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PloS One 2016Human familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is characterized by low HDL, accumulation of an abnormal cholesterol-rich multilamellar...
Human familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is characterized by low HDL, accumulation of an abnormal cholesterol-rich multilamellar particle called lipoprotein-X (LpX) in plasma, and renal disease. The aim of our study was to determine if LpX is nephrotoxic and to gain insight into the pathogenesis of FLD renal disease. We administered a synthetic LpX, nearly identical to endogenous LpX in its physical, chemical and biologic characteristics, to wild-type and Lcat-/- mice. Our in vitro and in vivo studies demonstrated an apoA-I and LCAT-dependent pathway for LpX conversion to HDL-like particles, which likely mediates normal plasma clearance of LpX. Plasma clearance of exogenous LpX was markedly delayed in Lcat-/- mice, which have low HDL, but only minimal amounts of endogenous LpX and do not spontaneously develop renal disease. Chronically administered exogenous LpX deposited in all renal glomerular cellular and matrical compartments of Lcat-/- mice, and induced proteinuria and nephrotoxic gene changes, as well as all of the hallmarks of FLD renal disease as assessed by histological, TEM, and SEM analyses. Extensive in vivo EM studies revealed LpX uptake by macropinocytosis into mouse glomerular endothelial cells, podocytes, and mesangial cells and delivery to lysosomes where it was degraded. Endocytosed LpX appeared to be degraded by both human podocyte and mesangial cell lysosomal PLA2 and induced podocyte secretion of pro-inflammatory IL-6 in vitro and renal Cxl10 expression in Lcat-/- mice. In conclusion, LpX is a nephrotoxic particle that in the absence of Lcat induces all of the histological and functional hallmarks of FLD and hence may serve as a biomarker for monitoring recombinant LCAT therapy. In addition, our studies suggest that LpX-induced loss of endothelial barrier function and release of cytokines by renal glomerular cells likely plays a role in the initiation and progression of FLD nephrosis.
Topics: Animals; Apolipoprotein A-I; Cells, Cultured; Cytoskeleton; Endothelial Cells; Extracellular Matrix; Gene Expression Profiling; Glomerular Basement Membrane; Glomerular Mesangium; Human Umbilical Vein Endothelial Cells; Humans; Interleukin-6; Kidney Glomerulus; Lecithin Cholesterol Acyltransferase Deficiency; Lipoprotein-X; Lipoproteins, HDL; Lysosomes; Metabolic Clearance Rate; Mice; Mice, Inbred C57BL; Phosphatidylcholine-Sterol O-Acyltransferase; Phospholipases A2; Pinocytosis; Podocytes; Proteinuria
PubMed: 26919698
DOI: 10.1371/journal.pone.0150083 -
HIV/AIDS (Auckland, N.Z.) 2021Lipoproteins are complexes of lipids and proteins that are essential for the transport of cholesterol, triglycerides, and fat-soluble vitamins. The linkage between...
BACKGROUND
Lipoproteins are complexes of lipids and proteins that are essential for the transport of cholesterol, triglycerides, and fat-soluble vitamins. The linkage between chronic diseases like diabetes mellitus and HIV infection increases the complication of the diseases and worsens the clinical outcome of the patients.
PURPOSE
To assess and compare lipid and lipoprotein profiles among HIV-infected and non-infected diabetic patients, and to identify independent predictor variables for abnormal lipid and lipoprotein profiles.
PATIENTS AND METHODS
A comparative cross-sectional study design was used to carry out the research, and a convenient sampling technique was used to include 96 adult diabetic patients (48 HIV-infected and 48 non-infected diabetics). Socio-demographic and clinical data were collected by interviewer-administered questionnaire. Five milliliter blood sample was collected and processed for lipid and lipoprotein profile measurement. Multivariate and bivariate logistic regressions were used to identify independent predictor variables for abnormal lipid and lipoprotein profiles.
RESULTS
The prevalence of diabetic dyslipidemia was 41.7% and 37.5% in HIV-infected and non-infected diabetic patients, respectively. Hypercholesterolemia was more commonly detected among HIV-infected diabetic patients than non-HIV-infected, 25.0% versus 18.8%, respectively. Similarly, hypertriglyceridemia was more commonly observed in HIV-infected (31.3%) than non-infected diabetic patients (20.8%). About 25.0% HIV-infected diabetic patients had combined hyperlipidemia (hypercholesterolemia plus hypertriglyceridemia); and about 4.2% had hypoalphalipoproteinemia or isolated low HDL-C. Being female and long duration of diabetes mellitus were independent predictor variables for abnormal lipid and lipoprotein profiles in HIV-infected patients. Similarly, being female and high blood pressure were independent predictor variables in non-HIV-infected diabetic patients.
CONCLUSION
High prevalence lipid and lipoprotein abnormalities were detected in HIV-infected diabetic patients even though the abnormalities were also common in non-HIV co-morbid diabetic patients. Hence, proactive screening and treatment of blood glucose, lipid, and lipoprotein abnormalities are critically important and should be part of comprehensive HIV care.
PubMed: 34992470
DOI: 10.2147/HIV.S339539 -
Journal of Lipid Research Aug 2018Copy-number variations (CNVs) have been studied in the context of familial hypercholesterolemia but have not yet been evaluated in patients with extreme levels of HDL...
Copy-number variations (CNVs) have been studied in the context of familial hypercholesterolemia but have not yet been evaluated in patients with extreme levels of HDL cholesterol. We evaluated targeted, next-generation sequencing data from patients with very low levels of HDL cholesterol (i.e., hypoalphalipoproteinemia) with the VarSeq-CNV caller algorithm to screen for CNVs that disrupted the , , or genes. In four individuals, we found three unique deletions in : a heterozygous deletion of exon 4, a heterozygous deletion that spanned exons 8 to 31, and a heterozygous deletion of the entire gene. Breakpoints were identified with Sanger sequencing, and the full-gene deletion was confirmed by using exome sequencing and the Affymetrix CytoScan HD array. Previously, large-scale deletions in candidate HDL genes had not been associated with hypoalphalipoproteinemia; our findings indicate that CNVs in may be a previously unappreciated genetic determinant of low levels of HDL cholesterol. By coupling bioinformatic analyses with next-generation sequencing data, we can successfully assess the spectrum of genetic determinants of many dyslipidemias, including hypoalphalipoproteinemia.
Topics: ATP Binding Cassette Transporter 1; Adult; Computational Biology; DNA Copy Number Variations; Female; Gene Deletion; High-Throughput Nucleotide Sequencing; Humans; Hypoalphalipoproteinemias; Male; Middle Aged
PubMed: 29866657
DOI: 10.1194/jlr.P086280 -
Current Atherosclerosis Reports Jun 2011Lecithin cholesterol acyl transferase (LCAT) is a plasma enzyme that esterifies cholesterol and raises high-density lipoprotein cholesterol, but its role in... (Review)
Review
Lecithin cholesterol acyl transferase (LCAT) is a plasma enzyme that esterifies cholesterol and raises high-density lipoprotein cholesterol, but its role in atherosclerosis is not clearly established. Studies of various animal models have yielded conflicting results, but studies done in rabbits and non-human primates, which more closely simulate human lipoprotein metabolism, indicate that LCAT is likely atheroprotective. Although suggestive, there are also no biomarker studies that mechanistically link LCAT with cardiovascular disease. Imaging studies of patients with LCAT deficiency have also not yielded a clear answer to the role of LCAT in atherosclerosis. Recombinant LCAT, however, is currently being developed as a therapeutic product for enzyme replacement therapy of patients with genetic disorders of LCAT for the prevention and/or treatment of renal disease, but it may also have value for the treatment of acute coronary syndrome.
Topics: Animals; Atherosclerosis; Biological Transport; Cholesterol Esters; Cholesterol, HDL; Disease Models, Animal; Drug Evaluation, Preclinical; Fatty Acids; Humans; Lecithin Cholesterol Acyltransferase Deficiency; Lipid Metabolism; Mice; Phosphatidylcholine-Sterol O-Acyltransferase; Rabbits; Saimiri
PubMed: 21331766
DOI: 10.1007/s11883-011-0171-6 -
The Journal of Clinical Endocrinology... Oct 2012Patients with extremely low high-density lipoprotein-cholesterol (HDL-C) pose distinct challenges to clinical diagnosis and management. Confirmation of HDL-C levels... (Review)
Review
Patients with extremely low high-density lipoprotein-cholesterol (HDL-C) pose distinct challenges to clinical diagnosis and management. Confirmation of HDL-C levels below 20 mg/dl in the absence of severe hypertriglyceridemia should be followed by evaluation for secondary causes, such as androgen use, malignancy, and primary monogenic disorders, namely, apolipoprotein A-I mutations, Tangier disease, and lecithin-cholesterol acyltransferase deficiency. Global cardiovascular risk assessment is a critical component of comprehensive evaluation, although the association between extremely low HDL-C levels and atherosclerosis remains unclear. Therapeutic interventions address reversible causes of low HDL-C, multiorgan abnormalities that may accompany primary disorders and cardiovascular risk modification when appropriate. Uncommon encounters with patients exhibiting extremely low HDL-C provide an opportunity to directly observe the role of HDL metabolism in atherosclerosis and beyond the vascular system.
Topics: Apolipoprotein A-I; Cholesterol, HDL; Diagnosis, Differential; Humans; Lecithin Cholesterol Acyltransferase Deficiency; Male; Paraproteinemias; Tangier Disease; Young Adult
PubMed: 23043194
DOI: 10.1210/jc.2012-2185 -
Gut Jun 1978There are many changes in the plasma, lipids, and lipoproteins in patients with liver disease. They have proved difficult to study but our understanding of these changes... (Review)
Review
There are many changes in the plasma, lipids, and lipoproteins in patients with liver disease. They have proved difficult to study but our understanding of these changes has increased greatly during recent years. In obstructive jaundice hyperlipidaemia is a fairly constant finding and this appears to be due to the regurgitation of phospholipid from the obstructed biliary tree. The plasma lipids tend to fall with parenchymal liver disease. The composition of the lipoproteins depends on the activity of the plasma enzyme lecithin: cholesterol acyl transferase. When LCAT activity is high the individual lipoprotein fractions are normal. When it is reduced all of the lipoprotein fractions are affected but the pattern found with obstruction is quite different from that found with parenchymal disease. The changes in plasma lipoproteins appear to be associated with change in the lipid composition of cellular membranes and this may have important functional implications.
Topics: Cholestasis; Humans; Lecithin Cholesterol Acyltransferase Deficiency; Lipids; Lipoproteins; Liver Diseases; Phosphatidylcholine-Sterol O-Acyltransferase
PubMed: 355066
DOI: 10.1136/gut.19.6.526 -
Biomolecules Nov 2019Lecithin:cholesterol acyltransferase (LCAT) is an enzyme secreted by the liver and circulates with high-density lipoprotein (HDL) in the blood. The enzyme esterifies...
Lecithin:cholesterol acyltransferase (LCAT) is an enzyme secreted by the liver and circulates with high-density lipoprotein (HDL) in the blood. The enzyme esterifies plasma cholesterol and increases the capacity of HDL to carry and potentially remove cholesterol from tissues. Cholesterol accumulates within the extracellular connective tissue matrix of the cornea stroma in individuals with genetic deficiency of LCAT. LCAT can be activated by apolipoproteins (Apo) including ApoD and ApoA1. ApoA1 also mediates cellular synthesis of HDL. This study examined the expression of LCAT by epithelial cells, keratocytes, and endothelial cells, the cell types that comprise from anterior to posterior the three layers of the cornea. LCAT and ApoD were immunolocalized to all three cell types within the cornea, while ApoA1 was immunolocalized to keratocytes and endothelium but not epithelium. In situ hybridization was used to detect LCAT, ApoD, and ApoA1 mRNA to learn what cell types within the cornea synthesize these proteins. No corneal cells showed mRNA for ApoA1. Keratocytes and endothelium both showed ApoD mRNA, but epithelium did not. Epithelium and endothelium both showed LCAT mRNA, but despite the presence of LCAT protein in keratocytes, keratocytes did not show LCAT mRNA. RNA sequencing analysis of serum-cultured dedifferentiated keratocytes (commonly referred to as corneal stromal fibroblasts) revealed the presence of both LCAT and ApoD (but not ApoA1) mRNA, which was accompanied by their respective proteins detected by immunolabeling of the cultured keratocytes and Western blot analysis of keratocyte lysates. The results indicate that keratocytes in vivo show both ApoA1 and LCAT proteins, but do not synthesize these proteins. Rather, keratocytes in vivo must take up ApoA1 and LCAT from the corneal interstitial tissue fluid.
Topics: Aged; Apolipoprotein A-I; Apolipoproteins D; Cholesterol; Cornea; Corneal Dystrophies, Hereditary; Coronary Artery Disease; Endothelial Cells; Epithelial Cells; Female; Fibroblasts; Humans; Keratinocytes; Lecithin Cholesterol Acyltransferase Deficiency; Lipoproteins, HDL; Male; Microscopy, Electron; Middle Aged; Phosphatidylcholine-Sterol O-Acyltransferase; Phospholipids; RNA-Seq; Tangier Disease
PubMed: 31779197
DOI: 10.3390/biom9120785 -
Blood Aug 1986Platelets were obtained from patients with various hyperlipidemias [type II, type V, lecithin-cholesterol acyltransferase (LCAT) deficiency] and hypolipidemias... (Review)
Review
Platelets were obtained from patients with various hyperlipidemias [type II, type V, lecithin-cholesterol acyltransferase (LCAT) deficiency] and hypolipidemias (abetalipoproteinemia, Tangier disease) to ascertain relationships among plasma lipids, platelet lipids, thrombin binding and thrombin-induced platelet aggregation, and to compare these data with those previously obtained on stimulus-response coupling in platelets following in vitro modification of membrane microviscosity. Washed platelets were studied for their ability to bind 125I-thrombin in the range of 10(-10) to 10(-6) mol/L (10 mU/mL to 100 U/mL) and to aggregate with thrombin at concentrations less than 10(-9) mol/L (100 mU/mL). The values for binding and aggregation in eight patients from six kindred with familial hypercholesterolemia, taken as a group, fell in the low normal range. If divided into two groups, patients with overt cardiovascular disease bound normal amounts of thrombin but were more responsive to it, whereas patients without overt cardiovascular disease bound lower amounts of thrombin but gave an aggregation response in the normal range. These results suggest that platelet hyperresponsiveness in familial hypercholesterolemia arises from an alteration in the coupling mechanism between thrombin binding and response such that platelets from patients with familial hypercholesterolemia are able to respond with lower receptor occupancy than is the case with normal platelets. Thrombin binding and aggregation were within normal ranges for platelets from abetalipoproteinemia patients (N = 4) and type V hyperlipoproteinemia (N = 2), although in the latter case the response appeared to be less at very low thrombin concentrations (less than 30 mU/mL). Thrombin binding was elevated in Tangier disease (N = 3) but with lower responsiveness at lower thrombin concentrations. Thrombin binding was also elevated in LCAT deficiency (N = 2), and one patient showed increased and another showed decreased aggregation responses. In general, increased plasma cholesterol levels resulted in increased stimulus-response coupling (type II), whereas increased triglyceride levels resulted in decreased coupling (type V, Tangier), and there was no apparent alteration in the coupling mechanism with overall reduction in plasma lipid levels as in abetalipoproteinemia.
Topics: Abetalipoproteinemia; Adult; Blood Platelets; Blood Protein Disorders; Female; Humans; Hyperlipoproteinemia Type II; Lecithin Cholesterol Acyltransferase Deficiency; Lipoproteins; Male; Thrombin
PubMed: 3524709
DOI: No ID Found -
Journal of Lipid Research Jun 2022Low levels of high density lipoprotein-cholesterol (HDL-C) are associated with an elevated risk of arteriosclerotic coronary heart disease. Heritability of HDL-C levels...
Low levels of high density lipoprotein-cholesterol (HDL-C) are associated with an elevated risk of arteriosclerotic coronary heart disease. Heritability of HDL-C levels is high. In this research discovery study, we used whole-exome sequencing to identify damaging gene variants that may play significant roles in determining HDL-C levels. We studied 204 individuals with a mean HDL-C level of 27.8 ± 6.4 mg/dl (range: 4-36 mg/dl). Data were analyzed by statistical gene burden testing and by filtering against candidate gene lists. We found 120 occurrences of probably damaging variants (116 heterozygous; four homozygous) among 45 of 104 recognized HDL candidate genes. Those with the highest prevalence of damaging variants were ABCA1 (n = 20), STAB1 (n = 9), OSBPL1A (n = 8), CPS1 (n = 8), CD36 (n = 7), LRP1 (n = 6), ABCA8 (n = 6), GOT2 (n = 5), AMPD3 (n = 5), WWOX (n = 4), and IRS1 (n = 4). Binomial analysis for damaging missense or loss-of-function variants identified the ABCA1 and LDLR genes at genome-wide significance. In conclusion, whole-exome sequencing of individuals with low HDL-C showed the burden of damaging rare variants in the ABCA1 and LDLR genes is particularly high and revealed numerous occurrences in HDL candidate genes, including many genes identified in genome-wide association study reports. Many of these genes are involved in cancer biology, which accords with epidemiologic findings of the association of HDL deficiency with increased risk of cancer, thus presenting a new area of interest in HDL genomics.
Topics: Cholesterol, HDL; Genome-Wide Association Study; Heterozygote; Humans; Hypoalphalipoproteinemias; Exome Sequencing
PubMed: 35460704
DOI: 10.1016/j.jlr.2022.100209 -
Journal of Proteomics Apr 2019Genetic LCAT deficiency is a rare recessive autosomal disease due to loss-of-function mutations in the gene coding for the enzyme lecithin:cholesterol acyltransferase...
Genetic LCAT deficiency is a rare recessive autosomal disease due to loss-of-function mutations in the gene coding for the enzyme lecithin:cholesterol acyltransferase (LCAT). Homozygous carriers are characterized by corneal opacity, haemolytic anaemia and renal disease, which represent the first cause of morbidity and mortality in these subjects. Diagnostic and prognostic markers capable of early detecting declining kidney function in these subjects are not available, and the specific serum or urine proteomic signature of LCAT deficient carriers has never been assessed. Taking advantage of a proteomic approach, we performed 2-DE analysis of carriers' plasma and identified proteins present at different concentration in samples from homozygous carriers. Our data confirm the well-known alterations in the concentration of circulating apolipoproteins, with a statistically significant decrease of both apoA-I and apoA-II and a statistically significant increase of apoC-III. Furthermore, we observed increased level of alpha-1-antitrypsin, zinc-alpha-2-glycoprotein and retinol-binding protein 4, and reduced level of clusterin and haptoglobin. Interestingly, only beta but not alpha subunit of haptoglobin is significant reduced in homozygous subjects. Despite the limited sample size, our findings set the basis for assessing the identified protein in a larger population and for correlating their levels with clinical markers of renal function and anaemia. SIGNIFICANCE: This investigation defines the effects of LCAT deficiency on the level of the major plasma proteins in homozygous and heterozygous carriers. Increase for some proteins, with different function, together with a drop for haptoglobin, and specifically for haptoglobin beta chains, are reported for the first time as part of a coherent signature. We are glad to have the opportunity to report our findings on this subject, which is one of the main interests for our research group, when Journal of Proteomics celebrates its 10th anniversary. With its various sections devoted to different areas of research, this journal is a privileged forum for publishing proteomic investigations without restrictions either in sample type or in technical approach. It is as well a privileged forum for reviewing literature data on various topics related to proteomics investigation, as colleagues in our research group have done over the years; by the way, a good share of the reviewed papers were as well reports published in Journal of Proteomics itself. The journal also offers opportunities for focused surveys through thematic issues devoted to a variety of subjects, timely selected for their current relevance in research; it was an honour for colleagues in our group to recently act as editors of one of those. Out of this diverse experience, we express our appreciation for the endeavour of Journal of Proteomics in its first 10 years of life - and wish identical and possibly greater success for the time to come.
Topics: Adult; Biomarkers; Blood Proteins; Female; Humans; Lecithin Cholesterol Acyltransferase Deficiency; Male; Middle Aged; Proteomics
PubMed: 30529744
DOI: 10.1016/j.jprot.2018.12.005