High-density Lipoprotein Deficiency Research Articles

A case report of Tangier disease presents with acute sensorimotor polyneuropathy and its treatment approach

Polyneuropathy is a frequently encountered clinical presentation where peripheral nerves are affected due to the same cause and physiopathological processes. We report a case of acute sensorimotor polyneuropathy in a patient with Tangier disease (TD) who was treated with miglustat which is a glycosphingolipid synthesis inhibitor. TD is a very rare genetic disorder caused by mutations in the ATP-binding cassette transporter A1 (ABCA1) gene which encodes the cholesterol efflux regulatory protein. It leads to accumulation of cholesterol esters within various tissues and affects lipid metabolism by deficiency of high-density lipoprotein (HDL) in the blood. Due to the accumulation of cholesterol esters in Schwann cells, it could provoke polyneuropathy in TD. Our case presented to our clinic with quadriparesis and after treated with miglustat therapy his weakness regressed.

High-density lipoproteins and non-alcoholic fatty liver disease

Background and aimsNon-alcoholic fatty liver disease (NAFLD), a high incidence liver pathology, is associated with a ∼1.5-fold higher cardiovascular disease risk. This phenomenon is generally attributed to the NAFLD-associated increase in circulating levels of pro-atherogenic apolipoprotein B100-containing small dense low-density lipoprotein and plasma hypertriglyceridemia. However, also a significant reduction in cholesterol transported by anti-atherogenic high-density lipoproteins (HDL) is frequently observed in subjects suffering from NAFLD as compared to unaffected people. In this review, we summarize data regarding the relationship between NAFLD and plasma HDL-cholesterol levels, with a special focus on highlighting potential causality between the NAFLD pathology and changes in HDL metabolism. Methods and resultsPublications in PUBMED describing the relationship between HDL levels and NAFLD susceptibility and/or disease severity, either in human clinical settings or genetically-modified mouse models, were critically reviewed for subsequent inclusion in this manuscript. Furthermore, relevant literature describing effects on lipid loading in cultured hepatocytes of models with genetic alterations related to HDL metabolism have been summarized. ConclusionsAlthough in vitro observations suggest causality between HDL formation by hepatocytes and protection against NAFLD-like lipid accumulation, current literature remains inconclusive on whether relative HDL deficiency is actually driving the development of fatty liver disease in humans. In light of the current obesity pandemic and the associated marked rise in NAFLD incidence, it is of clear scientific and societal interest to gain further insight into the relationship between HDL-cholesterol levels and fatty liver development to potentially uncover the therapeutic potential of pharmacological HDL level and/or function modulation.

Hepatocyte ABCA1 deficiency is associated with reduced HDL sphingolipids.

ATP binding cassette transporter A1 (ABCA1) limits the formation of high density lipoproteins (HDL) as genetic loss of ABCA1 function causes virtual HDL deficiency in patients with Tangier disease. Mice with a hepatocyte-specific ABCA1 knockout (Abca1 HSKO) have 20% of wild type (WT) plasma HDL-cholesterol levels, suggesting a major contribution of hepatic ABCA1 to the HDL phenotype. Whether plasma sphingolipids are reduced in Tangier disease and to what extent hepatic ABCA1 contributes to plasma sphingolipid (SL) levels is unknown. Here, we report a drastic reduction of total SL levels in plasma of a Tangier patient with compound heterozygosity for mutations in ABCA1. Compared to mutation-free controls, heterozygous mutations in ABCA1 had no significant effect on total SLs in plasma; however, apoB-depleted plasma showed a reduction in total SL also in het carriers. Similarly, liver specific Abca1 KO mice (Abca1 HSKO) showed reduced total sphingolipids in plasma and liver. In parallel, apoM and sphingosine-1-phosphate (S1P) levels were reduced in plasma of Abca1 HSKO mice. Primary hepatocytes from Abca1 HSKO mice showed a modest, but significant reduction in total SLs concentration compared to WT hepatocytes, although SL de novo synthesis and secretion were slightly increased in Abca1 HSKO hepatocytes. We conclude that hepatic ABCA1 is a signficant contributor to maintaining total plasma pool of HDL sphingolipids, including sphingomyelins and S1P.

Two Cases of Acquired High-Density Lipoprotein Deficiency with Immunoglobulin G4-Related Lecithin-Cholesterol Acyltransferase Autoantibody.

Lecithin-cholesterol acyltransferase (LCAT) plays a significant role in the progression from premature to mature high-density lipoprotein (HDL) in circulation. Consequently, primary or secondary LCAT deletion or reduction naturally results in low serum HDL cholesterol levels. Recently, rare cases of acquired HDL deficiency with LCAT autoantibodies have been reported, mainly from Japan, where LCAT autoantibodies of immunoglobulin G (IgG) caused the HDL deficiency. Here to our knowledge, we report for the first time two cases of acquired HDL deficiency caused by IgG4 linked LCAT autoantibodies with or without a high serum IgG4 level. Furthermore, these cases can extend to a new concept of "IgG4 autoimmune disease" from the viewpoint of verifying the serum autoantibody and/or renal histopathology.

Serum Lipids and Risk of Incident Psoriasis: A Prospective Cohort Study from the UK Biobank Study and Mendelian Randomization Analysis

The association between dyslipidemia and psoriasis has been studied widely. However, which individual indicators of serum lipids determine an increasing risk of incident psoriasis is still underappreciated in prospective cohorts. On the basis of UK Biobank, we investigate the causal relationship between four serum lipids and incident psoriasis by Cox proportional hazard model and Mendelian randomization analysis. After adjusting for covariates, high-density lipoprotein deficiency (<1.0 mmol/l for men, <1.3 mmol/l for women) and high triglyceride level (≥1.7 mmol/l) at baseline were associated with 16.6% and 10.6% increased risk of incident psoriasis, respectively. The effects were more pronounced in women, with 16.9 and 19.7% additional risk of psoriasis, respectively. The effects in the younger group (aged <60 years) and obese group in women were also more pronounced. No similar effect was observed in low-density lipoprotein and total cholesterol. Our subsequent Mendelian randomization analysis reinforced the main finding that high-density lipoprotein deficiency and high triglyceride cause incident psoriasis genetically. In conclusion, serum high-density lipoprotein/triglyceride levels predict psoriasis, particularly in women, indicating a distinct role of lipids engaging in the pathogenesis of psoriasis modified by sex. More metabolic-targeted, sex-specific management of psoriasis is suggested in the future.

A novel homozygous frameshift mutation in the APOA1 gene associated with marked high-density lipoprotein deficiency

The proband was a 53-year-old Japanese woman. Despite having no atherosclerotic vascular lesions on a physiological examination, markedly decreased levels of high-density lipoprotein (HDL) were always noted at her annual medical checkup. She also had corneal opacities but neither xanthoma nor tonsillar hypertrophy. A biochemical examination showed decreased levels of both apolipoprotein A-I (apoA-I) (<5 mg/dL) and lecithin-cholesterol acyltransferase (LCAT) activity. Her brother and son also had low concentrations of HDL-cholesterol, suggesting the presence of a genetic abnormality. Therefore, a sequence analysis of the genes for ABCA1, LCAT and apoA-I proteins was performed in the proband. The analysis of the APOA1 gene revealed a novel homozygous two-nucleotide deletion in exon 4 (c.614_615delTC), which causes a frameshift after residue 205 of the apoA-I protein (p.Leu205fs). Since no mutation has been found in the ABCA1 or LCAT gene, functional abnormalities of the carboxyl-terminal region of the apoA-I protein in lipid binding might have caused the low HDL-cholesterol levels and decreased LCAT activity, possibly associated with corneal opacities but not premature CAD, in the patient.

LEFT ATRIAL RESERVOIR FUNCTION DECLINES IN HYPERTENSIVE SUBJECTS WITH DYSLIPIDEMIA

Objective: Abnormal metabolism of triglycerides and very low density lipoproteins was is involved in structural and electrical atrial remodeling as it was shown in several preclinical studies but data on such relationship with left atrium (LA) function is lacking. As far as we know, the link between LA function and dyslipidemia was never studied in hypertensive patients. We intended to compare LA reservoir function in young hypertensive subjects with or without dyslipidemia. Design and method: We included 87 young subjects (median of age 23 [21; 25] years, mean BMI 25,2 ± 4,5 kg/m2, median 24 hours systolic blood pressure (BP) and diastolic BP (134 [128; 145] and 79 [74,0; 87,0] mm Hg, respectively) with HTN diagnosed with 24-hours ambulatory blood pressure monitoring according to ESH guidelines criteria (2018). None of the patients was taking hypolipidemic drugs at the baseline. Patients were divided in groups according to national criteria for dyslipidemia (fasting total cholesterol &gt; 4,9 mmol/L or low density lipoproteins (LDL) &gt; 3,0 mmol/L or high density lipoproteins (HDL) &lt; 1,0 mmol/L in males and &lt; 1,2 mmol/L in females or triglycerides &gt; 1,7 mmol/L) in which we compared left atrial longitudinal strain during reservoir phase (LASr) ratio and left atrial volume index (LAVI). Results: 58% of patients were diagnosed with dyslipidemia. Left atrial structure and function differed in groups divided according to presence of dyslipidemia: LAVI was higher (24,7 [21,5; 28,3] vs 21,5 [17,9; 26,5] mL/m2, P = 0,045) and LASr was lower (34,9 [30,2; 40,2] vs 40,8 [33,2; 45,5] %, P = 0,017) in patients with dyslipidemia while BP levels were similar. In groups allocated according to isolated criteria for dyslipidemia LASr and LAVI did not differ except patients with or without HDL decrease. Patients with HDL deficiency had lower LASr (33,9 [28,7; 37,8] vs 39,4 [31,8; 43,8] %, P = 0,043) with similar LAVI ranges. Conclusions: Left atrial reservoir function is worse in hypertensive patients with dyslipidemia, in particular in those with HDL deficiency.

Lack of ApoA-I in ApoEKO Mice Causes Skin Xanthomas, Worsening of Inflammation, and Increased Coronary Atherosclerosis in the Absence of Hyperlipidemia.

Background:HDL (high-density lipoprotein) and its major protein component, apoA-I (apolipoprotein A-I), play a unique role in cholesterol homeostasis and immunity. ApoA-I deficiency in hyperlipidemic, atheroprone mice was shown to drive cholesterol accumulation and inflammatory cell activation/proliferation. The present study was aimed at investigating the impact of apoA-I deficiency on lipid deposition and local/systemic inflammation in normolipidemic conditions.Methods:ApoE deficient mice, apoE/apoA-I double deficient (DKO) mice, DKO mice overexpressing human apoA-I, and C57Bl/6J control mice were fed normal laboratory diet until 30 weeks of age. Plasma lipids were quantified, atherosclerosis development at the aortic sinus and coronary arteries was measured, skin ultrastructure was evaluated by electron microscopy. Blood and lymphoid organs were characterized through histological, immunocytofluorimetric, and whole transcriptome analyses.Results:DKO were characterized by almost complete HDL deficiency and by plasma total cholesterol levels comparable to control mice. Only DKO showed xanthoma formation and severe inflammation in the skin-draining lymph nodes, whose transcriptome analysis revealed a dramatic impairment in energy metabolism and fatty acid oxidation pathways. An increased presence of CD4+ T effector memory cells was detected in blood, spleen, and skin-draining lymph nodes of DKO. A worsening of atherosclerosis at the aortic sinus and coronary arteries was also observed in DKO versus apoE deficient. Human apoA-I overexpression in the DKO background was able to rescue the skin phenotype and halt atherosclerosis development.Conclusions:HDL deficiency, in the absence of hyperlipidemia, is associated with severe alterations of skin morphology, aortic and coronary atherosclerosis, local and systemic inflammation.

A case of mesenteric panniculitis in a patient with Tangier disease

Mesenteric panniculitis is a rare disease caused by idiopathic inflammation of adipose tissue, most commonly affecting the mesentery of the small bowel. We present a unique case of mesenteric panniculitis in a patient with Tangier disease; a rare genetic disorder caused by mutations in the ABCA1 gene, leading to deficiency of high-density lipoprotein in the blood and accumulation of cholesterol esters within various tissues. The accumulation of cholesterol esters in body tissues in patients with Tangier disease may contribute to the pathogenesis of mesenteric panniculitis; although there is limited evidence to support this hypothesis due to the rarity of concurrent disease.

Apolipoprotein A1 deficiency in mice primes bone marrow stem cells for T cell lymphopoiesis.

ABSTRACTThe bone marrow has emerged as a potentially important target in cardiovascular disease as it generates all leukocytes involved in atherogenesis. In the current study, we evaluated whether a change in bone marrow functionality underlies the increased atherosclerosis susceptibility associated with high-density lipoprotein (HDL) deficiency. We found that HDL deficiency in mice due to the genetic lack of hepatocyte-derived apolipoprotein A1 (APOA1) was associated with an increase in the Lin−Sca-1+Kit+ (LSK) bone marrow stem cell population and lymphoid-primed multipotent progenitor numbers, which translated into a higher production and systemic flux of T cell subsets. In accordance with APOA1 deficiency-associated priming of stem cells to increase T lymphocyte production, atherogenic diet-fed low-density lipoprotein receptor knockout mice transplanted with bone marrow from APOA1-knockout mice displayed marked lymphocytosis as compared to wild-type bone marrow recipients. However, atherosclerotic lesion sizes and collagen contents were similar in the two groups of bone marrow recipients. In conclusion, systemic lack of APOA1 primes bone marrow stem cells for T cell lymphopoiesis. Our data provide novel evidence for a regulatory role of HDL in bone marrow functioning in normolipidemic mice.

ЗМІНИ ХОЛЕЦИСТОКІНІНУ-ПАНКРЕОЗИМІНУ У ХВОРИХ НА ХРОНІЧНИЙ НЕКАМЕНЕВИЙ ХОЛЕЦИСТИТ У ПОЄДНАННІ З НЕАЛКОГОЛЬНОЮ ЖИРОВОЮ ХВОРОБОЮ ПЕЧІНКИ І СТАБІЛЬНОЮ ІШЕМІЧНОЮ ХВОРОБОЮ СЕРЦЯ

Disorders in the system of neurohumoral regulation, gastrointestinal peptide hormones, such as cholecystokinin-pancreozymin (CCK-PZ), which also acts as a neurotransmitter, are of great importance in the development of the biliary tract pathology. The influence of CCK-PZ on the gallbladder function in patients with chronic acalculous cholecystitis in combination with non-alcoholic fatty liver disease (NAFLD) and Stable ischemic heart disease (SIHD) remains unexplored.We have examined 60 patients with chronic acalculous cholecystitis, among which patients with concomitant NAFLD and SIHD or without comorbidity were distinguished. The lipid spectrum of the blood was determined for all patients, the level of CCK-PZ in the blood serum was determined by the enzyme immunoassay using reagents made by Peninsula Laboratories Inc (USA). A polypositional ultrasound examination of the gallbladder was performed, as well as a fractional multiple moment duodenal intubation. It was found that the combination of chronic acalculous cholecystitis with NAFLD and SIHD is manifested by a significant violation of lipid metabolism, dyslipidemia, an increase in cholesterol of proatherogenic lipoprotein fractions and a deficiency of high density lipoproteins. A decrease in the level of cholecystokinin-pancreosimin in patients with chronic acalculous cholecystitis leads to a decrease in the contractility of the gallbladder and an increase in the tone of the sphincter of Oddi. An increase in the level of triacylglycerols and total cholesterol leads to an increase in the flow of lipids into the wall of the gallbladder, which is manifested by its thickening and hypotension of the gallbladder.

Development of a novel, sensitive translational immunoassay to detect plasma glial fibrillary acidic protein (GFAP) after murine traumatic brain injury

BackgroundGlial fibrillary acidic protein (GFAP) has emerged as a promising fluid biomarker for several neurological indications including traumatic brain injury (TBI), a leading cause of death and disability worldwide. In humans, serum or plasma GFAP levels can predict brain abnormalities including hemorrhage on computed tomography (CT) scans and magnetic resonance imaging (MRI). However, assays to quantify plasma or serum GFAP in preclinical models are not yet available.MethodsWe developed and validated a novel sensitive GFAP immunoassay assay for mouse plasma on the Meso Scale Discovery immunoassay platform and validated assay performance for robustness, precision, limits of quantification, dilutional linearity, parallelism, recovery, stability, selectivity, and pre-analytical factors. To provide proof-of-concept data for this assay as a translational research tool for TBI and Alzheimer’s disease (AD), plasma GFAP was measured in mice exposed to TBI using the Closed Head Impact Model of Engineered Rotational Acceleration (CHIMERA) model and in APP/PS1 mice with normal or reduced levels of plasma high-density lipoprotein (HDL).ResultsWe performed a partial validation of our novel assay and found its performance by the parameters studied was similar to assays used to quantify human GFAP in clinical neurotrauma blood specimens and to assays used to measure murine GFAP in tissues. Specifically, we demonstrated an intra-assay CV of 5.0%, an inter-assay CV of 7.2%, a lower limit of detection (LLOD) of 9.0 pg/mL, a lower limit of quantification (LLOQ) of 24.8 pg/mL, an upper limit of quantification (ULOQ) of at least 16,533.9 pg/mL, dilution linearity of calibrators from 20 to 200,000 pg/mL with 90–123% recovery, dilution linearity of plasma specimens up to 32-fold with 96–112% recovery, spike recovery of 67–100%, and excellent analyte stability in specimens exposed to up to 7 freeze-thaw cycles, 168 h at 4 °C, 24 h at room temperature (RT), or 30 days at − 20 °C. We also observed elevated plasma GFAP in mice 6 h after TBI and in aged APP/PS1 mice with plasma HDL deficiency. This assay also detects GFAP in serum.ConclusionsThis novel assay is a valuable translational tool that may help to provide insights into the mechanistic pathophysiology of TBI and AD.

Prevalence and Risk Factors of Metabolic Syndrome among the Homeless in Taipei City: A Cross-Sectional Study.

The safety and health of homeless people are important social issues. Metabolic syndrome (MetS) is a sub-health-risk phenomenon that has been severely aggravated worldwide in recent years. The purpose of this study was to investigate the prevalence and risk factors of MetS among the homeless in Taipei City, Taiwan. In this study, a convenience sampling was conducted at homeless counseling agencies in Taipei City from April 2018 to September 2018. A total of 297 homeless participants were recruited, from whom clinical indicators and questionnaire information were collected. Through statistical verification, analysis of variance (ANOVA), and logistic regression, we found the following main conclusions for homeless adults in Taipei: (1) The prevalence of MetS was estimated to be 53%, with 50% meeting four or more diagnostic conditions. (2) Dyslipidemia (high-density lipoprotein (HDL) deficiency and elevated triglyceride (TG)) showed the strongest association with the prevalence of MetS; more than 83% of people with HDL deficiency or hypertriglyceridemia had MetS. For the patient groups meeting more MetS diagnostic conditions, the values of high-density lipoprotein cholesterol (HDL-C), TG, and total cholesterol (TC) increased significantly. (3) The deterioration of MetS was significantly related to the high prevalence of hyperlipidemia (HL). (4) The homeless who were divorced, separated or widowed were more likely to suffer from MetS.

P1591SERUM PARAOXONASE 1 ARYLESTERASE ACTIVITY AS AN ANTIOXIDANT MARKER IN DIALYSIS PATIENTS

Abstract Background and Aims Patients with chronic kidney disease (CKD) have the highest risk for cardiovascular disease associated with high-density lipoprotein deficiency, chronic inflammation and the development of oxidative stress (OS). This study aimed to investigate serum paraoxonase 1 (PON-1) arylesterase activity in patients with end-stage renal disease (ESRD) and its association with oxidative stress markers. Method We conducted a cross-sectional observational study involving 58 ESRD patients. Among them, there were 20 hemodialyses (HD) patients and 38 patients treated with peritoneal dialysis (PD). Serum PON1 arylesterase activity was determined spectrophotometrically by the number of formed phenolic complexes using phenylacetate. Also, the concentrations of malondialdehyde, serum concentrations of ceruloplasmin, thiol groups and total peroxidase activity (TPA) in erythrocyte were determined spectrophotometrically. In addition, the blood lipid spectrum (including high-density lipoproteins) was determined in all patients. The reference group consisted of 30 conditionally healthy individuals. For the statistical analysis, we used Kruskal-Wallis’s t-test and Spearman's rank correlation test. All statistical analyses were performed using MedCalc. Results Serum PON1 arylesterase activity was 6.57 kU/L in reference group versus 2.25 kU/L in HD patients and 4.26 kU/L in PD patients (p &amp;lt; 0.0001) (Fig. 1). A direct association was found between serum PON1 arylesterase activity and ceruloplasmin concentration (r = 0.38; p = 0.004) and TPA (r = 0.32; p = 0.02) in HD patients. In iddition, serum PON1 arylesterase activity was associated with high-density lipoproteins (r = 0.67; p &amp;lt; 0.0001) in PD patients (Fig. 2). Conclusion We observed a decrease in serumPON1 arylesterase activityin ESRD patients compared to the control group. The lowest level of serum PON1 arylesterase activity was determined in HD patients. Moreover, the association between serum PON1 arylesterase activity and a decrease in antioxidant blood markers was found. Our results support the hypothesis that OS is an important mediator in the progression of kidney diseases and indicates a potential antioxidant role of serum PON1 arylesterase activity in ESRD patients. We suggest using serum PON1 arylesterase activity as an antioxidant marker in dialysis patients.

Risk Factors, Clinical Features of the Course of Myocardial Infarction and Treatment of Young Patients Based on Two Hospital Registries

Aim.To identify specific risk factors and features of the course of myocardial infarction (MI) in young patients.Material and methods.The study design is based on a comparison of observation data for patients of different ages from the Russian RECORD-3 registry (n=2359) and the registry of acute coronary syndrome of the Kemerovo city in 2015 (n=1343). The clinical and anamnestic portrait was determined, the frequency of hospital complications and the “hard” endpoints were evaluated.Results.Young patients with myocardial infarction (MI) according to RECORD-3 are more often male smokers (p=0.001) with a heredity in cardiovascular pathology (p=0.034), who have an uncomplicated STEMI upon admission to the hospital, and are sent for coronary angiography with stenting (p=0.001), without prescribing statins in the primary and secondary prevention (p=0.050 and p=0.016, respectively). There were no differences with other age groups by endpoints a year later; during the current hospitalization, young patients less often died (p=0.001) or had a relapse of MI (p=0.011). Young patients with MI from Kemerovo were also mostly male smokers (p=0.001), who more often had a history of chronic kidney disease, chronic heart failure, and lipid metabolism disorders (p=0.001), who admitted to the hospital with uncomplicated STEMI, actively undergoing thrombolytic therapy and endovascular diagnosis and treatment (p=0.001). However, it should be noted that these patients were less likely to receive aspirin (p=0.015), dual antiplatelet therapy (p=0.003), angiotensin converting enzyme (ACE) inhibitors (p=0.040) and statins (p=0.001). Moreover, in young patients with MI, deficiency of high density lipoproteins (p=0.005) was more often found in the absence of very high values of low density lipoproteins (p=0.001). Among the complications of inpatient treatment, it should be noted a tendency to bleeding (p=0.001). One year after referent MI a high proportion of repeated non-fatal MI (p=0.005) and deaths (p=0.001) were observed. A comparison of the registries showed that young patients from Kemerovo were more likely to have STEMI (p=0.032), they were more likely to have stenting (p=0.004), they were more often diagnosed with chronic renal and heart failure (p=0.001), and more often ACE inhibitors was prescribed (p=0.017), and MI during hospitalization was more often complicated by bleeding (p=0.003).Conclusion.From 1.7 to 2.4% of all MI occurs in young patients. The most frequent version of the debut is STEMI. The leading factors of cardiovascular risk in such patients are the male gender, active smoking, a hereditary history of cardiovascular diseases, low cholesterol of high density lipoproteins with insufficient statins prevention. In young patients of the Kemerovo registry, chronic heart failure and chronic kidney disease were more often observed, and ACE inhibitors were prescribed, hospitalization was often accompanied by bleeding. In a young age differences in the frequency and structure of outcomes in one year after referent MI were not found when comparing registries.

The brave new world of genetic testing in the management of the dyslipidaemias.

With the exception of familial hypercholesterolaemia, the value of genetic testing for managing dyslipidaemias is not established. We review the genetics of major dyslipidaemias in context of clinical practice. Genetic testing for familial hypercholesterolaemia is valuable to enhance diagnostic precision, cascade testing, risk prediction and the use of new medications. Hypertriglyceridaemia may be caused by rare recessive monogenic, or by polygenic, gene variants; genetic testing may be useful in the former, for which antisense therapy targeting apoC-III has been approved. Familial high-density lipoprotein deficiency is caused by specific genetic mutations, but there is no effective therapy. Familial combined hyperlipidaemia (FCHL) is caused by polygenic variants for which there is no specific gene testing panel. Familial dysbetalipoproteinaemia is less frequent and commonly caused by APOE ε2ε2 homozygosity; as with FCHL, it is responsive to lifestyle modifications and statins or/and fibrates. Elevated lipoprotein(a) is a quantitative genetic trait whose value in risk prediction over-rides genetic testing; treatment relies on RNA therapeutics. Genetic testing is not at present commonly available for managing dyslipidaemias. Rapidly advancing technology may presage wider use, but its worth will require demonstration of cost-effectiveness and a healthcare workforce trained in genomic medicine.

Analysis of Low Molecular Weight Substances and Related Processes Influencing Cellular Cholesterol Efflux.

Cholesterol efflux is the key process protecting the vascular system from the development of atherosclerotic lesions. Various extracellular and intracellular events affect the ability of the cell to efflux excess cholesterol. To explore the possible pathways and processes that promote or inhibit cholesterol efflux, we applied a combined cheminformatic and bioinformatic approach. We performed a comprehensive analysis of published data on the various substances influencing cholesterol efflux and found 153 low molecular weight substances that are included in the Chemical Entities of Biological Interest (ChEBI) database. Pathway enrichment was performed for substances identified within the Reactome database, and 45 substances were selected in 93 significant pathways. The most common pathways included the energy-dependent processes related to active cholesterol transport from the cell, lipoprotein metabolism and lipid transport, and signaling pathways. The activators and inhibitors of cholesterol efflux were non-uniformly distributed among the different pathways: the substances influencing ‘biological oxidations’ activate cholesterol efflux and the substances influencing ‘Signaling by GPCR and PTK6’ inhibit efflux. This analysis may be used in the search and design of efflux effectors for therapies targeting structural and functional high-density lipoprotein deficiency.

Emerging roles for high-density lipoproteins in neurodegenerative disorders.

Lipoproteins are the complexes of different lipids and proteins, which are devoted to the transport and clearance of lipids or lipid-related molecules in the circulation. Lipoproteins have been found to play a crucial role in brain function and may influence myelination process. Among lipoproteins, high-density lipoproteins (HDLs) and their major protein component, apoA-I, are directly involved in cholesterol efflux in the brain. It has been suggested that inadequate or dysfunctional brain HDLs may contribute to cerebrovascular dysfunctions, neurodegeneration, or neurovascular instability. HDL deficiency could also promote cognitive decline through impacting on atherosclerotic risk. The focus of this review is to discuss knowledge on HDL dysregulation in neurological disorders. A better understanding on how changes in cellular HDL and apolipoprotein homeostasis affect central nervous system function may provide promising novel avenues for the treatment of specific HDL-related neurological disorders.

HDL is essential for atherosclerotic lesion regression in Apoe knockout mice by bone marrow Apoe reconstitution

Background and aimsAlthough studies in mice have suggested that lesion regression is feasible, the underlying mechanisms remain largely unknown. Here we determined the impact of high-density lipoprotein (HDL) on atherosclerosis regression outcome. MethodsAtherosclerotic lesion dynamics were studied upon bone marrow transplantation-mediated re-introduction of apolipoprotein E (Apoe) in Apoe knockout mice. Probucol was used to pharmacologically deplete HDL. ResultsRestoration of Apoe function was associated with an initial growth of atherosclerotic lesions and parallel decrease in lesional macrophage foam cell content (47 ± 4% at 4 weeks versus 72 ± 2% at baseline: p < 0.001), despite the fact that cholesterol levels were markedly reduced. Notably, significant lesion regression was detected from 4 weeks onwards, when plasma cholesterol levels had returned to the normolipidemic range. As a result, lesions were 41% smaller (p < 0.05) at 8 weeks than at 4 weeks after bone marrow transplantation. Regressed lesions contained an even lower level of macrophage foam cells (33 ± 5%: p < 0.001) and were rich in collagen. Probucol co-treatment was associated with a 3.2-fold lower (p < 0.05) plasma HDL-cholesterol level and a more pro-inflammatory (CCR2+) monocyte phenotype. Importantly, probucol-treated mice exhibited atherosclerotic lesions that were larger than those of regular chow diet-fed bone marrow transplanted mice at 8 weeks (186 ± 15*103 μm2 for probucol-treated versus 120 ± 19*103 μm2 for controls: p < 0.05). ConclusionsWe have shown that probucol-induced HDL deficiency impairs the ability of established lesions to regress in response to reversal of the genetic hypercholesterolemia in Apoe knockout mice. Our studies thus highlight a crucial role for HDL in the process of atherosclerosis regression.

Progression of Chronic Kidney Disease Affects HDL Impact on Lipoprotein Lipase (LPL)-Mediated VLDL Lipolysis Efficiency

Background/Aims: Hypertriglyceridaemia (HTG) and reduction and dysfunction of high density lipoprotein (HDL) are common lipid disturbances in chronic kidney disease (CKD). HTG in CKD is caused mainly by the decreased efficiency of lipoprotein lipase (LPL)-mediated very low density lipoprotein triglyceride (VLDL-TG) lipolysis. It has not been clarified whether HDL dysfunction in CKD contributes directly to HTG development; thus, the aim of this study was to assess the impact of CKD progression on the ability of HDL to enhance LPL-mediated VLDL-TG lipolysis efficiency. Methods: VLDL was isolated from non-dialysis patients in CKD stages 3 and 4 and from non-CKD patients. The VLDL was incubated with LPL at the constant LPL:VLDL-TG ratio, in the absence or presence of HDL. After incubation, the VLDL was separated and the percentage (%) of hydrolyzed TG was calculated. Results: HDL presence increased the lipolysis efficiency of VLDL isolated from CKD and non-CKD patients, for the VLDL-TG> 50 mg/dl. Its effect was dependent on the VLDL-TG and HDL-cholesterol concentrations in the reaction mixtures: the higher the concentrations of VLDL-TG and HDL-cholesterol, the greater the effect. The positive impact of HDL on VLDL lipolysis was modified by CKD progression: the percentage of lipolyzed VLDL-TG in the presence of HDL decreased with a reduction in eGFR (r=0.43, p=0.009), and for patients with stage 4 CKD, no positive impact of HDL on lipolysis was observed. The percentage of lipolyzed TG correlated negatively with apoE and apoCs content in VLDL, and positively with HDL-apoCII, as well as with VLDL and HDL apoCII/ apoCIII ratios. The progression of CKD was associated with unfavourable changes in VLDL and HDL composition; apoE and apoCs levels increased in VLDL with a decrease in eGFR whereas the HDL-cholesterol level decreased. Conclusion: The progression of CKD affects lipoprotein composition and properties, and modulates the positive impact of HDL on VLDL lipolysis efficiency. In CKD patients, HDL deficiency and dysfunction can directly affect hypertriglyceridaemia development.