situated at the C-terminus of the N-terminal domain EEDEDEVEEEETC is projected to establish direct contact with the LPL region positioned at the junction of the C-terminal domain and hinge region. Other segments within the N-terminal domain are not directly engaged. Their influence on the interaction likely stems from long-range electrostatic effects. All examined peptides demonstrated interaction with this region in the modeled complexes.

In summary, in this report we show that the interaction between the strongly negatively charged disordered N-terminal domain of GPIHBP1 and the natively folded LPL is highly specific in human plasma environment. The sequential cluster of negatively charged residues ensures this specificity. Other plasma components do not substantially influence this interaction.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported by Tallinn University of Technology (Grant SS22005 to A.L). The authors thank Jette Rindesalu for her contribution to several experiments.

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Robert Risti, Mart Reimund, Natjan-Naatan Seeba & Aivar Lõokene

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A.L. and M.R. conceptualized the study. M.R. performed the experiments shown in Figs. 1 , 2 , 3 and 4 . R.R. compiled the data for Fig.  5 . R.R and N.-N.S. performed the experiments shown in Fig.  6 . R.R. performed the structural modeling on Fig.  7 . A.L. acquired funding for the project and supervised the project. R.R, M.R, A.L. wrote the main manuscript text. All authors reviewed the manuscript.

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Risti, R., Reimund, M., Seeba, NN. et al. A negatively charged cluster in the disordered acidic domain of GPIHBP1 provides selectivity in the interaction with lipoprotein lipase. Sci Rep 14 , 19639 (2024). https://doi.org/10.1038/s41598-024-70468-6

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DOI : https://doi.org/10.1038/s41598-024-70468-6

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The role of selected lncrnas in lipid metabolism and cardiovascular disease risk, 1. introduction, 2. long noncoding rnas, 3. high-density lipoproteins, reverse cholesterol transport and cardiovascular risk, 4. lncrnas affecting lipoproteins, lipid metabolism, and atherosclerosis risk, 4.1. lncrna with beneficial effects, 4.1.1. nfia antisense rna 1.

• Name/organism: RP5-833A20.1/ NFIA antisense RNA 1/NFIA-AS1; Homo sapiens
• Databases &Code: Ensembl ENSG00000237853; HGNC: 40402; NCBI Gene: 645030
• Chromosomal location& size: 1p31.3: 61,248,945–61,253,510 reverse strand; 4 exons, is associated with 1718 variant alleles
• Interaction with other molecules: hsa-miR-382-5p
• Biological consequence of such interaction: Increases circulation of HDL-C, reduces levels of LDL-C, and VLDL-C

4.1.2. Liver-Expressed LXR-Induced Sequence

• Name/organism: LeXis/CT70 (cancer/testis associated transcript 70); Homo sapiens
• Databases &Code: Ensembl ENSG00000230013; HGNC:37195
• Chromosomal location& size: 9q31.1
• Interaction with other molecules: Raly
• Biological consequence of such interaction: Modulates expression of cholesterol biosynthetic genes

4.1.3. Macrophage-Expressed LXR-Induced Sequence

• Name/organism: MeXis/AI427809/LOC381524; Homo sapiens
• Databases &Code: Ensembl ENSMUSG00000086712.3
• Chromosomal location& size: Chromosome 4: 53,261,356–53,270,232 reverse strand.
• 4 transcripts (splice variants), 3 orthologues and is associated with 4 phenotypes
• Interaction with other molecules: Raly, DDX17
• Biological consequence of such interaction: Macrophage expressed LXRa (NR1H3)-dependent amplifier of Abca1 transcription lncRNA

4.1.4. LncRNA RP1-13D10.2

• Name/organism: RP1-13D10.2;
• Interaction with other molecules: LXR, SREBF2
• Biological consequence of such interaction: Regulates LDLR gene expression in a sterol-responsive and SNP genotype–dependent manner in vitro

4.1.5. LncLSTR

• Name/organism: LncLSTR (lncRNA liver-specific triglyceride regulator);
• Chromosomal location& size: Syntenic to human chromosome 1q25
• Interaction with other molecules: TDP-43
• Biological consequence of such interaction: Modulates bile acid composition to regulate APOC2 expression, via FXR,85 and to control serum triglyceride levels

4.1.6. Cholesterol-Induced Regulator of Metabolism RNA

• Name/organism: CHROME, PRKRA-AS1; Homo sapiens
• Databases &Code: Ensemble: ENSG00000223960.9; HGNC:54059
• Chromosomal location& size: 2q31.2: 178,413,635–178,440,243 forward strand; 35 transcripts (splice variants)
• Interaction with other molecules: miR-27b, miR-33a, miR-33b, and miR-128
• Biological consequence of such interaction: Promotes cholesterol secretion and HDL synthesis via suppressing the activity of specific miRNAs

4.1.7. Lipid-Droplet Transporter

• Name/organism: LIPTER/LINC00881; Homo sapiens
• Databases &Code: Ensemble: ENSG00000241135.8; HGNC: 48567; NCBI Gene: 100498859
• Chromosomal location& size: 3q25.31: 157,089,634–157,135,557 forward strand; 11 transcripts
• Interaction with other molecules: Phosphatidic acid, phosphatidylin-ositol 4-phosphate MYH10 motor protein
• Biological consequence of such interaction: Facilitates the connection between LDs and the cytoskeleton for intracellular transport

4.1.8. Regulator of Hyperlipidaemia Long Noncoding RNA

• Name/organism: lncRHPL; Mus musculus (house mouse)
• Databases &Code: NIH Gene ID: 105244982
• Chromosomal location& size: Chromosome 8
• Interaction with other molecules: hnRNPU, BMAL1
• Biological consequence of such interaction: Modulates hepatic VLDL secretion.

4.1.9. LncNONMUG027912

• Name/organism: LncNONMMUG027912/lnc027912
• Interaction with other molecules: AMPKα/mTOR signalling axis
• Biological consequence of such interaction: Upregulates p-AMPKα, reduces p-mTOR levels, suppresses nuclear expression of SREBP1C, and hinders the expression of lipid synthesis genes

4.1.10. Maternally Expressed 3

• Name/organism: MEG3/GTL2/LINC00023/NCRNA00023/ONCO-LNCRNA-83;
• Databases &Code: ENSG00000214548.18; HGNC (14575); NCBI Gene (55384); OMIM ® (605636); Open Targets Plat-form (ENSG00000214548)
• Chromosomal location& size: Chromosome 14: 100,779,410–100,861,031 forward strand;
• 50 transcripts and is associated with 6 phenotypes
• Interaction with other molecules: miR-21
• Biological consequence of such interaction: Modulates hepatic lipogenesis

4.1.11. Cyclin-Dependent Kinase Inhibitor 2B Antisense RNA 1

• Name/organism: ANRIL/CDKN2B-AS1/RP11-145E5.4/NCRNA00089/p15AS/PCAT12; Homo sapiens
• Databases &Code: HGNC: 34341; Ensembl: ENSG00000240498; NCBI Gene: 100048912; OMIM ® : 613149
• Chromosomal location& size: located within the CDKN2B-CDKN2A gene cluster at chromosome 9p21.3: 21,994,139–22,128,103 forward strand; 28 transcripts
• Interaction with other molecules: polycomb repressive complex-1 (PRC1) and -2 (PRC2),
• Biological consequence of such interaction: Epigenetic silencing of other genes in this cluster.

4.1.12. HOXC Cluster Antisense RNA 1

• Name/organism: HOXC-AS1/NONHSAG011268.2/HSALNG0091321; Homo sapiens
• Databases &Code: HGNC: 43749; NCBI Gene: 100874363; Ensembl: ENSG00000250451
• Chromosomal location& size: 12q13.13; Ch 12: 53,999,022–54,000,010 reverse strand; 2 transcripts
• Biological consequence of such interaction: Inhibition of intracellular lipid accumulation

4.2. LncRNA with Adverse Effects

4.2.1. ac068234.2–202 and ap001033.3–201.

• Name/organism: AC068234.2–202; Homo sapiens
• Databases &Code: AC068234.2
• Chromosomal location& size: Ch17:47,303,474–47,323,613 reverse strand; transcript with 3 exons, associated with 4518 variant alleles
• Interaction with other molecules: TBXA2R
• Biological consequence of such interaction: Possibly contribute to the trans-regulation of the protein-coding gene thromboxane A2 receptor (TBXA2R)
• Name/organism: AP001033.3–201; Homo sapiens
• Databases &Code: AP001033.3
• Chromosomal location& size: Ch18: 9,310,522–9,334,445 reverse strand; transcript with 3 exons and 5282 reported variant alleles
• Interaction with other molecules: antisense to ITGB3
• Biological consequence of such interaction: Acts a cis-regulator of the protein-coding gene integrin subunit beta 3 (ITGB3)

4.2.2. LncRNA ENST00000602558.1

• Name/organism: ENST00000602558.1; Homo sapiens
• Databases &Code: Ensembl: ENST00000602558.1
• Chromosomal location& size: Chromosome 12: 123,971,457-123,971,714 reverse strand;
• Exons: 1, Coding exons: 0, Transcript length: 258 bps; sense intronic to CCDC92
• Interaction with other molecules: p65
• Biological consequence of such interaction: Downregulates ABCG1 mRNA

4.2.3. Long Intergenic Non-Protein Coding RNA 1228

• Name/organism: LINCRNA-DYNLRB2-2/LINC01228;
• Databases &Code: Ensembl: ENST00000567966.1
• Chromosomal location& size: Chromosome 16: 79,798,050–79,827,150 reverse strand; Size: 623 bp
• Interaction with other molecules: GPR119
• Biological consequence of such interaction: Facilitates cholesterol efflux and diminishes neutral lipid accumulation

4.2.4. Taurine Upregulated Gene 1

• Name/organism: TUG1/FLJ20618/LINC00080/NCRNA00080; Homo sapiens
• Databases &Code: Ensembl: ENSG00000253352.10
• Chromosomal location& size: 22q12.2: 30,969,245–30,979,395 forward strand; 20 transcripts (splice variants) and 9 orthologues
• Interaction with other molecules: miR-92a, miR-133a
• Biological consequence of such interaction: Suppression of FGF1activation

4.2.5. Myocardial Infarction-Associated Transcript

• Name/organism: MIAT/RNCR2/GOMAFU/C22orf35/LINC00066/NCRNA00066/lncRNA-MIAT; Homo sapiens
• Databases &Code: HGNC: 33425; NCBI Gene: 440823; Ensembl: ENSG00000225783; OMIM ® : 611082
• Chromosomal location& size: 22q12.1: 26,646,411–26,676,475 forward strand; 30 transcripts (splice variants) and is associated with 1 phenotype
• Interaction with other molecules: PI3K/Akt signalling pathway
• Biological consequence of such interaction: May constitute a component of the nuclear matrix; enhances angiogenesis and increases the expression of inflammatory factors

4.2.6. LncRNA RP11-728F11

• Name/organism: LncRNA RP11-728F11;
• Interaction with other molecules: EWSR1 (Ewings sarcoma RNA binding protein-1)
• Biological consequence of such interaction: Induction of cholesterol uptake in monocytes-derived macrophages and proinflammatory cytokine production

4.2.7. lncRNA ENST00000416361

• Name/organism: ENST00000416361; Homo sapiens
• Databases &Code: Ensembl: ENST00000416361
• Chromosomal location& size: 2102 bp
• Interaction with other molecules: SREBP
• Biological consequence of such interaction: Affects the occurrence and development of CAD

4.2.8. LncRNA RAPIA

• Name/organism: RAPIA;
• Chromosomal location& size: 10,252 nucleotides
• Interaction with other molecules: miR-183-5p-ItgB1 (integrin β1)
• Biological consequence of such interaction: Coordination of proliferation and apoptosis of macrophages

4.2.9. Nuclear Paraspeckle Assembly Transcript 1

• Name/organism: NEAT1/LINC00084/MENEPSILON/BETA/NCRNA00084/TNCRNA/TP53LC15/VINC; Homo sapiens
• Databases &Code: HGNC: 30815; NCBI Gene: 283131; Ensembl: ENSG00000245532; OMIM ® : 612769
• Chromosomal location& size: 11q13.1; 11: 65,422,774–65,445,540 forward strand; 9 transcripts
• Interaction with other molecules: miR-342-3p
• Biological consequence of such interaction: Regulation of lipid droplet aggregation; affect TG metabolism

4.2.10. Nipsnap Homolog 3B

• Name/organism: NIPSNAP3B/FP944/LOC286367/FLJ11275, SNAP1
• Databases &Code: HGNC: 23641, NCBI Gene: 55335; Ensembl: ENSG00000165028; OMIM ® : 608872; UniProtKB/Swiss-Prot: Q9BS92
• Chromosomal location& size: 9q31.1; Ch9: 104,764,129–104,777,764 forward strand; 3 transcripts (splice variants), 160 orthologues and 3 paralogues
• Biological consequence of such interaction: Putative role in vesicular trafficking; promotion of intracellular lipid accumulation

4.2.11. Long Noncoding RNA Regulator of Akt Signalling Associated with HCC and RCC

• Name/organism: LNCARSR/ lnc-TALC
• Databases &Code: HGNC: 53864; NCBI Gene: 102723932; Ensembl: ENSG00000233086
• Chromosomal location& size: 9q21.31; Ch 9: 79,505,804–79,567,802 reverse strand; 10 transcripts (splice variants)
• Interaction with other molecules: SREBP-2
• Biological consequence of such interaction: Promotion of the expression of HMG-CoA reductase (HMGCR), enhancement of hepatic de novo cholesterol synthesis rate

4.2.12. LDLR Antisense RNA 1

• Name/organism: BM450697/LDLR-AS1
• Databases &Code: HGNC: 54407, NCBI Gene: 115271120
• Chromosomal location& size: 19p13.2; overlaps the 5′ UTR and coding sequence of the LDLR n the antisense orientation
• Interaction with other molecules: PolII and potentially SREBP1a
• Biological consequence of such interaction: Downregulation of the production of the low density lipoprotein receptor.

4.2.13. Long Non-Coding RNA Growth Arrest-Specific 5

• Name/organism: GAS5/NCRNA00030/SNHG2; Homo sapiens
• Databases &Code: HGNC: 16355; NCBI Gene: 60674; Ensembl: ENSG00000234741; OMIM ® : 608280
• Chromosomal location& size: 1q25.1; Ch 1: 173,858,559–173,868,882 reverse strand; 91 transcripts (splice variants)
• Interaction with other molecules: bind to the DNA binding domain of the glucocorticoid receptor (nuclear receptor subfamily 3, group C, member 1)
• Biological consequence of such interaction: blockage of the activation of glucocorticoid receptor, regulation of the transcriptional activity of other receptors, such as androgen, progesterone and mineralocorticoid receptors

4.3. LncRNA with Ambiguous Effects

4.3.1. apolipoprotein a1 and a4 antisense rnas.

• Name/organism: ApoA1-AS; Homo sapiens
• Databases &Code: GeneCaRNA, HGNC: 40079, NCBI Gene: 104326055, Ensembl: ENSG00000235910, OMIM ® : 620112
• Chromosomal location& size: 11q23.3, Size: 20,898 bases, Orientation: Plus strand
• Interaction with other molecules: SUZ12, a component of the polycomb repressive complex 2 (PRC2)
• Biological consequence of such interaction: Suppression of APOA1 expression
• Name/organism: ApoA4-AS; mouse
• Databases &Code: Ensembl and UCSC Genome Database
• Chromosomal location& size: ∼900-nt
• Interaction with other molecules: APOA4
• Biological consequence of such interaction: APOA4-AS may regulate the expression of APOA4

4.3.2. lncRNA Induced by HCV, Regulator of SREBF1

• Name/organism: LNCHR1; Homo sapiens
• Databases &Code: Ensemble: ENSG00000257400.1; HGNC:56254
• Chromosomal location& size: 12q22: 94,491,546–94,496,442 reverse strand; Size: 420 bp
• Interaction with other molecules: SREB-1c
• Biological consequence of such interaction: Regulation of the expression of SREBP-1-responsive genes

4.3.3. Solute Carrier Family 25 Member 15 (SLC25A15/lnc-HC)

• Name/organism: lnc-HC/SLC25A15/HHH/ORC1/ORNT1/D13S327
• Databases &Code: GenBank: MN026163.1
• Chromosomal location& size: 1063 bp, linear
• Interaction with other molecules: Coregulator: hnRNPA2B1
• Biological consequence of such interaction: Reduction of the stability of mRNAs encoding Cyp7a1 and Abca1 (critical enzymes that contribute to cholesterol catabolism).

4.3.4. Metastasis-Associated Lung Adenocarcinoma Transcript 1

• Name/organism: MALAT1; HCN, LINC00047, MASCRNA, NCRNA00047, NEAT2, PRO1073; Homo sapiens
• Databases &Code: Ensembl: ENSG00000251562.11; HGNC:29665
• Chromosomal location& size: 11q13.1: 65,497,640–65,508,073 forward strand; 66 transcripts (splice variants)
• Interaction with other molecules: miR-17-ABCA1; miRNA-124-3p (sponge)
• Biological consequence of such interaction: Contribution to cholesterol efflux, promotion of the upregulation of inflammatory CRP, modulation of PPARα expression.

4.3.5. A Novel Long Non-Coding RNA in Lipid Associated Single Nucleotide Polymorphism Gene Region

• Name/organism: LASER/ LINC02702; Homo sapiens
• Databases &Code: HGNC:54217; Ensembl: ENSG00000237937; NCBI Gene: 101929011
• Chromosomal location& size: 11q23.3; 11: 116,639,422–116,658,295 forward strand; 4 transcripts
• Interaction with other molecules: probably PCSK9
• Biological consequence of such interaction: Enhancement of the expression of cholesterol metabolism genes

5. LncRNAs as Diagnostic and Therapeutic Targets in Lipid Disorders

6. conclusions, institutional review board statement, informed consent statement, data availability statement, conflicts of interest.

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Gluba-Sagr, A.; Franczyk, B.; Rysz-Górzyńska, A.; Olszewski, R.; Rysz, J. The Role of Selected lncRNAs in Lipid Metabolism and Cardiovascular Disease Risk. Int. J. Mol. Sci. 2024 , 25 , 9244. https://doi.org/10.3390/ijms25179244

Gluba-Sagr A, Franczyk B, Rysz-Górzyńska A, Olszewski R, Rysz J. The Role of Selected lncRNAs in Lipid Metabolism and Cardiovascular Disease Risk. International Journal of Molecular Sciences . 2024; 25(17):9244. https://doi.org/10.3390/ijms25179244

Gluba-Sagr, Anna, Beata Franczyk, Aleksandra Rysz-Górzyńska, Robert Olszewski, and Jacek Rysz. 2024. "The Role of Selected lncRNAs in Lipid Metabolism and Cardiovascular Disease Risk" International Journal of Molecular Sciences 25, no. 17: 9244. https://doi.org/10.3390/ijms25179244

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Lipoprotein lipase and lipolysis: central roles in lipoprotein metabolism and atherogenesis

Affiliation.

• 1 Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032.
• PMID: 8732771

Although it has been known for over 50 years that lipoprotein lipase (LPL) hydrolyzes triglyceride in chylomicrons, during the past half decade there has been a reinterest in the physiologic and pathophysiologic actions of this enzyme. In part, this has coincided with clinical studies implicating increased postprandial lipemia as a risk factor for atherosclerosis development. In addition, the recent creation of genetically altered mice with hypertriglyceridemia has focused the interest of geneticists and physiologists on the pathophysiology of triglyceride metabolism. As reviewed in this article, it is apparent that the lipolysis reaction is only partially understood. Several factors other than LPL are critical modulators of this process, in part, because the reaction requires the lipoproteins to interact with the arterial or capillary wall. Among the factors that affect this are the apolipoprotein composition of the particles, the size of the lipoproteins, and how LPL is displayed along the endothelial luminal surface. Zilversmit's observation that LPL activity is found in greater amounts in atherosclerotic than normal arteries has led to a large number of experiments linking LPL with atherogenesis. In medium and large arteries LPL is found on the luminal endothelial surface and in macrophage-rich areas within the plaque. LPL actions in both of these locations probably have major effects on the biology of the blood vessel. Possible atherogenic actions for this LPL based on in vitro experiments are reviewed.

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Lipoprotein lipase deficiency.

Suryakumar Balasubramanian ; Pearl Aggarwal ; Saurabh Sharma .

Affiliations

Last Update: July 3, 2023 .

• Continuing Education Activity

Lipoprotein lipase deficiency is a rare autosomal recessive genetic disorder of lipid metabolism. It is characterized by severe hypertriglyceridemia and chylomicronemia. Early diagnosis and early dietary modification help the prevention of symptoms and medical complications to manifest. This activity reviews the evaluation and treatment of lipoprotein lipase deficiency and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

• Identify the etiology of lipoprotein lipase enzyme deficiency.
• Review the appropriate evaluation of lipoprotein lipase enzyme deficiency.
• Outline the management options available for lipoprotein lipase enzyme deficiency.
• Describe the importance of collaboration and communication among the interprofessional team to enhance the delivery of care and improve outcomes for patients affected by lipoprotein lipase deficiency.
• Introduction

Lipoprotein lipase deficiency is a genetic disorder with an autosomal recessive pattern of inheritance. It usually presents in childhood and is characterized by severe hypertriglyceridemia and chylomicronemia. It is the most common form of chylomicronemia and was formerly known as hyperlipoproteinemia type 1a. [1]  Lipoprotein lipase deficiency was first described by Dr. Burger and Dr. Grutz in 1932.

Lipoprotein lipase deficiency occurs due to the presence of the defective gene for lipoprotein lipase that leads to the reduction or complete absence of lipoprotein lipase enzyme activity. Pathogenic deletions, nonsense mutations, and splice-site variants lead to the formation of an abnormal LPL gene product that leads to absent or truncated LPL enzyme with a defective catalytic activity. More than 220 pathological variants, including 70 percent missense mutations, 18 percent nucleotide insertions and deletions, 10 percent nonsense mutations, and a few splice site variants, have been identified. [2] [3]

Because lipoprotein lipase deficiency has an autosomal recessive pattern of inheritance, the risk of two heterozygote parents to have a child affected with lipoprotein lipase deficiency is 25 percent, and the risk of having a heterozygote child is 50 percent, with each pregnancy. Each of the siblings of an affected individual has a 25 percent chance of being homozygous, a 50 percent chance of being heterozygous(carrier), and a 25 percent chance of being unaffected.

• Epidemiology

Lipoprotein lipase deficiency is a rare disorder. Its prevalence is approximately 1 in 1,000,000 in the general population. Two LPL mutations G118E and P207L cause complete loss of LPL activity in homozygotes and 50% loss in heterozygotes have been reported in Quebec, Canada. Most cases of lipoprotein lipase deficiency are identified in childhood, usually, before ten years of age, and 25 % of the affected patients are identified during the first year of life. However, some individuals may not develop symptoms until adulthood, like women may present for the first time during pregnancy. [1] [4] Males and females are affected equally.

• Pathophysiology

The lipoprotein lipase gene is mapped to human chromosome 8p22, divided into ten exons and encodes the enzyme lipoprotein lipase, which is expressed in the adipose tissues and muscles. Lipoprotein lipase (LPL), a 475-aminoacid enzyme, is involved in the hydrolysis of triglyceride-rich lipoproteins, mainly chylomicrons and very high-density lipoproteins (VLDL). The catalytic center of the enzyme has three amino acids, namely, Ser132, Asp156, His241.

LPL activity is regulated by several factors, such as hormones, non-esterified fatty acids, and apolipoproteins. Apo AV, apolipoprotein C-II, insulin, acylation stimulating protein increase the LPL activity, while apolipoprotein C-III and TNF-alpha decrease the LPL activity. After LPL is produced in adipose tissues and muscles, which are the two most important sites of production, it is secreted and translocated to the luminal surface of capillary endothelial cells of extrahepatic tissues. The dietary fat absorbed in the intestines is transported in the form of triglycerides by large lipoproteins, known as chylomicrons. Once the chylomicrons are released into the bloodstream, they receive a lipoprotein known as apolipoprotein C-II from high-density lipoproteins.

Apolipoprotein C-II is a cofactor for the lipoprotein lipase enzyme. The lipoprotein lipase recognizes apolipoprotein C-II and gets activated, which results in the breaking down of the chylomicrons and VLDL triglycerides to nonesterified free fatty acids and 2-monoacylglycerol to be stored as triglyceride in adipose tissues or used as an energy source in muscles. [5] [6]  Lipoprotein lipase is also required for maturation of small particles of high-density lipoproteins into larger particles. [7]

Most of the mutations in the lipoprotein lipase gene are located on exons 2, 5, and 6. The well-known mutations include the following

• Asn291Ser, located on Exon 6, AAT-->AGT. It is the most common mutation in Whites. It is present in 2 to 5 percent of the heterozygote carrier population among the Whites. It is associated with an increased risk of Alzheimer disease. [8]
• 93T-->G, located on the promotor. The G allele is the most common mutation seen in South African Black ethnicity (76.4 percent). The T allele is seen in Whites (1.7 percent). [9]
• Asp9Asn, located on Exon 2, GAC-->AAC. It is less common. (1.56 to 4.4 percent of the population). The homozygous mutation causes only a 20 percent decrease in lipoprotein lipase activity. [10]
• Gly188glu, located on wxon 5, GGG-->GAG. (0.06 percent of the population). [11]  It leads to homozygous chylomicronemia, most common among French Canadians in Quebec. It is known to have the strongest link leading to an increased risk of coronary artery disease. [11]
• Ala221del, located on exon 5, 916gCT-->CT. It leads to homozygote chylomicronemia. It is the most common mutation in Japanese ethnicity, also known as LPL Arita. [12]
• Carriers of Asn291Ser or the combined mutation Asp9Asn/T93G are known to have an increased risk of preeclampsia. [13]
• Ser447sto, located on exon 9, TCA-->TGA. This is a gain of function mutation leading to an increase in LPL activity. It is associated with a 0.8 fold reduced risk of ischemic heart disease, maximum benefit to those using beta-blockers. [14]  Carriers of this mutation have lower plasma triglyceride levels and higher high-density lipoprotein levels. Therefore they have a lower incidence of cardiovascular disease as compared to non-carriers of this mutation. [15]

A reduction or elimination of lipoprotein lipase enzyme activity prevents the break down of triglycerides. Therefore, there is an accumulation of the triglycerides in the blood and tissues, leading to the clinical manifestations of lipoprotein lipase deficiency. [1]  In homozygous individuals, the serum triglyceride levels may reach 10,000 mg/dL or higher. In heterozygous individuals, the serum triglyceride levels may range between 200 to 750 mg/dL.

According to many studies, Lipoprotein lipase deficiency is known to have no atherogenic potential because it causes a low level of low-density lipoproteins. But some studies show that a defect in lipolysis can be a risk factor for premature atherosclerosis. These studies were based on other metabolic disturbances, which have been described as follows. Lipoprotein lipase deficiency also leads to increased serum triglycerides and low high-density lipoproteins. Also, the postprandial clearance of triglycerides is delayed, exposing them to lipoproteins, thus leading to oxidative damage. Even reverse cholesterol transport is impaired as the high-density lipoprotein has structural changes, leading to increased and faster clearance. [16] [7]  

Thus the lipoprotein profile of the patients of lipoprotein lipase deficiency is similar to the postprandial profile in which atherogenic particles are produced, predisposing to atherosclerosis. [17]  However, the association of atherogenesis with lipoprotein lipase deficiency remains debated.

• History and Physical

Lipoprotein lipase deficiency usually presents with the following:

• Abdominal pain is the most common presentation and occurs due to acute pancreatitis, intensity varying from mild to incapacitating (mimicking acute abdomen). The attacks of acute pancreatitis are recurrent and usually culminate in chronic pancreatitis. [18]  Although the mechanism of acute pancreatitis following hypertriglyceridemia in LPL enzyme deficiency is not fully understood, oral antioxidants reduce the frequency of pancreatitis episodes, implying the role of oxidant damage in causing acute pancreatitis. [19] [20]  The risk of acute pancreatitis is about 5% when the serum triglycerides reach 1000 mg/dL or higher, and 10% to 20% when the serum triglycerides reach 2000 mg/dL or higher. [21] [22]
• Xanthomas - In about 50 % of the individuals with lipoprotein lipase deficiency, eruptive xanthomas, which are yellow papules of around 1 mm in size, appear mostly on the trunk, knees, buttocks, and extensor surfaces of arms. These may coalesce to form larger patches. The formation of xanthomas occurs as a result of extravascular phagocytosis of chylomicrons by macrophages and deposition in the skin. They happen when plasma triglyceride levels rise above 2000 mg/dL and disappear when the plasma triglyceride levels return to normal. They are painless unless exposed to repetitive abrasion. [1]
• Loss of appetite
• Nausea, vomiting
• Hepatomegaly and splenomegaly occur as a result of markedly increased plasma triglyceride levels. The excessive chylomicrons in the bloodstream are ingested by macrophages(phagocytes), which then travel to the liver and spleen. The fatty cells accumulate in the liver and spleen, leading to an increase in their size. [1]
• Retinalis lipemia - the retinal arterioles, venules, and fundus appear pale-pink as a result of scattering of light by the large chylomicrons. This change is reversible, and the vision gets spared. Retinalis lipemia is seen when the plasma triglyceride levels rise above 2500 mg/dL. When the triglyceride levels are between 2500 and 3499 mg/dL, the peripheral vessels of the retina appear thin. At triglyceride levels of 3500 to 5000 mg/dL, the retinal vessels at the posterior pole appear creamy in color. At triglyceride levels above 5000 mg/dL, the retina appears salmon in color with the creamy appearance of the retinal venules and arteries. [23] [24] [1]
• Neuropsychiatric changes like mild cognitive dysfunction, depression, and memory loss have been reported. These changes are reversible. [25] [5]

Infants may present additionally with the following:

• Abdominal pain which appears as colic
• Irritability
• Intestinal bleeding
• Failure to thrive [23]

In women, the presentation may be delayed until pregnancy. A woman with lipoprotein lipase deficiency may present with marked signs and symptoms during pregnancy due to increased uptake of triglyceride-rich lipoproteins by the macrophages, owing to the increased apolipoprotein E during pregnancy. [4]

The severity of the clinical presentation of lipoprotein lipase deficiency correlates with the chylomicron levels.

Lipoprotein lipase deficiency is suspected in young individuals with the following clinical findings in addition to the supportive laboratory findings.

Clinical Findings

• Recurrent attacks of acute pancreatitis
• Eruptive xanthoma
• Hepatosplenomegaly
• Retinalis lipemia

Lab Findings

• Milky appearing plasma. This occurs due to the impaired clearance of the chylomicrons from the plasma.
• Plasma triglyceride levels exceeding 2000 mg/dL. These levels are considered regardless of the fasting state.

The diagnosis of lipoprotein lipase deficiency is established by molecular genetic testing, which identifies the proband by identifying the biallelic pathogenic variants in the lipoprotein lipase gene. [26] Two test methods are used, which include:

• Sequence analysis - This identifies 97 % of probands with the biallelic pathogenic variants.
• Gene targeted duplication/deletion analysis - this identifies 4% of probands with biallelic pathogenic variants.

Molecular genetic testing can be done for only lipoprotein lipase gene identification, or to identify the other four genes as well, which can lead to chylomicronemia. It is described as follows :

• Single gene testing - The sequence analysis of only the lipoprotein lipase gene is performed. If one or no pathogenic variant is found, the sequence analysis is followed by the gene-targeted duplication/deletion analysis.
• Multigene panel - It includes the lipoprotein lipase gene as well as of the other four genes, namely, apolipoprotein C- II gene, apolipoprotein A-V gene, lipase maturation factor 1 gene, and glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein gene, for the chylomicronemia syndrome. Sequence analysis and gene-targeted duplication/deletion, any method may be used. [1] [26]

Measurement of Lipoprotein Lipase Activity

• Assay of the lipoprotein lipase activity in the plasma, after ten minutes of post Intravenous administration of heparin. Here the post heparin plasma is added to VLDL substrate and the liberated free fatty acids are assayed, and the lipoprotein lipase activity is expressed as micromoles of the released free fatty acids released per minute per liter of the plasma, that is, micromoles/l/min, after subtraction of hepatic lipase activity. Carriers of pathogenic mutations in either the lipoprotein lipase enzyme or its cofactor, that is, apolipoprotein C-II, will lead to undetectable lipoprotein lipase activity in the post heparin plasma which is a diagnostic of familial lipoprotein lipase deficiency. [27] [28] [26] [28]
• Biopsies of the adipose tissue may also be used to determine the lipoprotein lipase activity directly.
• Treatment / Management

Medical nutrition therapy involves following a fat-restricted diet to keep the individual diagnosed with lipoprotein lipase deficiency free of signs and symptoms. The targeted goal is to keep the plasma triglyceride levels below 2000 mg/dL, with the greatest benefit obtained when the plasma triglyceride levels are kept below 1000 mg/dL. This can be achieved by restricting the dietary fat intake to not above 20 g/day or 15% of total energy intake.

Fish oil supplements are not beneficial and are contraindicated in lipoprotein lipase deficiency, unlike the disorders of excess hepatic triglyceride production. This is because fish oils contribute to chylomicrons. Certain agents like alcohol, oral estrogens, beta-adrenergic blockers, diuretics, selective serotonin reuptake inhibitors, isotretinoin, are avoided as they are known to increase the endogenous triglyceride levels. [1] [26]  For individuals who take a very low-fat diet, it is recommended that they should supplement fat-soluble vitamins, that is, vitamin A, D, E, K, and minerals in their diet.

Acute pancreatitis associated with lipoprotein lipase deficiency is treated in the same manner as acute pancreatitis due to other causes. Prevention of recurrent acute pancreatitis helps to decrease the risk of secondary complications of pancreatitis like diabetes mellitus.

Plasma triglycerides are followed overtime of the affected individual as this helps to evaluate the success of the fat-restricted diet. 

Pregnant women need to follow an extreme fat-restricted diet, that is, less than 2 g/day, especially during the second and third trimesters. This, along which close monitoring of the plasma triglyceride levels, leads to the delivery of normal infants with normal plasma levels of essential fatty acids. A combination of a very low-fat diet with the use of gemfibrozil has been safely implicated in pregnancy. [1] [29]

For family planning, it is appropriate to offer genetic counseling to young adults who are affected, are carriers, or at risk of being a carrier.

Lipoprotein lipase (LPL) gene therapy, that is, alipogene tiparvovec gene therapy, consists of the LPL Ser447X variant in a genetically engineered adeno-associated virus genotype 1 (alipogene tiparvovec). The intramuscular administration of the adenovirus vector introduces a functional copy of the lipoprotein lipase gene into the patient's muscle cells, thus lowering the fasting triglyceride levels. [30] [31] [32]  The maximum benefit is for individuals with the highest risk of complications. However, due to low demand from the patient community, it has been taken off the market. [1] [33] [34]

Currently, there are some promising treatment approaches, that include the following:

• Pradigastat is a diacylglycerol  O -acyltransferase 1 (DGAT1) inhibitor that is orally administered. It functions by catalyzing the final step in triglyceride synthesis and decreases the chylomicron-triglyceride secretion. [23] [35] [23]
• Evinacumab is a monoclonal antibody to angiopoietin-like protein 3 (ANGPTL3). It is an inhibitor of LPL and endothelial lipase. [23]
• Differential Diagnosis

LPL deficiency is considered in young individuals with chylomicronemia and triglyceride levels of more than 2000 mg/dl. However, it has been found that such individuals do not necessarily have familial LPL deficiency. Instead, they may have one of the more common genetic disorders of triglyceride metabolism, like familial combined hyperlipidemia and monogenic familial hypertriglyceridemia, or there may be some secondary causes leading to hypertriglyceridemia. [1]

Other than LPL deficiency, that constitutes 95.0 percent of primary monogenic variants of chylomicronemia, the differential diagnoses for primary monogenic chylomicronemia include:

• Familial apolipoprotein C- II deficiency - severe chylomicronemia in childhood or adolescence, constitutes 2.0 percent of monogenic variants.
• Familial apolipoprotein A-V deficiency-chylomicronemia in late adulthood constitutes 0.6 percent of monogenic variants.
• Familial lipase maturation factor 1 deficiency- chylomicronemia in late adulthood, constitutes 0.4 percent of monogenic variants.
• Familial glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 deficiency-Chylomicronemia in late adulthood, constitutes 2.0 percent of monogenic variants. [1] [36] [37] [38]  

The following secondary causes can also cause hypertriglyceridemia:

• Diabetes mellitus
• Paraproteinemia and lymphoproliferative disorders
• Alcohol use
• Estrogen therapy
• Drugs like selective serotonin receptor reuptake inhibitors, glucocorticoids, atypical antipsychotics, isotretinoin, certain antihypertensives [1]

Medical nutrition therapy is the mainstay for the treatment of lipoprotein lipase deficiency. Thus, treatment success depends on the acceptance of the fat-restricted diet of the individual affected. The ultimate prognosis of lipoprotein lipase deficiency appears to be good with high compliance for a fat-restricted diet that leads to a decrease in plasma triglyceride levels. The enlarged liver and spleen usually return to normal size within one week of lowering down of the plasma triglyceride levels, eruptive xanthomas clear within a few weeks to months. [1]  In lipoprotein lipase deficiency, even with a history of recurrent attacks of acute pancreatitis, the pancreatic function declines slowly, so it is not associated with high mortality. [20] [1]

• Complications

In an individual with lipoprotein lipase deficiency, recurrent attacks of acute pancreatitis lead to chronic pancreatitis. The secondary complications of chronic pancreatitis are as follows:

• Steatorrhea, that is, stools containing excess fat due to fat malabsorption
• Pancreatic calcifications

However, these complications are rare in an individual with lipoprotein lipase deficiency. Even if these complications occur, they are rare before mid-age. Pancreatitis might be rarely associated with serious complications like total pancreatic necrosis and death. [1]

• Deterrence and Patient Education

The quality of life of the individuals affected with lipoprotein lipase deficiency is poor, mainly due to recurrent attacks of acute pancreatitis. Patients and their family members are noted to be anxious, depressed, and frustrated during and after hospitalizations for the attacks of pancreatitis. Recurrent hospitalizations affect various aspects of daily life, for example, work-life due to absenteeism, financial implications, and increased dependency on family and friends for support. [39] [40]

It is essential to educate the patient about the importance of following a strict fat-restricted diet to get relief from the signs and symptoms of lipoprotein lipase deficiency and to prevent its secondary manifestations. Daily life modifications, for example, using sources of medium-chain fatty acids for cooking, which get absorbed into the portal vein directly without getting incorporated into the chylomicron triglyceride, should be encouraged. A dietician consult could be helpful to achieve the goal of required daily fat consumption in the diet. Periodic follow-up for diet review along with the plasma triglyceride levels can help ensure therapy success. [1]

Genetic counseling, that is, educating the affected individual about the nature, mode of inheritance, and the impact of this condition, is also quite important. This is because early diagnosis of this condition and early dietary modification helps the prevention of symptoms and medical complications to manifest. [37]  This will help the patient to make informed medical and personal decisions.

• Enhancing Healthcare Team Outcomes

Though lipoprotein lipase deficiency is a rare genetic disorder, its implications on the life of an affected individual are quite debilitating. Most of it is attributed to the recurrent attacks of acute pancreatitis that leads to multiple hospitalizations. The manifestations of this disorder, the need to follow a strict fat-restricted diet and associated impaired psychosocial functioning have a poor impact on the Health-Related Quality of Life (HRQoL). The lack of proven effective and cost-effective therapies further increase the disease burden. 

 The unmet need for proper and consistent dietary advice, as well as the education of the patients and their friends and family, can be addressed by the following measures:

• Healthcare professionals must obtain complete knowledge and understanding of the disorder. This will ensure appropriate diets to be followed during hospitalizations and allow patients to better understand their condition and follow a strict diet at home.
• Emotional support services and support groups that would help to decrease the uncertainty and the fear of having future attacks of acute pancreatitis. 
• Provision of materials offering the sources of information on the disorder. It will ease the anxiety and tension that the patients and their friends and family face.

It is essential to consult with an interprofessional team of specialists that include a pediatrician, gastroenterologist, surgeon, endocrinologist, ophthalmologist, gynecologist, and a dietician. The nurses are also a vital member of the interprofessional group as they will monitor the patient's vital signs and assist with the education of the patient and family. The pharmacist will ensure that the patient is on the right analgesics in the event of attacks of acute pancreatitis. The radiologist also plays a vital role in determining the cause of abdominal pain. In cases where evidence is not definitive or minimal, expert opinion from the specialist may be utilized to recommend the type of diagnostic test or treatment. However, to improve outcomes, prompt consultation with an interprofessional group of specialists is recommended.

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Disclosure: Suryakumar Balasubramanian declares no relevant financial relationships with ineligible companies.

Disclosure: Pearl Aggarwal declares no relevant financial relationships with ineligible companies.

Disclosure: Saurabh Sharma declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Balasubramanian S, Aggarwal P, Sharma S. Lipoprotein Lipase Deficiency. [Updated 2023 Jul 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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