Phospholipid Transfer Protein Research Articles

Phospholipid transfer protein and alpha-1 antitrypsin regulate Hck kinase activity during neutrophil degranulation

Excessive neutrophil degranulation is a common feature of many inflammatory disorders, including alpha-1 antitrypsin (AAT) deficiency. Our group has demonstrated that phospholipid transfer protein (PLTP) prevents neutrophil degranulation but serine proteases, which AAT inhibits, cleave PLTP in diseased airways. We propose to identify if airway PLTP activity can be restored by AAT augmentation therapy and how PLTP subdues degranulation of neutrophils in AAT deficient subjects. Airway PLTP activity was lower in AAT deficient patients but elevated in the airways of patients on augmentation therapy. Functional AAT protein (from PiMM homozygotes) prevented PLTP cleavage unlike its mutated ZZ variant (PiZZ). PLTP lowered leukotriene B4 induced degranulation of primary, secondary and tertiary granules from neutrophils from both groups (n = 14/group). Neutrophils isolated from Pltp knockout mice have enhance neutrophil degranulation. Both AAT and PLTP reduced neutrophil degranulation and superoxide production, possibly though their inhibition of the Src tyrosine kinase, Hck. Src kinase inhibitors saracatinib and dasatinib reduced neutrophil degranulation and superoxide production. Therefore, AAT protects PLTP from proteolytic cleavage and both AAT and PLTP mediate degranulation, possibly via Hck tyrosine kinase inhibition. Deficiency of AAT could contribute to reduced lung PLTP activity and elevated neutrophil signaling associated with lung disease.

HMGB1: LPS Delivery Vehicle for Caspase-11-Mediated Pyroptosis

Recognition of cytoplasmic lipopolysaccharide (LPS) by caspase-11 leads to pyroptosis and secretion of inflammatory mediators. In this issue of Immunity, Deng etal. (2018) report that high-mobility group box 1 (HMGB1) secreted by hepatocytes delivers extracellular LPS into the cytoplasm and mediates pyroptosis.

Salivary biomarkers in association with periodontal parameters and the periodontitis risk haplotype

Genetic factors play a role in periodontitis. Here we examined whether the risk haplotype of MHC class III region BAT1-NFKBIL1-LTA and lymphotoxin-α polymorphisms associate with salivary biomarkers of periodontal disease. A total of 455 individuals with detailed clinical and radiographic periodontal health data were included in the study. A 610 K genotyping chip and a Sequenom platform were used in genotyping analyses. Phospholipid transfer protein activity, concentrations of lymphotoxin-α, IL-8 and myeloperoxidase, and a cumulative risk score (combining Porphyromonas gingivalis, IL-1β and matrix metalloproteinase-8) were examined in saliva samples. Elevated IL-8 and myeloperoxidase concentrations and cumulative risk scores associated with advanced tooth loss, deepened periodontal pockets and signs of periodontal inflammation. In multiple logistic regression models adjusted for periodontal parameters and risk factors, myeloperoxidase concentration (odds ratio (OR); 1.37, P = 0.007) associated with increased odds for having the risk haplotype and lymphotoxin-α concentration with its genetic variants rs2857708, rs2009658 and rs2844482. In conclusion, salivary levels of IL-8, myeloperoxidase and cumulative risk scores associate with periodontal inflammation and tissue destruction, while those of myeloperoxidase and lymphotoxin-α associate with genetic factors as well.

Cardiac MRI characteristics of epicardial fat in a very high risk patients with a multivessel coronary artery disease

Aim: Our aim was to evaluate the association between epicardial fat characteristics and serum levels of pasma phospholipid transfer protein (PLTP) and sLDL in individuals with CAD.

Alteration of HDL Protein Composition with Hemodialysis Initiation.

HDL particles obtained from patients on chronic hemodialysis exhibit lower cholesterol efflux capacity and are enriched in inflammatory proteins compared with those in healthy individuals. Observed alterations in HDL proteins could be due to effects of CKD, but also may be influenced by the hemodialysis procedure, which stimulates proinflammatory and prothrombotic pathways. We compared HDL-associated proteins in 143 participants who initiated hemodialysis within the previous year with those of 110 participants with advanced CKD from the Hemodialysis Fistula Maturation Study. We quantified concentrations of 38 HDL-associated proteins relative to total HDL protein using targeted mass spectrometry assays that included a stable isotope-labeled internal standard. We used linear regression to compare the relative abundances of HDL-associated proteins after adjustment and required a false discovery rate q value ≤10% to control for multiple testing. We further assessed the association between hemodialysis initiation and cholesterol efflux capacity in a subset of 80 participants. After adjustment for demographics, comorbidities, and other clinical characteristics, eight HDL-associated proteins met the prespecified false discovery threshold for association. Recent hemodialysis initiation was associated with higher HDL-associated concentrations of serum amyloid A1, A2, and A4; hemoglobin-β; haptoglobin-related protein; cholesterylester transfer protein; phospholipid transfer protein; and apo E. The trend for participants recently initiating hemodialysis for lower cholesterol efflux capacity compared with individuals with advanced CKD did not reach statistical significance. Compared with advanced CKD, hemodialysis initiation within the previous year is associated with higher concentrations of eight HDL proteins related to inflammation and lipid metabolism. Identified associations differ from those recently observed for nondialysis-requiring CKD. Hemodialysis initiation may further impair cholesterol efflux capacity. Further work is needed to clarify the clinical significance of the identified proteins with respect to cardiovascular risk. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_07_25_CJASNPodcast_18_8_W.mp3.

Plasma lecithin:cholesterol acyltransferase and phospholipid transfer protein activity independently associate with nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent condition which contributes to atherogenic apolipoprotein B dyslipoproteinemias. Lecithin:cholesterol acyltransferase (LCAT) and phospholipid transfer protein (PLTP) are both synthesized by the liver and are important in lipid metabolism. Here, we interrogated the impact of NAFLD on plasma LCAT and PLTP activities. Plasma LCAT activity (exogenous substrate assay) and PLTP activity (phospholipid vesicles-HDL assay) were determined in 348 subjects (279 men; 81 subjects with type 2 diabetes (T2DM); 123 with metabolic syndrome (MetS)). A Fatty Liver Index (FLI) ≥60 was used as a proxy of NAFLD. Insulin resistance was determined by homoeostasis model assessment (HOMA-IR). A total of 147 participants had an FLI ≥60 coinciding with T2DM and MetS (P<0.001 for each). Plasma LCAT activity and PLTP activity were on average 12% and 5% higher, respectively, in subjects with an FLI≥60 (P<0.001 for each). In age- and sex-adjusted partial linear regression analysis, LCAT activity and PLTP activity were positively related to various obesity measures and HOMA-IR (P<0.001 for each). In multivariable linear regression analyses adjusted for age and sex, LCAT activity was associated with an FLI≥60 independent of T2DM and MetS, the waist/hip ratio, or HOMA-IR (β=0.307 to 0.366, P<0001 for all models). PLTP activity was also associated with an FLI≥60 independent of these variables (β=0.151 to 0223, P=0.013 to 0.001). NAFLD, as inferred from an FLI≥60, confers higher plasma LCAT and to a lesser extent PLTP activity, even when taking account of T2DM, MetS, central obesity and insulin resistance.

Structural basis of the lipid transfer mechanism of phospholipid transfer protein (PLTP)

Human phospholipid transfer protein (PLTP) mediates the transfer of phospholipids among atheroprotective high-density lipoproteins (HDL) and atherogenic low-density lipoproteins (LDL) by an unknown mechanism. Delineating this mechanism would represent the first step towards understanding PLTP-mediated lipid transfers, which may be important for treating lipoprotein abnormalities and cardiovascular disease. Here, using various electron microscopy techniques, PLTP is revealed to have a banana-shaped structure similar to cholesteryl ester transfer protein (CETP). We provide evidence that PLTP penetrates into the HDL and LDL surfaces, respectively, and then forms a ternary complex with HDL and LDL. Insights into the interaction of PLTP with lipoproteins at the molecular level provide a basis to understand the PLTP-dependent lipid transfer mechanisms for dyslipidemia treatment.

TAILS N-terminomics and proteomics reveal complex regulation of proteolytic cleavage by O-glycosylation

Proteolytic processing is an irreversible post-translational modification functioning as a ubiquitous regulator of cellular activity. Protease activity is tightly regulated via control of gene expression, enzyme and substrate compartmentalization, zymogen activation, enzyme inactivation, and substrate availability. Emerging evidence suggests that proteolysis can also be regulated by substrate glycosylation and that glycosylation of individual sites on a substrate can decrease or, in rare cases, increase its sensitivity to proteolysis. Here, we investigated the relationship between site-specific, mucin-type (or GalNAc-type) O-glycosylation and proteolytic cleavage of extracellular proteins. Using in silico analysis, we found that O-glycosylation and cleavage sites are significantly associated with each other. We then used a positional proteomic strategy, terminal amine isotopic labeling of substrates (TAILS), to map the in vivo cleavage sites in HepG2 SimpleCells with and without one of the key initiating GalNAc transferases, GalNAc-T2, and after treatment with exogenous matrix metalloproteinase 9 (MMP9) or neutrophil elastase. Surprisingly, we found that loss of GalNAc-T2 not only increased cleavage, but also decreased cleavage across a broad range of other substrates, including key regulators of the protease network. We also found altered processing of several central regulators of lipid homeostasis, including apolipoprotein B and the phospholipid transfer protein, providing new clues to the previously reported link between GALNT2 and lipid homeostasis. In summary, we show that loss of GalNAc-T2 O-glycosylation leads to a general decrease in cleavage and that GalNAc-T2 O-glycosylation affects key regulators of the cellular proteolytic network, including multiple members of the serpin family.

Abstract 172: Prodomain of Furin Promotes Phospholipid Transfer Protein Proteasomal Degradation in Hepatocytes

PLTP is one of the major modulators of lipoprotein metabolism and atherosclerosis development, however, very little is known about the regulation of PLTP. The effect of hepatic profurin expression on PLTP processing and function is investigated. We utilized adenovirus overexpressing prodomain of furin (profurin) in mouse liver to evaluate PLTP activity, mass, and plasma lipid levels. We co-expressed PLTP and profurin in Huh7 cells and studied their interaction. We found profurin expression significantly reduced plasma lipids, plasma PLTP activity and mass in all tested mouse models, compared with controls. Moreover, the expression of profurin dramatically reduced liver PLTP activity and protein level. We further explore the mechanism using in vivo and ex vivo approaches. We found that profurin can interact with intracellular PLTP, and promote its ubiquitination and proteasomal degradation, resulting in less PLTP secretion from the hepatocytes. Furin does not cleave PLTP, instead it forms a complex with PLTP, likely through its prodomain. Our study reveals that hepatic PLTP protein is targeted for proteasomal degradation by profurin overexpression, which could be a novel post-translational mechanism underlying PLTP regulation.

Prodomain of Furin Promotes Phospholipid Transfer Protein Proteasomal Degradation in Hepatocytes.

BackgroundPhospholipid transfer protein (PLTP) is one of the major modulators of lipoprotein metabolism and atherosclerosis development; however, little is known about the regulation of PLTP. The effect of hepatic prodomain of furin (profurin) expression on PLTP processing and function is investigated.Methods and ResultsWe used adenovirus expressing profurin in mouse liver to evaluate PLTP activity, mass, and plasma lipid levels. We coexpressed PLTP and profurin in human hepatoma cell line cells and studied their interaction. We found profurin expression significantly reduced plasma lipids, plasma PLTP activity, and mass in all tested mouse models, compared with controls. Moreover, the expression of profurin dramatically reduced liver PLTP activity and protein level. We further explored the mechanism using in vivo and ex vivo approaches. We found that profurin can interact with intracellular PLTP and promote its ubiquitination and proteasomal degradation, resulting in less PLTP secretion from the hepatocytes. Furin does not cleave PLTP; instead, it forms a complex with PLTP, likely through its prodomain.ConclusionsOur study reveals that hepatic PLTP protein is targeted for proteasomal degradation by profurin expression, which could be a novel posttranslational mechanism underlying PLTP regulation.

Deletion of plasma Phospholipid Transfer Protein (PLTP) increases microglial phagocytosis and reduces cerebral amyloid-β deposition in the J20 mouse model of Alzheimer's disease.

Plasma phospholipid transfer protein (PLTP) binds and transfers a number of amphipathic compounds, including phospholipids, cholesterol, diacylglycerides, tocopherols and lipopolysaccharides. PLTP functions are relevant for many pathophysiological alterations involved in neurodegenerative disorders (especially lipid metabolism, redox status, and immune reactions), and a significant increase in brain PLTP levels was observed in patients with Alzheimer's disease (AD) compared to controls. To date, it has not been reported whether PLTP can modulate the formation of amyloid plaques, i.e. one of the major histopathological hallmarks of AD.We thus assessed the role of PLTP in the AD context by breeding PLTP-deficient mice with an established model of AD, the J20 mice. A phenotypic characterization of the amyloid pathology was conducted in J20 mice expressing or not PLTP. We showed that PLTP deletion is associated with a significant reduction of cerebral Aβ deposits and astrogliosis, which can be explained at least in part by a rise of Aβ clearance through an increase in the microglial phagocytic activity and the expression of the Aβ-degrading enzyme neprilysin.PLTP arises as a negative determinant of plaque clearance and over the lifespan, elevated PLTP activity could lead to a higher Aβ load in the brain.

Plasma lipid transfer proteins: The role of PLTP and CETP in atherogenesis.

Cardiovascular diseases are still the main cause of death in Poland and throughout the world. Independent risk factors of cardiovascular disease, in addition to elevated LDL cholesterol, are both low HDL levels and high levels of non-HDL cholesterol. Plasma phospholipid-transfer protein (PLTP) and cholesteryl ester transfer protein (CETP) both play a major role in the metabolism of those lipoproteins. A lack of these proteins increases HDL and lowers LDL levels. In the light of current knowledge, it seems reasonable to search for compounds that may decrease the activity of CETP, and thus reduce the incidence of cardiovascular disease. Whereas on the one hand there are reports about the adverse effect of torcetrapib and the lack of therapeutic effects of dalcetrapib, on the other hand the question arises whether the CETP inhibitors that are currently in clinical trials will rise to the challenges before them. Currently, it is known that the activity of PLTP, while affecting the metabolism of lipoproteins, especially HDL, plays a major role in atherogenesis. Still, there are some contradictions and controversies about the effect of PLTP on reverse cholesterol transport (RCT). There are a number of studies about the role that PLTP plays in the pathogenesis of various diseases. Further studies are needed to clearly determine the impact of PLTP activity on the formation and development of pathological processes in the cardiovascular system.

Plasma angiopoietin-like 4 is related to phospholipid transfer protein activity in diabetic and non-diabetic subjects: role of enhanced low grade inflammation

BackgroundAngiopoietin-like 4 (ANGPTL4) inhibits lipoprotein lipase, whereas phospholipid transfer protein (PLTP) enhances hepatic triglyceride secretion. Both factors may be upregulated by inflammatory pathways. Since the extent to which these circulating factors are interrelated is unknown, we determined the relationship between plasma ANGPTL4 and PLTP activity, and assessed whether such a relationship could be explained by high sensitivity C-reactive protein (hsCRP) levels as a marker of low-grade chronic inflammation.MethodsFasting plasma ANGPTL4, PLTP activity (liposome-vesicle high density lipoprotein system) and hsCRP were measured in 41 type 2 diabetic (T2DM) subjects and 36 non-diabetic subjects.ResultsPlasma ANGPTL4 and PLTP activity were increased in T2DM (p < 0.001 for each), coinciding with elevated hsCRP, triglycerides and non-esterified fatty acids (NEFA) (p = 0.031 to 0.001). In univariate analysis, ANGTLP4 was correlated with PLTP activity (Rs = 0.309, p = 0.006), whereas both factors were related to hsCRP and NEFA levels (Rs = 0.304 to 0.411, p < 0.01 to < 0.001). In multivariable linear regression analysis adjusting for age, sex, glucose, total cholesterol, triglycerides and NEFA, ANGPTL4 and PLTP activity each remained positively associated with hsCRP (β = 0.315, p = 0.003 and β = 0.299, p = 0.034, respectively). Plasma ANGPTL4 remained positively associated with PLTP activity when taking account of age, sex, glucose, total cholesterol, triglycerides and NEFA (β = 0.315, p = 0.003). Notably, this association disappeared after further adjustment for hsCRP (β = 0.131, p = 0.25).ConclusionsIn conclusion, plasma ANGPTL4 and PLTP activity are interrelated, which may at least in part be explained by low-grade chronic inflammation. A pro-inflammatory state could affect triglyceride metabolism via concerted effects on ANGPTL4 and PLTP.

PhosphoLipid transfer protein (PLTP) exerts a direct pro-inflammatory effect on rheumatoid arthritis (RA) fibroblasts-like-synoviocytes (FLS) independently of its lipid transfer activity.

Rheumatoid arthritis (RA) is a chronic inflammatory rheumatic disease with modification of lipids profile and an increased risk of cardiovascular events related to inflammation. Plasma phospholipid transfer protein (PLTP) exerts a lipid transfer activity through its active form. PLTP can also bind to receptors such as ATP-binding cassette transporter A1 (ABCA1). In addition to its role in lipoprotein metabolism and atherosclerosis, the latest advances came in support of a complex role of PLTP in the regulation of the inflammatory response, both with pro-inflammatory or anti-inflammatory properties. The aim of the present study was to decipher the role of PLTP in joint inflammation and to assess its relevance in the context of RA. PLTP expression was examined by western-blot and by immunochemistry. ABCA1 expression was analyzed by flow cytometry. Lipid transfer activity of PLTP and pro-inflammatory cytokines were measured in sera and synovial fluid (SF) from RA patients and controls (healthy subjects or osteoarthritis patients [OA]). FLS were treated with both lipid-transfer active form and inactive form of recombinant human PLTP. IL-8, IL-6, VEGF and MMP3 produced by FLS were assessed by ELISA, and proliferation by measuring 3H-Thymidine incorporation. RA synovial tissues showed higher PLTP staining than OA and PLTP protein levels were also significantly higher in RA-FLS. In addition, RA, unlike OA patients, displayed elevated levels of PLTP activity in SF, which correlated with pro-inflammatory cytokines. Both lipid-transfer active and inactive forms of PLTP significantly increased the production of cytokines and proliferation of FLS. ABCA1 was expressed on RAFLS and PLTP activated STAT3 pathway. To conclude, PLTP is highly expressed in the joints of RA patients and may directly trigger inflammation and FLS proliferation, independently of its lipid transfer activity. These results suggest a pro-inflammatory role for PLTP in RA.

The SEC14 phospholipid transfer protein regulates pathogen-associated molecular pattern-triggered immunity in Nicotiana benthamiana

We previously revealed that the SEC14 phospholipid transfer protein from Nicotiana benthamiana (NbSEC14) has a role in plant immune responses against phytopathogenic bacteria in a hypersensitive response-independent manner. To characterize the role of NbSEC14 on plant immunity, we analyzed the relationship between NbSEC14 and pathogen-associated molecular pattern-triggered immunity (PTI). NbSEC14-silenced plants exhibited down-regulated expression of PTI marker genes (NbAcre31 and NbPti5) after being inoculated with Pseudomonas syringae pv. tabaci. Additionally, we observed accelerated bacterial growth and inhibited expression of PTI marker genes in NbSEC14-silenced plants infected with the hrp-deficient P. syringae pv. tabaci mutant. We used Pseudomonas fluorescens and flg22 as PTI inducers to further examine the association between NbSEC14 and the induction of PTI. The expression of PTI marker genes was compromised in NbSEC14-silenced plants infiltrated with P. fluorescens and flg22. Meanwhile, a cell death-based PTI assay indicated NbSEC14 was required for PTI. Furthermore, callose deposition and disease resistance induced by flg22 were compromised in NbSEC14-silenced plants. These results suggest that NbSEC14 may help regulate the induction of PTI.

High-Density Lipoprotein Function in Cardiovascular Disease and Diabetes Mellitus.

Cardiovascular disease (CVD) is the most common cause of death worldwide.1 Major CVD risk factors are hypertension, smoking, physical inactivity, abnormal glucose levels/diabetes mellitus, and dyslipidemia. Among these, dyslipidemia characterized by a low level of HDL-C (high-density lipoprotein cholesterol) is strongly and inversely correlated with CVD risk,2–4 and low HDL-C levels is part of the atherogenic dyslipidemia complex associated with diabetes mellitus.5 These observations triggered intense interest in increasing HDL-C levels for therapeutic intervention of CVD.6,7 However, several recent lines of evidence now suggest that the association between HDL-C levels and CVD status may be indirect or more complicated than previously recognized.7 Thus, human genetic studies demonstrate that genetically altered HDL-C levels do not necessarily translate to an altered risk of CVD.8–12 Phase III clinical trials of drugs that elevate HDL-C, such as niacin and CETP (cholesteryl ester transfer protein) inhibitors, also have largely failed to reduce CVD events in statin-treated subjects with established CVD.13–15 For several CETP inhibitors, improvement in CVD prevention was unsuccessful because of off-target effects (torcetrapib) or lack of efficacy (dalcetrapib and evacetrapib).14,16–18 The exception is the recent REVEAL trial (Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification), which included more subjects and was performed for longer than previous CETP inhibitor trials. The REVEAL demonstrated that the CETP inhibitor anacetrapib exhibited beneficial effects on cardiovascular outcomes on top of those of statin therapy, although the risk reduction was moderate19,20 and might have been due, at least in part, to a reduction in non-HDL-C rather than elevated HDL-C.21 Considering these cumulative observations, it remains uncertain whether increased HDL-C directly impacts atherosclerosis and the …

Phospholipid transfer protein: its impact on lipoprotein homeostasis and atherosclerosis

Phospholipid transfer protein (PLTP) is one of the major modulators of lipoprotein metabolism and atherosclerosis development in humans; however, we still do not quite understand the mechanisms. In mouse models, PLTP overexpression induces atherosclerosis, while its deficiency reduces it. Thus, mouse models were used to explore the mechanisms. In this review, I summarize the major progress made in the PLTP research field and emphasize its impact on lipoprotein metabolism and atherosclerosis, as well as its regulation.

Genetic Insights of Cholesterol and Atherosclerosis: Complex Biology

Atherosclerosis is multifaceted arterial disease involving collaboration of chromosomal and conservational factors, around seven million Americans are experiencing a heart attack during their lifetime. Many biomolecules play different roles in atherosclerosis such as 5-LO enzyme which play vital role in synthesis of leukotrienes inflammatory intermediates and proteins. Previous studies show that individuals suffering from coronary artery disease more commonly have C. pneumonia antibody than inhabitant’s controls. In recent years the genes and genetic polymorphism which are associated with atherosclerosis had been identified. Phospholipid transfer protein will subsequently decrease the HDL mass and cholesterol efflux capacity due to its overexpression and deletation. Our aim of this review is to demonstrate complex biology of atherosclerosis and effect of cholesterol in cardiovascular diseases.

Lipid transfer proteins in the assembly of apoB-containing lipoproteins

A better understanding of intracellular lipoprotein assembly may help identify proteins with important roles in lipid disorders. apoB-containing lipoproteins (B-lps) are macromolecular lipid and protein micelles that act as specialized transport vehicles for hydrophobic lipids. They are assembled predominantly in enterocytes and hepatocytes to transport dietary and endogenous fat, respectively, to different tissues. Assembly occurs in the endoplasmic reticulum (ER) and is dependent on lipid resynthesis in the ER and on a chaperone, namely, microsomal triglyceride transfer protein (MTTP). Precursors for lipid synthesis are obtained from extracellular sources and from cytoplasmic lipid droplets. MTTP is the major and essential lipid transfer protein that transfers phospholipids and triacylglycerols to nascent apoB for the assembly of lipoproteins. Assembly is aided by cell death-inducing DFF45-like effector B and by phospholipid transfer protein, which may facilitate additional deposition of triacylglycerols and phospholipids, respectively, to apoB. Here, we summarize the current understanding of the different steps in the assembly of B-lps and discuss the role of lipid transfer proteins in these steps to help identify new clinical targets for lipid-associated disorders, such as heart disease.

ANGPTL3 serum concentration and rare genetic variants in Finnish population

Genetic variants of angiopoietin-like protein 3 (ANGPTL3) are associated with serum triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) concentration in GWASs. ANGPTL3 deficiency causes declined TG, total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (apoB) and apolipoprotein A-I (apoA-I) serum concentration, a phenotype defined as familial combined hypolipidaemia (FHBL2). Our aim is to establish whether ANGPTL3 serum protein concentration correlates with lipoproteins and lipids in hyper- or hypolipidaemic subjects, and whether ANGPTL3 sequence variants are associated with untypical lipid profiles. Additionally, 10 subjects with very low lipoprotein concentrations were sequenced for ANGPTL3 for possible loss-of-function (LOF) variants. Study subjects were selected from Finnish FINRISK and Health 2000 surveys. ANGPTL protein concentrations were measured by ELISA method. As a result, ANGPTL3 serum concentration correlated positively with age, phospholipid transfer protein (PLTP) and cholesteryl ester transfer protein (CETP) activities, but not with any of the lipid or lifestyle attributes. No ANGPTL3 variants were found among sequenced samples. Subjects who carried ANGPTL3 sequence variants rs12563308 (n = 4) and rs199772471 (n = 1) had abnormally high TC and LDL-C concentrations. Whole exome sequencing data of these five subjects were further analyzed for rare and deleterious missense variants in genes associated with cholesterol metabolism. In conclusion, ANGPTL3 serum protein concentration did not predict lipid concentrations, unlike apolipoprotein C-III (apoC-III) which positively correlated with most of the lipid attributes. ANGPTL3 variant screen yielded five carriers with abnormally high TC concentration; the actual genetic causality, however, could not be verified.