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1 H/ 15 N HSQC spectrum of 13 C/ 15 N-labeled apoCIII in complex with SDS micelles. Peaks are labeled as assigned. The unlabeled cross-peak, at 7.65/117.8 ppm, appears after a few weeks.
Source publication
Human apolipoprotein CIII (apoCIII) is a surface component of chylomicrons, very low density lipoproteins, and high density lipoproteins. ApoCIII inhibits lipoprotein lipase as well as binding of lipoproteins to cell surface heparan sulfate proteoglycans and receptors. High levels of apoCIII are often correlated with elevated levels of blood lipids...
Contexts in source publication
Context 1
... quality NMR spectra were obtained of 13 C/ 15 N apoCIII in complex with SDS micelles as dem- onstrated by 1 H/ 15 N HSQC (Fig. 1). Complete sequential resonance assignments were obtained of N HN , H N , C , C , C, and H using stand- ard 13 C/ 15 N triple resonance ex- periments, whereas NOEs were assigned via three-dimensional 1 H/ 15 N NOESY-type ...
Context 2
... establish internal dynamics, T 1 , T 1rho , and 15 N( 1 H) NOE data were measured at 600 and 800 MHz (Fig. S1). The unstruc- tured terminal regions (positions 1-7 and 82-87) and large loop (positions 65-73) are clearly visible in the T 1 , T 1rho , and 15 N( 1 H) NOE data (Fig. S1). Analysis of the relaxation data shows that the backbone undergoes both pico-and nanosecond time scale motions, similar to what we observed for apoCII (23). The mean ...
Context 3
... establish internal dynamics, T 1 , T 1rho , and 15 N( 1 H) NOE data were measured at 600 and 800 MHz (Fig. S1). The unstruc- tured terminal regions (positions 1-7 and 82-87) and large loop (positions 65-73) are clearly visible in the T 1 , T 1rho , and 15 N( 1 H) NOE data (Fig. S1). Analysis of the relaxation data shows that the backbone undergoes both pico-and nanosecond time scale motions, similar to what we observed for apoCII (23). The mean helix order parameters for the pico-and nanosecond time scale motions (Table S1) indicate, as for apoCII, well formed helices (S f 2 values are high, 0.8) that undergo ...
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Background
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Citations
... APOC3, which is primarily expressed in hepatocytes, is an apolipoprotein of 79 amino acid residues and is an important component of VLDL and HDL [51]. APOC3 has long been considered one of the most critical factors in TRL metabolism, which is closely related to the increase in the plasma TG level (Figure 1). ...
The APOA1/C3/A4/A5 cluster is an essential component in regulating lipoprotein metabolism and maintaining plasma lipid homeostasis. A genome-wide association analysis and Mendelian randomization have revealed potential associations between genetic variants within this cluster and lipid metabolism disorders, including hyperlipidemia and cardiovascular events. An enhanced understanding of the complexity of gene regulation has led to growing recognition regarding the role of epigenetic variation in modulating APOA1/C3/A4/A5 gene expression. Intensive research into the epigenetic regulatory patterns of the APOA1/C3/A4/A5 cluster will help increase our understanding of the pathogenesis of lipid metabolism disorders and facilitate the development of new therapeutic approaches. This review discusses the biology of how the APOA1/C3/A4/A5 cluster affects circulating lipoproteins and the current progress in the epigenetic regulation of the APOA1/C3/A4/A5 cluster.
... This predicted structure is very similar to the human ApoC-III structure as determined by solution nuclear magnetic resonance (NMR; PDB accession: 2JQ3). 5 The ApoC-III of lions with Val30 (Fig. 4a) was predicted to shorten the N-terminal α-helix by 2 residues compared with ApoC-III of leopards with Met30 ( Fig. 4b). The evaluation of the helical wheel of this α-helix shows that the hydrophobic face is altered due to the Val30 substitution (Fig. 4c, d). ...
Apolipoprotein C-III (ApoC-III) amyloidosis in humans is a hereditary amyloidosis caused by a D25V mutation in the APOC3 gene. This condition has only been reported in a French family and not in animals. We analyzed a 19-year-old white lion ( Panthera leo) that died in a Japanese safari park and found renal amyloidosis characterized by severe deposition confined to the renal corticomedullary border zone. Mass spectrometry-based proteomic analysis identified ApoC-III as a major component of renal amyloid deposits. Amyloid deposits were also positive for ApoC-III by immunohistochemistry. Based on these results, this case was diagnosed as ApoC-III amyloidosis for the first time in nonhuman animals. Five additional white lions were also tested for amyloid deposition retrospectively. ApoC-III amyloid deposition was detected in 3 white lions aged 19 to 21 years but not in 2 cases aged 0.5 and 10 years. Genetic analysis of white and regular-colored lions revealed that the APOC3 sequences of the lions were identical, regardless of amyloid deposition. These results suggest that ApoC-III amyloidosis in lions, unlike in humans, may not be a hereditary condition but an age-related condition. Interestingly, lion ApoC-III has a Val30 substitution compared with other species of Panthera that have Met30. Structural predictions suggest that the conformation of ApoC-III with Met30 and ApoC-III with Val30 are almost identical, but this substitution may alter the ability to bind to lipids. As with the D25V mutation in human ApoC-III, the Val30 substitution in lions may increase the proportion of free ApoC-III, leading to amyloid formation.
... Prior experimental studies of apoE-Aβ interactions verified key aspects of the proposed models. Additional support comes from docking the NMR structure of apoC-III (79 a. a.) [65], which is an Aβ-binding apolipoprotein and a biomarker of AD [66] with apparent neuroprotective properties [67]. The results reveal the driving forces for apolipoprotein binding to amyloid fibrils, help reconcile conflicting evidence from prior experimental studies, explain why apolipoproteins co-deposit with amyloids, and provide a structural basis for understanding how apolipoproteins can modulate amyloid formation, proliferation and interactions with other factors. ...
... In addition, we used the NMR solution structure of full-length human apoC-III in complex with sodium dodecyl sulfate micelles (PDB ID: 2JQ3, supplemental Fig. 3a), which represents the lipidbound conformation [65]. The structures of apoE and apoC-III were docked to the Aβ fibril structures as described below. ...
... In addition to lipid-free apoE, the NMR structure of apoC-III was docked to the structures of Aβ 1-40 and Aβ 1-42 fibrils. The apoC-III molecule in this structure wraps around the SDS micelle, with the hydrophobic α-helical faces projecting inward, mimicking the lipid-bound conformation; relative helical positions are constrained by the micelle size of ~4.4 nm [65]. Like apoE, full-length apoC-III did not produce any plausible docking poses. ...
Apolipoproteins co-deposit with amyloids, yet apolipoprotein-amyloid interactions are enigmatic. To understand how apoE interacts with Alzheimers amyloid-beta (Abeta) peptide in fibrillary deposits, the NMR structure of full-length human apoE was docked to four structures of patient-derived Abeta(1-40) and Abeta(1-42) fibrils determined previously using cryo-electron microscopy or solid-state NMR. Similar docking was done using the NMR structure of human apoC-III. In all complexes, conformational changes in apolipoproteins were required to expose large hydrophobic faces of their amphipathic alpha-helices for sub-stoichiometric binding to hydrophobic surfaces on sides or ends of fibrils. Basic residues flanking hydrophobic helical faces in apolipoproteins interacted favorably with acidic or basic residue ladders, respectively, in some amyloid polymorphs. Molecular dynamics simulations of selected apoE-fibril complexes confirmed their stability. Amyloid binding via cryptic sites, which became available upon opening of flexibly linked apolipoprotein alpha-helices, resembled apolipoprotein-lipid binding. This mechanism probably extends to other apolipoprotein-amyloid interactions. Apolipoprotein binding alongside fibrils could interfere with fibril fragmentation and secondary nucleation, while binding at the fibril ends could halt amyloid elongation and dissolution in a polymorph-specific manner. The proposed mechanism is supported by extensive prior experimental evidence and helps reconcile disparate reports on apoEs role in Abeta aggregation. Furthermore, apoE domain opening and direct interaction of Arg/Cys158 with amyloid potentially contributes to isoform-specific effects in Alzheimers disease. In summary, current modeling supported by prior experimental studies suggests similar mechanisms for apolipoprotein-amyloid and apolipoprotein-lipid interactions; explains why apolipoproteins co-deposit with amyloids; and helps reconcile conflicting reports on the chaperone-like apoE action in Abeta aggregation.
... ApoC3 is a 79 amino acid glycopeptide having a molecular weight of 8.8 KDa, that contains two amphipathic helices 39 . It is possible that ApoC3 binds or intercalates within the LNP structure via utilising its amphipathic helices. ...
Mast cells (MCs), are hematopoetically-derived secretory immune cells that release preformed as well as de novo synthesized inflammatory mediators in response to activation by several stimuli. Based on their role in inflammatory responses, particularly in the lung and skin, MCs provide an effective target for anti-inflammatory therapeutic strategies. Drug-delivery of lipophilic payloads to MCs can be challenging due to their functionally distinct intracellular structures. In the present study, pH-sensitive cationic lipid-based nanoparticles (LNPs) composed of DODMA, DODAP or DOTAP lipids that encapsulated a GFP or eGFP plasmid were constructed using non-turbulent microfluidic mixing. This approach achieved up to 75–92% encapsulation efficiency. Dynamic light scattering revealed a uniformly sized and homogeneous dispersion of LNPs. To promote cellular internalization, LNPs were complexed with apolipoproteins, amphipathic proteins capable of binding lipids and facilitating their transport into cells. Cryo-TEM analysis showed that LNP structure was differentially modified when associated with different types of apolipoproteins. LNP preparations made up of DODMA or DODMA, DODAP and DOTAP lipids were coated with seven apolipoproteins (Apo A1, B, C3, D, E2, E4 and H). Differentiated bone-marrow derived mouse mast cells (BMMCs) were exposed to apolipoprotein-LNP and internalization was measured using flow cytometry. Out of all the apolipoproteins tested, ApoC3 most efficiently facilitated cellular internalization of the LNP into BMMCs as determined by GFP fluorescence using flow cytometry. These effects were confirmed in a less differentiated but also interleukin-3-dependent model of mouse mast cells, MC/9. ApoC3-LNP enhanced internalization by BMMC in a concentration-dependent manner and this was significantly increased when BMMC were pre-treated with inhibitors of actin polymerization, suggesting a dependence on intracellular shuttling. Activation of peroxisome proliferator-activated receptor gamma (PPARγ) decreased ApoC3-LNP internalization and reduced the expression of apolipoprotein E receptor 2 (ApoER2), suggesting that ApoC3-LNP binding to ApoER2 may be responsible for its enhanced internalization. Furthermore, ApoC3 fails to facilitate internalization of LNPs in Lrp8−/− KO BMMC that do not express ApoER2 on their cell surface. Altogether, our studies reveal an important role of ApoC3 in facilitating internalization of cationic LNPs into MCs.
... We found that APOC3 was analyzed using all proteomic platforms (including gel image, labelfree and chemical labeling). APOC3 is a small apolipoprotein of 79 amino acid residues [71]. In the circulation, APOC3 is mainly present on triglyceride (TG)-rich lipoproteins (TRLs) and high-density lipoprotein (HDL) and on low-density lipoprotein (LDL) particles [72]. ...
Gestational Diabetes Mellitus (GDM) is the most common metabolic complication during pregnancy and is associated with serious maternal and fetal complications such as pre-eclampsia and stillbirth. Further, women with GDM have approximately 10 times higher risk of diabetes later in life. Children born to mothers with GDM also face a higher risk of childhood obesity and diabetes later in life. Early prediction/diagnosis of GDM leads to early interventions such as diet and lifestyle, which could mitigate the maternal and fetal complications associated with GDM. However, no biomarkers identified to date have been proven to be effective in the prediction/diagnosis of GDM. Proteomic approaches based on mass spectrometry have been applied in various fields of biomedical research to identify novel biomarkers. Although a number of proteomic studies in GDM now exist, a lack of a comprehensive and up-to-date meta-analysis makes it difficult for researchers to interpret the data in the existing literature. Thus, we undertook a systematic review and meta-analysis on proteomic studies and GDM. We searched MEDLINE, EMBASE, Web of Science and Scopus from inception to January 2022. We searched Medline, Embase, CINHAL and the Cochrane Library, which were searched from inception to February 2021. We included cohort, case-control and observational studies reporting original data investigating the development of GDM compared to a control group. Two independent reviewers selected eligible studies for meta-analysis. Data collection and analyses were performed by two independent reviewers. The PROSPERO registration number is CRD42020185951. Of 120 articles retrieved, 24 studies met the eligibility criteria, comparing a total of 1779 pregnant women (904 GDM and 875 controls). A total of 262 GDM candidate biomarkers (CBs) were identified, with 49 CBs reported in at least two studies. We found 22 highly replicable CBs that were significantly different (nine CBs were upregulated and 12 CBs downregulated) between women with GDM and controls across various proteomic platforms, sample types, blood fractions and time of blood collection and continents. We performed further analyses on blood (plasma/serum) CBs in early pregnancy (first and/or early second trimester) and included studies with more than nine samples (nine studies in total). We found that 11 CBs were significantly upregulated, and 13 CBs significantly downregulated in women with GDM compared to controls. Subsequent pathway analysis using Database for Annotation, Visualization and Integrated Discovery (DAVID) bioinformatics resources found that these CBs were most strongly linked to pathways related to complement and coagulation cascades. Our findings provide important insights and form a strong foundation for future validation studies to establish reliable biomarkers for GDM.
... APOC3 is primarily presented on the surface of chylomicrons, very low-density proteins (VLDL), and HDL [63], so it participates in regulating triglycerides (TG)-rich lipoprotein [64] and plasma VLDL metabolism, also act as a pro-inflammatory factor in vivo [65,66]. Comparing to plasma APOC3 levels in humans (~6 mg/dL) [67], mice (~4-5 mg/ dL) [68] and cows (~6 mg/dL, in non-lactating stage); the pig has an unusual low level of ~50 μg/dL and consequently, a low circulating TG level [57]. ...
This study aimed to investigate the characteristic proteomic pattern of plasma from sows supplemented with low dietary ω6:ω3 fatty acids (FAs) ratio during gestation and lactation. Two dietary treatments (n = 8 each) comprised either a control ratio of ω6:ω3 FAs (CR, 13:1 during gestation and 10:1 during lactation) or a low ratio (LR, 4:1 during gestation and lactation) by adding soybean oil or linseed oil, respectively. High-resolution mass spectrometry-based quantitative proteomics was applied on plasma (n = 5 each) at day 108 of gestation (G108) and at the end of lactation (L-End), and a total of 379 proteins and 202 master proteins were identified. Out of these, four differentially abundant proteins between LR and CR samples at G108 may relate to serine-type endopeptidase inhibitor activity. Differentially abundant proteins in L-End versus G108 (12 up-regulated and 10 down-regulated) were positively correlated with the events that regulate plasma lipoproteins, stimulus- and defence-responses. These findings demonstrate the benefit of increased dietary ω3 FAs in modifying proteins involved in protective mechanisms against increased stresses in key life cycle phases in pigs. In addition, proteome changes from late gestation to late lactation disclosed the underlying mechanism of pigs in response to reproduction-related stimuli.
Significance
This study aimed to provide a proteomics insight into the beneficial effects of maternal diet supplementation with a low ω6:ω3 fatty acids ratio, based on previously reported performance and zootechnical data. The results suggest that a low dietary ω6:ω3 fatty acids ratio could enhance the cellular defence mechanisms against increased stresses and in particular to oxidative stress in sows during gestation and lactation, as reflected in proteomic changes of haptoglobin (HP), alpha-1-antitrypsin (SERPINA1) and serum amyloid P-component (APCS). Furthermore, significantly changed proteome profiles in sow plasma between late gestation and lactation phases have been revealed for the first time. This finding identified the adaptation mechanisms of sows to changing physiological events during reproduction.
... (B) Hydrolysis of TG by LPL is halted by the association of ANGPTLs with LPL resulting in LPL degradation [166]. To prevent binding of ANGPTLs to LPL, ANGPTLs are targeted by mAbs to permit generation of glycerol and fatty acids from TG. (C) apoC-III triggers the hydrolysis of VLDL to IDL by LPL thereby forming LDL from IDL via LPL activity [184]. With the presence of apoC-III, the binding of both apoB and apoE to LDLR for LDL removal is interfered [185]. ...
... The human apoC-III consists of 79 amino acid residues that forms several helices connected by semiflexible hinges. The curving flexibility nature of apoC-III allows it to adapt on the surface of different lipoprotein sizes such as VLDL and HDL [184]. ...
... Lipolysis of lipoproteins involves LPL on the capillary endothelium surface activated by apolipoprotein C-II (apoC-II). Though it is still not fully understood, it is thought that the presence of apoC-III displaces other apolipoprotein that is instrumental for the binding of lipoprotein to the endothelial cell surface or towards the LPL protein [184]. A review also suggested apoC-III interferes with the binding of apoB or apolipoprotein E (apoE) to LDLR for uptake and removal from blood circulation [185]. ...
Cardiovascular disease (CVD) is one of the leading causes of death worldwide. CVD includes coronary artery diseases such as angina, myocardial infarction, and stroke. “Lipid hypothesis” which is also known as the cholesterol hypothesis proposes the linkage of plasma cholesterol level with the risk of developing CVD. Conventional management involves the use of statins to reduce the serum cholesterol levels as means for CVD prevention or treatment. The regulation of serum cholesterol levels can potentially be regulated with biological interventions like monoclonal antibodies. Phage display is a powerful tool for the development of therapeutic antibodies with successes over the recent decade. Although mainly for oncology, the application of monoclonal antibodies as immunotherapeutic agents could potentially be expanded to CVD. This review focuses on the concept of phage display for antibody development and discusses the potential target antigens that could potentially be beneficial for serum cholesterol management.
Graphical abstract
... APO-CIII. Apolipoprotein CIII (Apo-CIII) is a small apolipoprotein synthesized mainly in the liver and regulates plasma TG homeostasis by inhibiting lipoprotein lipase (LPL) activity [83]. Apo-CIII plays an important role in HDL metabolism as well as in TG physiology. ...
Hyperalphalipoproteinemia (HALP) is a lipid disorder characterized by elevated plasma high-density lipoprotein cholesterol (HDL-C) levels above the 90th percentile of the distribution of HDL-C values in the general population. Secondary non-genetic factors such as drugs, pregnancy, alcohol intake, and liver diseases might induce HDL increases. Primary forms of HALP are caused by mutations in the genes coding for cholesteryl ester transfer protein (CETP), hepatic lipase (HL), apolipoprotein C-III (apo C-III), scavenger receptor class B type I (SR-BI) and endothelial lipase (EL). However, in the last decades, genome-wide association studies (GWAS) have also suggested a polygenic inheritance of hyperalphalipoproteinemia. Epidemiological studies have suggested that HDL-C is inversely correlated with cardiovascular (CV) risk, but recent Mendelian randomization data have shown a lack of atheroprotective causal effects of HDL-C. This review will focus on primary forms of HALP, the role of polygenic inheritance on HDL-C, associated risk for cardiovascular diseases and possible treatment options.
... Most members of this peptide/protein family range in mass from 6 to 36 kDa [5][6][7][8][9][10][11][12][13][14][15]. This places them well within the mass range for direct (i.e., intact) analysis on many mass spectrometers ( Table 2 and Fig. 1). ...
... ncbi.nlm.nih.gov/structure/) [5][6][7][8][9][10][11][12][13][14][15] 2.1 Nature of the Sample ...
The apolipoproteins are well known for their roles in both health and disease, as components of plasma lipoprotein particles, such as high-density lipoprotein (HDL), low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL), chylomicrons, and metabolic, vascular- and inflammation-related disorders, such as cardiovascular disease, atherosclerosis, metabolic syndrome, and diabetes. Increasingly, their roles in neurovascular and neurodegenerative disorders are also being elucidated. They play major roles in lipid and cholesterol transport between blood and organs and are, therefore, critical to maintenance and homeostasis of the lipidome, with apolipoprotein–lipid interactions, including cholesterol, fatty acids, triglycerides, phospholipids, and isoprostanes. Further, they have important pleiotropic roles related to aging and longevity, which are largely managed through their many structural variants, including multiple isoforms, and a diversity of post-translational modifications. Consequently, tools for the characterization and accurate quantification of apolipoproteins, including their diverse array of variant forms, are required to understand their salutary and disease related roles. In this chapter we outline three distinct quantitative approaches suitable for targeting apolipoproteins: (1) multiplex immunoassays, (2) mass spectrometric immunoassay, and (3) multiple reaction monitoring, mass spectrometric quantification. We also discuss management of pre-analytical and experimental design variables.
... For apoE ELISA, HJ15.3 and HJ15.7b were used as capture and detection antibodies, respectively. For Aβ x-40 ELISA, HJ2 (anti-Aβ [35][36][37][38][39][40] ) was used as a capture antibody and for Aβ x-42 ELISA, HJ7.4 (anti-Aβ [37][38][39][40][41][42] ) was used as a capture antibody. HJ5.1-biotin (anti-Aβ [13][14][15][16][17][18] [33,34] was used as the detecting antibody for both Aβ ELISAs. ...
... For apoE ELISA, HJ15.3 and HJ15.7b were used as capture and detection antibodies, respectively. For Aβ x-40 ELISA, HJ2 (anti-Aβ [35][36][37][38][39][40] ) was used as a capture antibody and for Aβ x-42 ELISA, HJ7.4 (anti-Aβ [37][38][39][40][41][42] ) was used as a capture antibody. HJ5.1-biotin (anti-Aβ [13][14][15][16][17][18] [33,34] was used as the detecting antibody for both Aβ ELISAs. ...
... These data demonstrated that the newly generated APOE-KI mice expressing different apoE isoforms have similar levels of human APOE mRNA in the brain. Some differences in protein levels (higher apoE2, lower apoE4) are likely secondary to differences in protein stability, half-life, and metabolism, as has been seen in previous APOE knock-in mice [6,[37][38][39][40][41][42][43][44]. ...
Background:
The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease (AD). ApoE is produced by both astrocytes and microglia in the brain, whereas hepatocytes produce the majority of apoE found in the periphery. Studies using APOE knock-in and transgenic mice have demonstrated a strong isoform-dependent effect of apoE on the accumulation of amyloid-β (Aβ) deposition in the brain in the form of both Aβ-containing amyloid plaques and cerebral amyloid angiopathy. However, the specific contributions of different apoE pools to AD pathogenesis remain unknown.
Methods:
We have begun to address these questions by generating new lines of APOE knock-in (APOE-KI) mice (ε2/ε2, ε3/ε3, and ε4/ε4) where the exons in the coding region of APOE are flanked by loxP sites, allowing for cell type-specific manipulation of gene expression. We assessed these mice both alone and after crossing them with mice with amyloid deposition in the brain. Using biochemical and histological methods. We also investigated how removal of APOE expression from hepatocytes affected cerebral amyloid deposition.
Results:
As in other APOE knock-in mice, apoE protein was present predominantly in astrocytes in the brain under basal conditions and was also detected in reactive microglia surrounding amyloid plaques. Primary cultured astrocytes and microglia from the APOE-KI mice secreted apoE in lipoprotein particles of distinct size distribution upon native gel analysis with microglial particles being substantially smaller than the HDL-like particles secreted by astrocytes. Crossing of APP/PS1 transgenic mice to the different APOE-KI mice recapitulated the previously described isoform-specific effect (ε4 > ε3) on amyloid plaque and Aβ accumulation. Deletion of APOE in hepatocytes did not alter brain apoE levels but did lead to a marked decrease in plasma apoE levels and changes in plasma lipid profile. Despite these changes in peripheral apoE and on plasma lipids, cerebral accumulation of amyloid plaques in APP/PS1 mice was not affected.
Conclusions:
Altogether, these new knock-in strains offer a novel and dynamic tool to study the role of APOE in AD pathogenesis in a spatially and temporally controlled manner.
