Approach to the patient with extremely low HDL-cholesterol.
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ABSTRACT:
SUBMITTER: Rader DJ
PROVIDER: S-EPMC3462950 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Plasma levels of HDL cholesterol (HDL-C) have a strong inherited basis with heritability estimates of 40-60%. The well-established inverse relationship between plasma HDL-C levels and the risk of coronary artery disease (CAD) has led to an extensive search for genetic factors influencing HDL-C concentrations. Over the past 30 years, candidate gene, genome-wide linkage, and most recently genome-wide association (GWA) studies have identified several genetic variations for plasma HDL-C levels. However, the functional role of several of these variants remains unknown, and they do not always correlate with CAD. In this review, we will first summarize what is known about HDL metabolism, monogenic disorders associated with both low and high HDL-C levels, and candidate gene studies. Then we will focus this review on recent genetic findings from the GWA studies and future strategies to elucidate the remaining substantial proportion of HDL-C heritability. Comprehensive investigation of the genetic factors conferring to low and high HDL-C levels using integrative approaches is important to unravel novel pathways and their relations to CAD, so that more effective means of diagnosis, treatment, and prevention will be identified.
| S-EPMC2903789 | biostudies-literature
Project description:To date, few mutations are described to underlie highly-elevated HDLc levels in families. Here we sequenced the coding regions and adjacent sequence of the LIPG, CETP, and GALNT2 genes in 171 unrelated Dutch Caucasian probands with HDLc?90th percentile and analyzed segregation of mutations with lipid phenotypes in family members. In these probands, mutations were most frequent in LIPG (12.9%) followed by GALNT2 (2.3%) and CETP (0.6%). A total of 6 of 10 mutations in these three genes were novel (60.0%), and mutations segregated with elevated HDLc in families. Interestingly, the LIPG mutations N396S and R476W, which usually result in elevated HDLc, were unexpectedly found in 6 probands with low HDLc (i.e., ?10th percentile). However, 5 of these probands also carried mutations in ABCA1, LCAT, or LPL. Finally, no CETP and GALNT2 mutations were found in 136 unrelated probands with low HDLc. Taken together, we show that rare coding and splicing mutations in LIPG, CETP, and GALNT2 are enriched in persons with hyperalphalipoproteinemia and segregate with elevated HDLc in families. Moreover, LIPG mutations do not overcome low HDLc in individuals with ABCA1 and possibly LCAT and LPL mutations, indicating that LIPG affects HDLc levels downstream of these proteins.
| S-EPMC3428317 | biostudies-literature
Project description:Dyslipidemia (high concentrations of LDL-c and low concentrations of HDL-c) is a major cause of cardiovascular events, which are the leading cause of death in the world. On the other hand, nutrition and regular exercise can be an interesting strategy to modulate lipid profile, acting as prevention or treatment, inhibiting the risk of diseases due to its anti-inflammatory and anti-atherogenic characteristics. Additionally, the possibility of controlling different training variables, such as type, intensity and recovery interval, can be used to maximize the benefits of exercise in promoting cardiovascular health. However, the mechanisms by which exercise and nutrients act in the regulation of cholesterol and its fractions, such as reverse cholesterol transport, receptors and transcription factors involved, such as PPARs and their role related to exercise, deserve further discussion. Therefore, the objective of this review is to debate about non-medical approaches to increase HDL-c, such as nutritional and training strategies, and to discuss the central mechanisms involved in the modulation of lipid profile during exercise, as well as that can be controlled by physical trainers or sports specialists in attempt to maximize the benefits promoted by exercise. The search for papers was performed in the databases: Medline (Pubmed), Science Direct, Scopus, Sport Discus, Web of Science, Scielo and Lilacs until February 2016.
| S-EPMC5962737 | biostudies-other
Project description:Background. Abnormal lipid homeostasis in sickle cell disease (SCD) is characterized by defects in plasma and erythrocyte lipids and may increase the risk of cardiovascular disease. This study assessed the lipid profile and non-HDL cholesterol level of SCD patients. Methods. A hospital-based cross-sectional study was conducted in 50 SCD patients, in the steady state, aged 8-28 years, attending the SCD clinic, and 50 healthy volunteers between the ages of 8-38 years. Serum lipids were determined by enzymatic methods and non-HDL cholesterol calculated by this formula: non-HDL-C = TC-HDL-C. Results. Total cholesterol (TC) (p = 0.001) and high-density lipoprotein cholesterol (HDL-C) (p < 0.0001) were significantly decreased in cases compared to controls. The levels of non-HDL-C, low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were similar among the participants. The levels of decrease in TC and HDL were associated with whether a patient was SCD-SS or SCD-SC. Systolic blood pressure and diastolic blood pressure were each significantly associated with increased VLDL [SBP, p = 0.01, OR: 0.74 (CI: 0.6-0.93); DBP, p = 0.023, OR: 1.45 (CI: 1.05-2.0)]. Conclusion. Dyslipidemia is common among participants in this study. It was more pronounced in the SCD-SS than in SCD-SC. This dyslipidemia was associated with high VLDL as well as increased SBP and DBP.
| S-EPMC5203913 | biostudies-literature
Project description:A low level of high density lipoprotein cholesterol (HDL-C) is a powerful risk factor for cardiovascular disease. However, despite the reported key role of apolipo-proteins, specifically, apoA-I, in HDL metabolism, lipid molecular composition of HDL particles in subjects with high and low HDL-C levels is currently unknown. Here lipidomics was used to study HDL derived from well-characterized high and low HDL-C subjects. Low HDL-C subjects had elevated triacylglycerols and diminished lysophosphatidylcholines and sphingomyelins. Using information about the lipid composition of HDL particles in these two groups, we reconstituted HDL particles in silico by performing large-scale molecular dynamics simulations. In addition to confirming the measured change in particle size, we found that the changes in lipid composition also induced specific spatial distributions of lipids within the HDL particles, including a higher amount of triacylglycerols at the surface of HDL particles in low HDL-C subjects. Our findings have important implications for understanding HDL metabolism and function. For the first time we demonstrate the power of combining molecular profiling of lipoproteins with dynamic modeling of lipoprotein structure.
| S-EPMC2903811 | biostudies-other
Project description:Plasma membrane cholesterol is required for proper trafficking and localization of receptors that facilitate severe acute respiratory syndrome coronavirus 2 infection. High-density lipoproteins (HDL) mobilize plasma membrane cholesterol, and HDL-cholesterol levels are associated with the severity of COVID-19 disease and mortality. However, HDL-cholesterol levels poorly reflect the function of this complex family of particles, and a detailed assessment of COVID-19-associated changes in HDL functionality and its prognostic value is lacking. In the present study, we assessed HDL cholesterol efflux capacity, HDL anti-inflammatory and antioxidant properties, and changes in HDL composition and metabolism in COVID-19 (n = 48) and non-COVID pneumonia patients (n = 32). COVID-19 infection markedly reduced the activity of lecithin-cholesteryl-acyltransferase and functional parameters of HDL, such as the cholesterol efflux capacity, arylesterase activity of paraoxonase 1, and anti-oxidative capacity of apoB-depleted serum when compared to non-COVID pneumonia at baseline, paralleled by markedly reduced levels of HDL-cholesterol. Of particular interest, low HDL cholesterol efflux capacity was associated with increased mortality risk in COVID-19 patients, independent of HDL-C levels. Our results highlight profound effects of COVID-19 infection on HDL function, metabolism, and composition. Low HDL cholesterol efflux capacity indicates a fatal course of COVID-19, independent of HDL-cholesterol levels.
| S-EPMC9598682 | biostudies-literature
Project description:Purpose of the reviewTo evaluate recent studies related to the paradox of high HDL-C with mortality and atherosclerotic cardiovascular disease (ASCVD) risk.Recent findingsTwo observational studies (Cardiovascular Health in Ambulatory Care Research Team [CANHEART] and Copenhagen City Heart Study and the Copenhagen General Population Study [Copenhagen Heart Studies]) of adults without pre-existing ASCVD have shown a significant U-shaped association of HDL-C with all-cause and cause-specific mortality. Both studies showed that low HDL-C levels consistently increased hazard risk (HR) for all-cause and cause-specific mortality. In the CANHEART study, high HDL-C levels, HDL-C >?90 mg/dL, were associated with increased HR for non-CVD/non-cancer mortality. In the Copenhagen Heart Studies, women with HDL-C ??135 mg/dL showed increased HR for all-cause and CVD mortality, while men with HDL-C?>?97 mg/dL showed increased HR for all-cause and CVD mortality. Genetic association studies failed to show that genetic etiologies of high HDL-C significantly reduced risk for myocardial infarction (MI), while hepatocyte nuclear factor-4 (HNF4A) was significantly associated with high HDL-C and increased MI risk. Candidate gene studies have identified scavenger receptor B class I (SCARB1) and lymphocyte activation gene-3 (LAG3) as genes significantly associated with high HDL-C and increased MI risk. Low HDL-C remains as a significant factor for increased disease risk while high HDL-C levels are not associated with cardioprotection. Clinical CVD risk calculators need revision.
| S-EPMC7782461 | biostudies-literature
Project description:OBJECTIVE:To characterize the fate of protein and lipid in nascent HDL (high-density lipoprotein) in plasma and explore the role of interaction between nascent HDL and mature HDL in promoting ABCA1 (ATP-binding cassette transporter 1)-dependent cholesterol efflux. Approach and Results: Two discoidal species, nascent HDL produced by RAW264.7 cells expressing ABCA1 (LpA-I [apo AI containing particles formed by incubating ABCA1-expressing cells with apo AI]), and CSL112, human apo AI (apolipoprotein AI) reconstituted with phospholipids, were used for in vitro incubations with human plasma or purified spherical plasma HDL. Fluorescent labeling and biotinylation of HDL were employed to follow the redistribution of cholesterol and apo AI, cholesterol efflux was measured using cholesterol-loaded cells. We show that both nascent LpA-I and CSL112 can rapidly fuse with spherical HDL. Redistribution of the apo AI molecules and cholesterol after particle fusion leads to the formation of (1) enlarged, remodeled, lipid-rich HDL particles carrying lipid and apo AI from LpA-I and (2) lipid-poor apo AI particles carrying apo AI from both discs and spheres. The interaction of discs and spheres led to a greater than additive elevation of ABCA1-dependent cholesterol efflux. CONCLUSIONS:These data demonstrate that although newly formed discs are relatively poor substrates for ABCA1, they can interact with spheres to produce lipid-poor apo AI, a much better substrate for ABCA1. Because the lipid-poor apo AI generated in this interaction can itself become discoid by the action of ABCA1, cycles of cholesterol efflux and disc-sphere fusion may result in net ABCA1-dependent transfer of cholesterol from cells to HDL spheres. This process may be of particular importance in atherosclerotic plaque where cholesterol acceptors may be limiting.
| S-EPMC7176342 | biostudies-literature
Project description:Objective: Chronic kidney disease (CKD) and cardiovascular disease (CVD) have a high morbidity and mortality among the elderly. Low levels of high-density lipoprotein cholesterol (HDL-C), a traditional risk marker for CVD, are common in CKD patients. Little is known about the association of low HDL-C with renal dysfunction in the community dwelling population. Methods: This was a population-based cross-sectional study included 4,753 participants enrolled in a prospective study, the Shanghai Elderly Cardiovascular Health (SHECH) study. Estimated glomerular filtration rate (eGFR), calculated by the Chinese Modification of Diet in Renal Disease (C-MDRD equation), was used to assess renal dysfunction. Associations between renal dysfunction and low HDL-C were evaluated using multiple logistic regression models and restricted cubic splines. Results: Of 4,649 individuals who met inclusion criteria, 620 (13.34%) had low HDL-C at <40 mg/dl. In the fully adjusted model, lower eGFR of <60 ml/min/1.73 m2 (OR, 2.03; 95% CI, 1.21-3.43) and marginal eGFR of 60 to 90 ml/min/1.73 m2 (OR, 1.26; 95% CI, 1.01-1.58) were significantly associated with low HDL-C, compared with normal eGFR of ≥90 ml/min/1.73 m2. Moreover, consistent findings were obtained in subsidiary analyses using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Fully adjusted cubic spline models indicated a significant dose-response relationship between eGFR and low HDL-C (P for non-linearity, 0.356). Conclusion: In this general elderly population, renal dysfunction was independently and significantly associated with low HDL-C, and the prevalence of low HDL-C increased with decreasing eGFR, such that even slight changes in renal function may be associated with altered lipid levels.
| S-EPMC8149893 | biostudies-literature
Project description:Background & aimsDysmetabolic conditions could drive liver fibrosis in patients with non-alcoholic fatty liver disease (NAFLD), increasing susceptibility to hepatocellular carcinoma (HCC). We therefore aimed to identify novel predictive biomarkers of HCC in patients with and without liver fibrosis.MethodsA total of 1,234 patients with putative metabolic conditions and NAFLD were consecutively assessed in our outpatient clinic. Clinical and biochemical data were recorded, and then liver ultrasonography was performed annually for 5 years to detect HCC onset. For the analysis, the population was first divided according to HCC diagnosis; then a further subdivision of those who did not develop HCC was performed based on the presence or absence of liver fibrosis at time 0.ResultsSixteen HCC cases were recorded in 5 years. None of our patients had been diagnosed with cirrhosis before HCC was detected. Compared to patients who did not develop HCC, those who did had higher liver transaminases and fibrosis scores at time 0 (p <0.001). In addition, they presented with increased glycated haemoglobin levels and lower 25-OH vitamin D levels (p <0.05). Intriguingly, patients with higher liver fibrosis scores who subsequently developed HCC had lower HDL-cholesterol (HDL-c) levels at time 0 (p <0.001). Furthermore, in the 484 patients presenting with lower HDL-c at baseline, we found that waist circumference, and then vitamin D and glycated haemoglobin levels, were significantly different in those who developed HCC, regardless of liver fibrosis (p <0.05).ConclusionsThis study identifies HDL-c as a bona fide novel marker to predict HCC in patients with NAFLD. Increased waist circumference and deranged metabolic pathways represent additional predisposing factors among patients with low HDL-c, highlighting the importance of studying cholesterol metabolism and integrating clinical approaches with dietary regimens and a healthy lifestyle to prevent HCC.Impact and implicationsVisceral adiposity and its associated conditions, such as chronic inflammation and insulin resistance, may play a pivotal role in hepatocellular carcinoma development in patients with non-alcoholic fatty liver disease. We provide new insights on the underlying mechanisms of its pathogenesis, shedding light on the involvement of low levels of "good" HDL-cholesterol. We recommend integrating dietary regimens and advice on healthy lifestyles into the clinical management of non-alcoholic fatty liver disease, with the goal of reducing the incidence of hepatocellular carcinoma.
| S-EPMC9763866 | biostudies-literature