Clearance Of Chylomicron Remnants Research Articles

Sleep and Late-Onset Alzheimer's Disease: Shared Genetic Risk Factors, Drug Targets, Molecular Mechanisms, and Causal Effects.

Late-onset Alzheimer’s disease (AD) is associated with sleep-related phenotypes (SRPs). The fact that whether they share a common genetic etiology remains largely unknown. We explored the shared genetics and causality between AD and SRPs by using high-definition likelihood (HDL), cross-phenotype association study (CPASSOC), transcriptome-wide association study (TWAS), and bidirectional Mendelian randomization (MR) in summary-level data for AD (N = 455,258) and summary-level data for seven SRPs (sample size ranges from 359,916 to 1,331,010). AD shared a strong genetic basis with insomnia (r g = 0.20; p = 9.70 × 10–5), snoring (r g = 0.13; p = 2.45 × 10–3), and sleep duration (r g = −0.11; p = 1.18 × 10–3). The CPASSOC identifies 31 independent loci shared between AD and SRPs, including four novel shared loci. Functional analysis and the TWAS showed shared genes were enriched in liver, brain, breast, and heart tissues and highlighted the regulatory roles of immunological disorders, very-low-density lipoprotein particle clearance, triglyceride-rich lipoprotein particle clearance, chylomicron remnant clearance, and positive regulation of T-cell–mediated cytotoxicity pathways. Protein–protein interaction analysis identified three potential drug target genes (APOE, MARK4, and HLA-DRA) that interacted with known FDA-approved drug target genes. The CPASSOC and TWAS demonstrated three regions 11p11.2, 6p22.3, and 16p11.2 may account for the shared basis between AD and sleep duration or snoring. MR showed insomnia had a causal effect on AD (ORIVW = 1.02, P IVW = 6.7 × 10–6), and multivariate MR suggested a potential role of sleep duration and major depression in this association. Our findings provide strong evidence of shared genetics and causation between AD and sleep abnormalities and advance our understanding of the genetic overlap between them. Identifying shared drug targets and molecular pathways can be beneficial for treating AD and sleep disorders more efficiently.

Meal-Related Changes in Apolipoprotein Particles After Treatment With an Antisense Oligonucleotide to Apolipoprotein CIII

Background: Lipodystrophy (LD) is defined by partial or complete absence of adipose tissue causing metabolic complications such as high triglycerides (TG). Apolipoprotein CIII (ApoCIII) contributes to high TG by inhibiting lipoprotein lipase (LPL). Measurement of lipoprotein particles using NMR can offer insights into lipid metabolism. Hypothesis: We hypothesized that during a mixed meal test (MMT), clearance of TG-rich lipoprotein particles (TRLP) measured by NMR would increase in LD patients given an antisense oligonucleotide (ASO) to lower ApoCIII. Experimental Design: Five adults with partial LD underwent an MMT (with 18g fat) at week 0 and after 16 weeks (wk) of the ApoCIII ASO. Blood samples were obtained at 0, 30, 60, 120, 180, 240, 300, and 360 minutes (min) and assessed using NMR with the LP4 deconvolution algorithm, which separates TRLPs into 5 size categories: very large (VL), large (L), medium (M), small (S), and very small (VS), all expressed as nmol/L. Major Results: At wk 0, patients had high fasting TG (median 523 mg/dL, IQR 335–1060 mg/dL, normal <150), which decreased after 16wk of ASO[BR([1] (196 mg/dL) Mean TRLP over the 360 min of the MMT was lower after ASO (181.6±14.1 at wk 0, 80.4±2.2 at wk 16). At wk 0, mean L_TRLP during the MMT was 26.8 ± 6.9 and decreased to 9.3±1.3 at wk 16. At wk 0, L_TRLP rose during the MMT to a peak at 180min; at wk 16 there was no rise in L_TRLP during the MMT. Mean S_TRLP during the MMT increased from wk 0 (5.4±3.9) to wk 16 (13.4±10.4). At wk 0, S_TRLP increased minimally during the MMT from 5.2±11.7 at 0 min to 10.9±15.2 at 360 min. At wk 16 there was a more notable rise in S_TRLP in the last 3 hrs of the MMT, from 12.2±15.1 at 0 min to 37.6±28.6 at 360 min. Interpretation of Results and Conclusions: As expected, an ApoCIII ASO lowered fasting and postprandial TG and TRLP. There was minimal rise or fall in any subclass of TRLP during the MMT, either before or after ASO, likely due to the small fat load, which was chosen due to concern for triggering pancreatitis in this at-risk group. The greater post-prandial fluctuation of L_TRLP prior to ASO may represent appearance and disappearance of chylomicron remnants; at wk 16 this was not seen, perhaps due to more rapid clearance of chylomicron remnants by LPL. The larger increase in S_TRLP at the end of the MMT at wk 16 may reflect more rapid lipolysis of L_TRLP by LPL during ASO treatment, thus generating S_TRLP. Next steps include measuring apoB48 and apoB100 during the MMT to distinguish VLDL from chylomicrons, accruing a larger sample size, and collecting MMT data in healthy controls.

Intestinal basolateral lipid substrate transport is linked to chylomicron secretion and is regulated by apoC-III

Chylomicron metabolism is critical for determining plasma levels of triacylglycerols (TAGs) and cholesterol, both of which are risk factors for CVD. The rates of chylomicron secretion and remnant clearance are controlled by intracellular and extracellular factors, including apoC-III. We have previously shown that human apoC-III overexpression in mice (apoC-IIITg mice) decreases the rate of chylomicron secretion into lymph, as well as the TAG composition in chylomicrons. We now find that this decrease in chylomicron secretion is not due to the intracellular effects of apoC-III, but instead that primary murine enteroids are capable of taking up TAG from TAG-rich lipoproteins (TRLs) on their basolateral surface; and via Seahorse analyses, we find that mitochondrial respiration is induced by basolateral TRLs. Furthermore, TAG uptake into the enterocyte is inhibited when excess apoC-III is present on TRLs. In vivo, we find that dietary TAG is diverted from the cytosolic lipid droplets and driven toward mitochondrial FA oxidation when plasma apoC-III is high (or when basolateral substrates are absent). We propose that this pathway of basolateral lipid substrate transport (BLST) plays a physiologically relevant role in the maintenance of dietary lipid absorption and chylomicron secretion. Further, when apoC-III is in excess, it inhibits BLST and chylomicron secretion.

Unappreciated role of low‐density lipoprotein receptor‐related protein 1 in pancreatic β cells: Multiple roles of low‐density lipoprotein receptor‐related protein 1 in glucose and lipid metabolism

Unappreciated role of low‐density lipoprotein receptor‐related protein 1 in pancreatic β cells: Multiple roles of low‐density lipoprotein receptor‐related protein 1 in glucose and lipid metabolism

Deletion of Lymphangiogenic and Angiogenic Growth Factor VEGF-D Leads to Severe Hyperlipidemia and Delayed Clearance of Chylomicron Remnants.

Objective- Dyslipidemia is one of the key factors behind coronary heart disease. Blood and lymphatic vessels play pivotal roles in both lipoprotein metabolism and development of atherosclerotic plaques. Recent studies have linked members of VEGF (vascular endothelial growth factor) family to lipid metabolism, but the function of VEGF-D has remained unexplored. Here, we investigated how the deletion of VEGF-D affects lipid and lipoprotein metabolism in atherogenic LDLR-/- ApoB100/100 mice. Approach and Results- Deletion of VEGF-D (VEGF-D-/-LDLR-/-ApoB100/100) led to markedly elevated plasma cholesterol and triglyceride levels without an increase in atherogenesis. Size distribution and hepatic lipid uptake studies confirmed a delayed clearance of large chylomicron remnant particles that cannot easily penetrate through the vascular endothelium. Mechanistically, the inhibition of VEGF-D signaling significantly decreased the hepatic expression of SDC1 (syndecan 1), which is one of the main receptors for chylomicron remnant uptake when LDLR is absent. Immunohistochemical staining confirmed reduced expression of SDC1 in the sinusoidal surface of hepatocytes in VEGF-D deficient mice. Furthermore, hepatic RNA-sequencing revealed that VEGF-D is also an important regulator of genes related to lipid metabolism and inflammation. The lack of VEGF-D signaling via VEGFR3 (VEGF receptor 3) led to lowered expression of genes regulating triglyceride and cholesterol production, as well as downregulation of peroxisomal β-oxidation pathway. Conclusions- These results demonstrate that VEGF-D, a powerful lymphangiogenic and angiogenic growth factor, is also a major regulator of chylomicron metabolism in mice.

Plasma clearance of chylomicron remnants is delayed in aged subjects: A study with artificial emulsions

Plasma clearance of chylomicron remnants is delayed in aged subjects: A study with artificial emulsions

The Role of Low-Density Lipoprotein Receptor-Related Protein 1 in Lipid Metabolism, Glucose Homeostasis and Inflammation.

Metabolic syndrome (MetS) is a highly prevalent disorder which can be used to identify individuals with a higher risk for cardiovascular disease and type 2 diabetes. This metabolic syndrome is characterized by a combination of physiological, metabolic, and molecular alterations such as insulin resistance, dyslipidemia, and central obesity. The low-density lipoprotein receptor-related protein 1 (LRP1—A member of the LDL receptor family) is an endocytic and signaling receptor that is expressed in several tissues. It is involved in the clearance of chylomicron remnants from circulation, and has been demonstrated to play a key role in the lipid metabolism at the hepatic level. Recent studies have shown that LRP1 is involved in insulin receptor (IR) trafficking and intracellular signaling activity, which have an impact on the regulation of glucose homeostasis in adipocytes, muscle cells, and brain. In addition, LRP1 has the potential to inhibit or sustain inflammation in macrophages, depending on its cellular expression, as well as the presence of particular types of ligands in the extracellular microenvironment. In this review, we summarize existing perspectives and the latest innovations concerning the role of tissue-specific LRP1 in lipoprotein and glucose metabolism, and examine its ability to mediate inflammatory processes related to MetS and atherosclerosis.

Identifying potentially common genes between dyslipidemia and osteoporosis using novel analytical approaches.

Dyslipidemia (DL) is closely related to osteoporosis (OP), while the exact common genetic mechanisms are still largely unknown. We proposed to use novel genetic analysis methods with pleiotropic information to identify potentially novel and/or common genes for the potential shared pathogenesis associated with OP and/or DL. We assessed the pleiotropy between plasma lipid (PL) and femoral neck bone mineral density (FNK BMD). We jointly applied the conditional false discovery rate (cFDR) method and the genetic analysis incorporating pleiotropy and annotation (GPA) method to the summary statistics provided by genome-wide association studies (GWASs) of FNK BMD (n = 49,988) and PL (n = 188,577) to identify potentially novel and/or common genes for BMD/PL. We found strong pleiotropic enrichment between PL and FNK BMD. Two hundred and forty-five PL SNPs were identified as potentially novel SNPs by cFDR and GPA. The corresponding genes were enriched in gene ontology (GO) terms "phospholipid homeostasis" and "chylomicron remnant clearance". Three SNPs (rs2178950, rs9939318, and rs9368716) might be the pleiotropic ones and the corresponding genes NLRC5 (rs2178950) and TRPS1 (rs9939318) were involved in NF-κB signaling pathway and Wnt signaling pathway as well as inflammation and innate immune processes. Our study validated the pleiotropy between PL and FNK BMD, and corroborated the reliability and high-efficiency of cFDR and GPA methods in further analyses of existing GWASs with summary statistics. We identified potentially common and/or novel genes for PL and/or FNK BMD, which may provide new insight and direction for further research.

Weighted gene co-expression network analysis of expression data of monozygotic twins identifies specific modules and hub genes related to BMI

BackgroundThe therapeutic management of obesity is challenging, hence further elucidating the underlying mechanisms of obesity development and identifying new diagnostic biomarkers and therapeutic targets are urgent and necessary. Here, we performed differential gene expression analysis and weighted gene co-expression network analysis (WGCNA) to identify significant genes and specific modules related to BMI based on gene expression profile data of 7 discordant monozygotic twins.ResultsIn the differential gene expression analysis, it appeared that 32 differentially expressed genes (DEGs) were with a trend of up-regulation in twins with higher BMI when compared to their siblings. Categories of positive regulation of nitric-oxide synthase biosynthetic process, positive regulation of NF-kappa B import into nucleus, and peroxidase activity were significantly enriched within GO database and NF-kappa B signaling pathway within KEGG database. DEGs of NAMPT, TLR9, PTGS2, HBD, and PCSK1N might be associated with obesity. In the WGCNA, among the total 20 distinct co-expression modules identified, coral1 module (68 genes) had the strongest positive correlation with BMI (r = 0.56, P = 0.04) and disease status (r = 0.56, P = 0.04). Categories of positive regulation of phospholipase activity, high-density lipoprotein particle clearance, chylomicron remnant clearance, reverse cholesterol transport, intermediate-density lipoprotein particle, chylomicron, low-density lipoprotein particle, very-low-density lipoprotein particle, voltage-gated potassium channel complex, cholesterol transporter activity, and neuropeptide hormone activity were significantly enriched within GO database for this module. And alcoholism and cell adhesion molecules pathways were significantly enriched within KEGG database. Several hub genes, such as GAL, ASB9, NPPB, TBX2, IL17C, APOE, ABCG4, and APOC2 were also identified. The module eigengene of saddlebrown module (212 genes) was also significantly correlated with BMI (r = 0.56, P = 0.04), and hub genes of KCNN1 and AQP10 were differentially expressed.ConclusionWe identified significant genes and specific modules potentially related to BMI based on the gene expression profile data of monozygotic twins. The findings may help further elucidate the underlying mechanisms of obesity development and provide novel insights to research potential gene biomarkers and signaling pathways for obesity treatment. Further analysis and validation of the findings reported here are important and necessary when more sample size is acquired.

The LDL Receptor-Related Protein 1: At the Crossroads of Lipoprotein Metabolism and Insulin Signaling.

The metabolic syndrome is an escalating worldwide public health concern. Defined by a combination of physiological, metabolic, and biochemical factors, the metabolic syndrome is used as a clinical guideline to identify individuals with a higher risk for type 2 diabetes and cardiovascular disease. Although risk factors for type 2 diabetes and cardiovascular disease have been known for decades, the molecular mechanisms involved in the pathophysiology of these diseases and their interrelationship remain unclear. The LDL receptor-related protein 1 (LRP1) is a large endocytic and signaling receptor that is widely expressed in several tissues. As a member of the LDL receptor family, LRP1 is involved in the clearance of chylomicron remnants from the circulation and has been demonstrated to be atheroprotective. Recently, studies have shown that LRP1 is involved in insulin receptor trafficking and regulation and glucose metabolism. This review summarizes the role of tissue-specific LRP1 in insulin signaling and its potential role as a link between lipoprotein and glucose metabolism in diabetes.

Low-Density Lipoprotein Receptor Signaling Mediates the Triglyceride-Lowering Action of Akkermansia muciniphila in Genetic-Induced Hyperlipidemia.

Akkermansia muciniphila (A muciniphila) is a mucin-degrading bacterium that resides in the mucus layer whose abundance inversely correlates with body weight and the development of diabetes mellitus in mice and humans. The objective of this study was to explore the regulatory effect of A muciniphila on host lipoprotein metabolism, insulin sensitivity, and hepatic metabolic inflammation. By establishing a novel mouse model that colonized the A muciniphila in the gastrointestinal tract of the cAMP-responsive binding protein H (CREBH)-deficient mouse and in vivo chylomicron assay, we found that increased colonization of A muciniphila in the gastrointestinal tract of wild-type mice protected mice from an acute fat load-induced hyperlipidemia compared with vehicle-treated mice. A muciniphila administration also significantly ameliorated chronic hypertriglyceridemia, improved insulin sensitivity, and prevented overproduction of postprandial chylomicrons in CREBH-null mice. Mechanistic studies revealed that increased A muciniphila colonization induced expression of low-density lipoprotein receptors and apolipoprotein E in the hepatocytes of CREBH-null mice, which facilitated the uptake of intermediate-density lipoprotein via the mediation of apolipoprotein B100 and apolipoprotein E, leading to the increased clearance of triglyceride-rich lipoprotein remnants, chylomicron remnants, and intermediate-density lipoproteins, from the circulation. Treatment with A muciniphila further improved hepatic endoplasmic reticulum stress and metabolic inflammation in CREBH-null mice. Increased colonization of the disease-protective gut bacteria A muciniphila protected the host from acute and chronic hyperlipidemia by enhancing the low-density lipoprotein receptor expression and alleviating hepatic endoplasmic reticulum stress and the inflammatory response in CREBH-null mice.

Low molecular weight heparin-induced increase in chylomicron-remnants clearance, is associated with decreased plasma TNF-α level and increased hepatic lipase activity

The acute effect of heparin on lipoprotein clearance is well characterized. Yet, the effect of prolonged low-molecular-weight-heparin (LMWH) administration on post-prandial lipemia has remained so far unexplored. Recent reports suggest that LMWH could modify lipid and carbohydrate metabolism by diminishing TNFα-mediated inflammatory response. This, together with the known negative effect of TNF-α on insulin sensitivity, prompted us to hypothesize that LMWH would favorably affect post-prandial lipoprotein disposal. Twenty four patients were given a vitamin A-fat loading meal at the end of 6-week enoxaparin treatment and after 3-month washout period. Post-prandial lipemia was assessed by measuring retinyl-palmitate (RP) during 8hours following the meal. Insulin sensitivity index (ISI), plasma lipolytic activity and plasma TNF-α were measured. Enoxaparin did not impact fasting plasma lipids and lipoproteins levels. Enoxaparin increased RP clearance in the chylomicron remnant (CMR) fraction by 32% (P<0.01). Additionally, enoxaparin decreased plasma TNF-α by 22% (P<0.01), increased hepatic lipase (HL) activity by 81% (P<0.01), along with a 2-fold increase in ISI (P<0.01). The decrease in CMR correlated with the reduction in TNFα and the increase in ISI and HL activity (R=0.48, -0.68, -0.56, respectively, p<0.05). Significant correlations were also found between the reduction in TNFα and both the increase in ISI and increase in HL activity (R=-0.43, -0.54, respectively, P<0.05). The association of the effect on post-prandial metabolism, plasma TNFα level and HL activity during prolonged enoxaparin treatment may support the hypothesis that the beneficial outcome of enoxaparin may possibly be linked to anti-inflammatory and lipase-potentiating impact.

Mecanismos básicos. Absorción y excreción de colesterol y otros esteroles

Cholesterol is of vital importance for vertebrate cell membrane structure and function. It is obvious that adequate regulation of cholesterol homeostasis is essential. Hypercholesterolemia promotes atherosclerosis and thereby represents a major risk factor for cardiovascular disease. The liver has been considered the major site of control in maintenance of cholesterol homeostasis. The liver facilitates clearance of (very) low density lipoprotein particles and cholesterol-containing chylomicron remnants, synthesizes cholesterol, synthesizes and secretes (nascent) high density lipoprotein particles, secretes cholesterol and bile salts to bile, and is involved in reverse cholesterol transport. In recent years, however, the importance of the intestine in many aspects of cholesterol physiology is increasingly recognized. It has become apparent that direct secretion of cholesterol from the blood compartment into the intestine, or transintestinal cholesterol excretion, plays a major role in disposal of cholesterol via the feces. This review will discuss current knowledge on the physiology of cholesterol homeostasis, with emphasis on cholesterol absorption, cholesterol synthesis and fecal excretion, and therapeutic options for hypercholesterolemia.

Obesity occurring in apolipoprotein E-knockout mice has mild effects on fertility

The Apolipoprotein (Apo) family is implicated in lipid metabolism. There are five types of Apo: Apoa, Apob, Apoc, Apod, and Apoe. Apoe has been demonstrated to play a central role in lipoprotein metabolism and to be essential for efficient receptor-mediated plasma clearance of chylomicron remnants and VLDL remnant particles by the liver. Apoe-deficient (Apoe(-/-)) mice develop atherosclerotic plaques spontaneously, followed by obesity. In this study, we investigated whether lipid deposition caused by Apoe knockout affects reproduction in female mice. The results demonstrated that Apoe(-/-) mice were severely hypercholesterolemic, with their cholesterol metabolism disordered, and lipid accumulating in the ovaries causing the ovaries to be heavier compared with the WT counterparts. In addition, estrogen and progesterone decreased significantly at D 100. Quantitative PCR analysis demonstrated that at D 100 the expression of cytochromeP450 aromatase (Cyp19a1), 3β-hydroxysteroid dehydrogenase (Hsd3b), mechanistic target of rapamycin (Mtor), and nuclear factor-κB (Nfkb) decreased significantly, while that of BCL2-associated agonist of cell death (Bad) and tuberous sclerosis complex 2 (Tsc2) increased significantly in the Apoe(-/-) mice. However, there was no difference in the fertility rates of the Apoe(-/-) and WT mice; that is, obesity induced by Apoe knockout has no significant effect on reproduction. However, the deletion of Apoe increased the number of ovarian follicles and the ratio of ovarian follicle atresia and apoptosis. We believe that this work will augment our understanding of the role of Apoe in reproduction.

Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis

Atherosclerosis is a chronic inflammatory disease promoted by hyperlipidemia. Several studies support FOXP3-positive regulatory T cells (Tregs) as inhibitors of atherosclerosis; however, the mechanism underlying this protection remains elusive. To define the role of FOXP3-expressing Tregs in atherosclerosis, we used the DEREG mouse, which expresses the diphtheria toxin (DT) receptor under control of the Treg-specific Foxp3 promoter, allowing for specific ablation of FOXP3+ Tregs. Lethally irradiated, atherosclerosis-prone, low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice received DEREG bone marrow and were injected with DT to eliminate FOXP3(+) Tregs. Depletion of Tregs caused a 2.1-fold increase in atherosclerosis without a concomitant increase in vascular inflammation. These mice also exhibited a 1.7-fold increase in plasma cholesterol and an atherogenic lipoprotein profile with increased levels of VLDL. Clearance of VLDL and chylomicron remnants was hampered, leading to accumulation of cholesterol-rich particles in the circulation. Functional and protein analyses complemented by gene expression array identified reduced protein expression of sortilin-1 in liver and increased plasma enzyme activity of lipoprotein lipase, hepatic lipase, and phospholipid transfer protein as mediators of the altered lipid phenotype. These results demonstrate that FOXP3(+) Tregs inhibit atherosclerosis by modulating lipoprotein metabolism.

Modulation of lipid metabolism with the overexpression of NPC1L1 in mouse liver

Niemann-Pick C1-like 1 protein (NPC1L1), a transporter crucial in intestinal cholesterol absorption, is expressed in human liver but not in murine liver. To elucidate the role of hepatic NPC1L1 on lipid metabolism, we overexpressed NPC1L1 in murine liver utilizing adenovirus-mediated gene transfer. C57BL/6 mice, fed on normal chow with or without ezetimibe, were injected with NPC1L1 adenovirus (L1-mice) or control virus (Null-mice), and lipid analyses were performed five days after the injection. The plasma cholesterol levels increased in L1-mice, and FPLC analyses revealed increased cholesterol contents in large HDL lipoprotein fractions. These fractions, which showed α-mobility on agarose electrophoresis, were rich in apoE and free cholesterol. These lipoprotein changes were partially inhibited by ezetimibe treatment and were not observed in apoE-deficient mice. In addition, plasma and VLDL triglyceride (TG) levels decreased in L1-mice. The expression of microsomal triglyceride transfer protein (MTP) was markedly decreased in L1-mice, accompanied by the reduced protein levels of forkhead box protein O1 (FoxO1). These changes were not observed in mice with increased hepatic de novo cholesterol synthesis. These data demonstrate that cholesterol absorbed through NPC1L1 plays a distinct role in cellular and plasma lipid metabolism, such as the appearance of apoE-rich lipoproteins and the diminished VLDL-TG secretion.

Apo E polymorphism among Egyptian patients with essential hypertension

Hypertension (HTN) is a chronic condition of concern due to its role in the causation of coronary artery disease (CAD), stroke, and other vascular complications. Essential hypertension (EH) is a multifactorial disorder arising from the influence of several susceptibility genes and environmental stimuli. Apolipoprotein E (Apo E) plays an essential role in clearance of chylomicron remnants and very low-density lipoproteins (VLDL). Apo E gene has three alleles (E2, E3, and E4) that give rise to six different genotypes. A significant association of E4 allele has been observed with HTN in addition to the other well-known risk factors and positive family history. Carriers of E4 allele form a higher risk group showing greater susceptibility to CAD. These observations emphasize the need of genotyping Apo E in patients with EH as an important molecular tool in personalized medicine. The aim of this work was to study the association between Apo E gene polymorphism and EH in Egyptian patients as well as correlating different Apo E genotypes with serum lipids. The study was conducted on 50 patients with EH and 50 age-matched controls. DNA analysis was performed using polymerase chain reaction restriction fragment length polymorphism. The E3/E3 genotype was found in 85.42 % of patients, compared to 80 % in controls. E3/E4 (8.33 %) and E2/E3 (6.25 %) were lower in patients compared to controls 12 and 8 %, respectively. E4/E4 and E2/E2 genotypes were only found in two patients (4 %). Total cholesterol and low-density lipoprotein were significantly higher in E3/E4 as compared to E3/E3 and E2/E3. However, there was no significant difference in triglyceride, high-density lipoprotein, and VLDL.

Influence of chylomicron remnants on human monocyte activation in vitro

Background and aimsAtherosclerosis is known to be an inflammatory disease and there is increasing evidence that chylomicron remnants (CMR), the lipoproteins which carry dietary fats in the blood, cause macrophage foam cell formation and inflammation. In early atherosclerosis the frequency of activated monocytes in the peripheral circulation is increased, and clearance of CMR from blood may be delayed, however, whether CMR contribute directly to monocyte activation and subsequent egress into the arterial wall has not been established. Here, the contribution of CMR to activation of monocyte pro-inflammatory pathways was assessed using an in vitro model. Methods and resultsPrimary human monocytes and CMR-like particles (CRLP) were used to measure several endpoints of monocyte activation. Treatment with CRLP caused rapid and prolonged generation of reactive oxygen species by monocytes. The pro-inflammatory chemokines MCP-1 and IL-8 were secreted in nanogram quantities by the cells in the absence of CRLP. IL-8 secretion was transiently increased after CRLP treatment, and CRLP maintained secretion in the presence of pharmacological inhibitors of IL-8 production. In contrast, exposure to CRLP significantly reduced MCP-1 secretion. Chemotaxis towards MCP-1 was increased in monocytes pre-exposed to CRLP and was reversed by addition of exogenous MCP-1. ConclusionOur findings indicate that CRLP activate human monocytes and augment their migration in vitro by reducing cellular MCP-1 expression. Our data support the current hypothesis that CMR contribute to the inflammatory milieu of the arterial wall in early atherosclerosis, and suggest that this may reflect direct interaction with circulating blood monocytes.

FABP4 plasma levels are increased in familial combined hyperlipidemia

FABP4 plasma levels are increased in familial combined hyperlipidemia

The diameter of liver sinusoidal fenestrae is not a major determinant of lipoprotein levels and atherosclerosis in cholesterol-fed rabbits

The liver is a key organ in lipid and lipoprotein metabolism. It has been postulated that a small diameter of sinusoidal fenestrae retards clearance of chylomicron remnants, resulting in hypercholesterolemia and atherosclerosis. However, this hypothesis has not been rigorously tested hitherto. In the current study, we compared plasma levels of proatherogenic lipoproteins and assessed the development of atherosclerosis at distinct locations throughout the arterial tree in heterozygous New Zealand White and Dutch Belt rabbits that are deficient in low-density lipoprotein receptor and with an average fenestrae size of 103 and 124 nm, respectively. Feeding of a 0.15% cholesterol diet for 4 months resulted in similar total plasma cholesterol levels in New Zealand White (420±20 mg/dl) and Dutch Belt (380±30 mg/dl) rabbits. Following isolation of lipoproteins by ultracentrifugation, no biologically significant differences in very-low-density lipoprotein, intermediate-density lipoprotein, and low-density lipoprotein cholesterol levels were observed between cholesterol-fed New Zealand White and Dutch Belt rabbits. Furthermore, the relative amount of intestinally derived apolipoprotein-B48-containing lipoproteins did not differ significantly between both strains (7.3±0.42% vs. 8.0±0.54%). Atherosclerosis was more pronounced in the thoracic aorta in New Zealand White rabbits than in Dutch Belt rabbits, but the reverse was observed with the abdominal aorta. These topographic differences cannot be explained by circulating lipoprotein levels. The data presented in this study do not support the hypothesis that the diameter of fenestrae is an important determinant of chylomicron remnant levels, diet-induced hypercholesterolemia, and atherosclerosis in cholesterol-fed rabbits.