scholarly journals Genetic control of the HDL proteome

2018 ◽  
Author(s):  
Nathalie Pamir ◽  
Calvin Pan ◽  
Deanna L. Plubell ◽  
Patrick M. Hutchins ◽  
Chongren Tang ◽  
...  
Keyword(s):  
Genetic Regulation ◽  
Interaction Network ◽  
Protein Composition ◽  
Hdl Cholesterol ◽  
Inbred Strains ◽  
High Density Lipoproteins ◽  
Functional Variation ◽  
Cis Acting ◽  
Protein Levels ◽  
Hybrid Mouse Diversity Panel

AbstractHigh-density lipoproteins (HDL) are nanoparticles with >80 associated proteins, phospholipids, cholesterol and cholesteryl esters. A comprehensive genetic analysis of the regulation of proteome of HDL isolated from a panel of 100 diverse inbred strains of mice, Hybrid Mouse Diversity Panel (HMDP), revealed widely varied HDL protein levels across the strains. Some of this variation was explained by local, cis-acting regulation, termed cis-protein quantitative trait loci. Variations in apolipoprotein A-II and apolipoprotein C-3 affected the abundance of multiple HDL proteins indicating a coordinated regulation. We identified modules of co-varying proteins and define a protein-protein interaction network describing the protein composition of the naturally occurring subspecies of HDL in mice. Sterol efflux capacity varied up to 3-fold across the strains and HDL proteins displayed distinct correlation patterns with macrophage and ABCA1 specific cholesterol efflux capacity and cholesterol exchange, suggesting that subspecies of HDL participate in discrete functions. The baseline and stimulated sterol efflux capacity phenotypes associated with distinct QTLs with smaller effect size suggesting a multi genetic regulation. Our results highlight the complexity of HDL particles by revealing high degree of heterogeneity and intercorrelation, some of which is associated with functional variation, supporting the concept that HDL-cholesterol alone is not an accurate measure of HDL’s properties such as protection against CAD.

scholarly journals Hypothalamic transcriptomes of 99 mouse strains reveal trans eQTL hotspots, splicing QTLs and novel non-coding genes

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Yehudit Hasin-Brumshtein ◽  
Arshad H Khan ◽  
Farhad Hormozdiari ◽  
Calvin Pan ◽  
Brian W Parks ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Genetic Regulation ◽  
Inbred Strains ◽  
Mouse Strains ◽  
Valuable Insight ◽  
Phenotypic Variance ◽  
Inbred Strains Of Mice ◽  
Hybrid Mouse Diversity Panel ◽  
The Many

Previous studies had shown that the integration of genome wide expression profiles, in metabolic tissues, with genetic and phenotypic variance, provided valuable insight into the underlying molecular mechanisms. We used RNA-Seq to characterize hypothalamic transcriptome in 99 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP), a reference resource population for cardiovascular and metabolic traits. We report numerous novel transcripts supported by proteomic analyses, as well as novel non coding RNAs. High resolution genetic mapping of transcript levels in HMDP, reveals both local and trans expression Quantitative Trait Loci (eQTLs) demonstrating 2 trans eQTL 'hotspots' associated with expression of hundreds of genes. We also report thousands of alternative splicing events regulated by genetic variants. Finally, comparison with about 150 metabolic and cardiovascular traits revealed many highly significant associations. Our data provide a rich resource for understanding the many physiologic functions mediated by the hypothalamus and their genetic regulation.

Environmental Factors Modifying HDL Functionality

2021 ◽  
Vol 28 ◽  
Author(s):  
Constantine E. Kosmas ◽  
Andreas Sourlas ◽  
Eliscer Guzman ◽  
Christina E. Kostara
Keyword(s):  
Environmental Factors ◽  
Cholesterol Efflux ◽  
Dietary Habits ◽  
Protein Composition ◽  
Hdl Cholesterol ◽  
Cardiovascular Effects ◽  
High Density Lipoproteins ◽  
Hdl Function ◽  
Hdl Functionality ◽  
The Impact

Background: Currently, it has been recognized that High-Density Lipoproteins (HDL) functionality plays a much more essential role in protection from atherosclerosis than circulating HDL-cholesterol (HDL-C) levels per se. Cholesterol efflux from macrophages to HDL, cholesterol efflux capacity (CEC) has been shown to be a key metric of HDL functionality. Thus, quantitative assessment of CEC may be an important tool for the evaluation of HDL functionality, as improvement of HDL function may lead to a reduction of the risk for Cardiovascular disease (CVD). Introduction: Although the cardioprotective action of HDLs is exerted mainly through their involvement in the reverse cholesterol transport (RCT) pathway, HDLs also have important anti-inflammatory, antioxidant, antiaggregatory and anticoagulant properties that contribute to their favorable cardiovascular effects. Certain genetic, pathophysiologic, disease states and environmental conditions may influence the cardioprotective effects of HDL either by inducing modifications in lipidome and/or protein composition or in the enzymes responsible for HDL metabolism. On the other hand, certain healthy habits or pharmacologic interventions may actually favorably affect HDL functionality. Method: The present review discusses the effects of environmental factors, including obesity, smoking, alcohol consumption, dietary habits, various pharmacologic interventions, as well as aerobic exercise, on HDL functionality. Result: Experimental and clinical studies or pharmacological interventions support the impact of these environmental factors in the modification of HDL functionality, although the mechanisms that are mediated are poorly understood. Conclusion: Further research should be conducted to unreal the underlying mechanisms of these environmental factors and to identify new pharmacologic interventions, capable of enhancing CEC, improving HDL functionality and potentially improving cardiovascular risk.

scholarly journals High-Density Lipoproteins and the Kidney

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 764
Author(s):  
Arianna Strazzella ◽  
Alice Ossoli ◽  
Laura Calabresi
Keyword(s):  
Kidney Disease ◽  
Renal Disease ◽  
Cholesterol Acyltransferase ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
High Density ◽  
High Density Lipoproteins ◽  
Lcat Deficiency ◽  
Progression Of Renal Disease ◽  
The Impact

Dyslipidemia is a typical trait of patients with chronic kidney disease (CKD) and it is typically characterized by reduced high-density lipoprotein (HDL)-cholesterol(c) levels. The low HDL-c concentration is the only lipid alteration associated with the progression of renal disease in mild-to-moderate CKD patients. Plasma HDL levels are not only reduced but also characterized by alterations in composition and structure, which are responsible for the loss of atheroprotective functions, like the ability to promote cholesterol efflux from peripheral cells and antioxidant and anti-inflammatory proprieties. The interconnection between HDL and renal function is confirmed by the fact that genetic HDL defects can lead to kidney disease; in fact, mutations in apoA-I, apoE, apoL, and lecithin–cholesterol acyltransferase (LCAT) are associated with the development of renal damage. Genetic LCAT deficiency is the most emblematic case and represents a unique tool to evaluate the impact of alterations in the HDL system on the progression of renal disease. Lipid abnormalities detected in LCAT-deficient carriers mirror the ones observed in CKD patients, which indeed present an acquired LCAT deficiency. In this context, circulating LCAT levels predict CKD progression in individuals at early stages of renal dysfunction and in the general population. This review summarizes the main alterations of HDL in CKD, focusing on the latest update of acquired and genetic LCAT defects associated with the progression of renal disease.

Abstract 3441: Paraoxonase-192 Polymorphism Interaction with Low HDL Cholesterol in Coronary Artery Risk

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Andreia M Pereira ◽  
Isabel M Mendonca ◽  
Ana I Freitas ◽  
Ana C Sousa ◽  
Susana Gomes ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Coronary Artery ◽  
Hdl Cholesterol ◽  
High Density Lipoproteins ◽  
Synergy Index ◽  
Attributable Proportion ◽  
Increased Risk ◽  
Low Hdl ◽  
Lower Ability ◽  
Male Sex

Background: Increased lipid peroxidation is associated with accelerated progression of atherosclerosis. Paraoxonase (PON1) is an antioxidative enzyme in high density lipoproteins (HDL), which protects against lipid per oxidation and Coronary Artery Disease (CAD). PON 1 activity is under genetic control and its molecular basis is a polymorphism in the PON 1 gene that shows two common isoforms: Q (192 Gln) with high ability to protect LDL from lipid peroxidation in vitro, and R (Arg) with lower ability. Aim: To explore the interaction of the R allele paraoxonase gene and low HDL cholesterol concentrations, in CAD risk emergence. Methods: 818 individuals participated in the study, 298 coronary patients, 55.0±10.3 years, 78.9% male sex, and 520 healthy controls, 47.3±12.6 years, 57.5% male sex, age and sex matched. Low HDL-C was defined as <0.90 mmol/L in men and < 1.11 mmol/L in the women. Comparisons of genotypes between cases and control subjects were performed by a chi-square test. Statistical significance was accepted at p<0.05. Odds ratio as well as their 95% confidence intervals for the RR genotypes and HDL deficient subjects were computed using univariate analysis (2x2 tables). To determine the interaction between the RR paraoxonase genotype and HDL-deficient subjects, we used the epidemiologic tables 4x2 and the synergy measures: the additive model (Rothman’s synergy index) and the multiplicative model (Khoury’s synergy index). We calculated the relative excess risk (RERI) and the attributable proportion (AP) due to interaction (Rothman). Results: The PON 1 RR192 is associated with coronary heart disease [OR=1.61; p=0.043] in whole population. The HDL-deficient subjects 192 RR homozygotes showed an increased risk of CAD (OR=17.38; p< 0.0001) compared to normal HDL 192 RR (OR=1.39; p=0.348) and HDL-deficient subjects not carrying RR genotype (OR=7.79; p<0.0001). The genotype PON 192 RR increases the risk of CAD in the HDL-deficient populations (SI=2.3, SIM=1.6). The attributable proportion due to this interaction (AP) was 0.53, meaning that 53% of CAD was explained by this interaction. Conclusion: These data suggest the existence of a synergistic effect of the RR 192 PON 1 genotype (with lower ability) and HDL-deficient subjects in CAD emergence.

Abstract 233: Isoproterenol-induced Cardiac Hypertrophy And Failure In Mice: Gene Network Modeling

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Christoph D Rau ◽  
Jessica Wang ◽  
Shuxun Ren ◽  
Zhihua Wang ◽  
Hongmei Ruan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Association Studies ◽  
Inbred Strains ◽  
Genome Wide Association Studies ◽  
Strong Correlations ◽  
Hotspot Analysis ◽  
Linear Relationships ◽  
Genome Wide ◽  
Echocardiographic Parameters ◽  
Hybrid Mouse Diversity Panel

Heart failure is highly heterogeneous and as a result, relatively few insights into the pathways and drivers of heart failure have been identified using system-wide methods such as genome-wide association studies (GWAS). We have developed a resource, the Hybrid Mouse Diversity Panel (HMDP) for high resolution GWAS and systems genetics in mice. Eight week old female mice from 93 unique inbred strains of the HMDP were given 20 μg/g/day of isoproterenol through an abdominally implanted Alzet micropump. Three weeks post-implantation, all mice were sacrificed, along with age-matched controls. The mice exhibited widely varying degrees of hypertrophy and heart functioning. A portion of the left ventricle was processed and arrayed on an Illumina Mouse Ref 8.0 platform. We used Maximal Information Component Analysis, a novel method of network construction which allows for non-linear relationships between genes as well as non-binary partitioning of genes into sub-networks to subdivide the expression data into a series of modules. In order to identify modules which may contribute to Isoproterenol-induced hypertrophy and failure, we examined the correlation of each module to clinically relevant cardiac traits traits such as organ weights and echocardiographic parameters. We identified several modules with strong correlations to multiple heart failure-related clinical traits, including one module of 41 genes which contained several genes of interest, including Lgals3, a diagnostic marker for heart failure. Utilizing eQTL hotspot analysis, we have identified a locus which is involved in the regulation of this module. A gene within this locus, Magi2, regulates the turnover of the β-adrenergic receptor and represents a likely candidate for the response to isoproterenol.

scholarly journals HDL-Mediated Lipid Influx to Endothelial Cells Contributes to Regulating Intercellular Adhesion Molecule (ICAM)-1 Expression and eNOS Phosphorylation

2018 ◽  
Vol 19 (11) ◽  
pp. 3394 ◽  
Author(s):  
Mónica Muñoz-Vega ◽  
Felipe Massó ◽  
Araceli Páez ◽  
Gilberto Vargas-Alarcón ◽  
Ramón Coral-Vázquez ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Adhesion Molecule ◽  
Hdl Cholesterol ◽  
Intercellular Adhesion ◽  
Intercellular Adhesion Molecule ◽  
High Density Lipoproteins ◽  
Type I ◽  
Intercellular Adhesion Molecule 1 ◽  
Apo Ai

Reverse cholesterol transport (RCT) is considered as the most important antiatherogenic role of high-density lipoproteins (HDL), but interventions based on RCT have failed to reduce the risk of coronary heart disease. In contrast to RCT, important evidence suggests that HDL deliver lipids to peripheral cells. Therefore, in this paper, we investigated whether HDL could improve endothelial function by delivering lipids to the cells. Internalization kinetics using cholesterol and apolipoprotein (apo) AI fluorescent double-labeled reconstituted HDL (rHDL), and human dermal microvascular endothelial cells-1 (HMEC-1) showed a fast cholesterol influx (10 min) and a slower HDL protein internalization as determined by confocal microscopy and flow cytometry. Sphingomyelin kinetics overlapped that of apo AI, indicating that only cholesterol became dissociated from rHDL during internalization. rHDL apo AI internalization was scavenger receptor class B type I (SR-BI)-dependent, whereas HDL cholesterol influx was independent of SR-BI and was not completely inhibited by the presence of low-density lipoproteins (LDL). HDL sphingomyelin was fundamental for intercellular adhesion molecule-1 (ICAM-1) downregulation in HMEC-1. However, vascular cell adhesion protein-1 (VCAM-1) was not inhibited by rHDL, suggesting that components such as apolipoproteins other than apo AI participate in HDL’s regulation of this adhesion molecule. rHDL also induced endothelial nitric oxide synthase eNOS S1177 phosphorylation in HMEC-1 but only when the particle contained sphingomyelin. In conclusion, the internalization of HDL implies the dissociation of lipoprotein components and a SR-BI-independent fast delivery of cholesterol to endothelial cells. HDL internalization had functional implications that were mainly dependent on sphingomyelin. These results suggest a new role of HDL as lipid vectors to the cells, which could be congruent with the antiatherogenic properties of these lipoproteins.

scholarly journals FXR activation by obeticholic acid or nonsteroidal agonists induces a human-like lipoprotein cholesterol change in mice with humanized chimeric liver

2018 ◽  
Vol 59 (6) ◽  
pp. 982-993 ◽  
Author(s):  
Romeo Papazyan ◽  
Xueqing Liu ◽  
Jingwen Liu ◽  
Bin Dong ◽  
Emily M. Plummer ◽  
...  
Keyword(s):  
Target Gene ◽  
Ldl Cholesterol ◽  
Ldl Receptor ◽  
Hdl Cholesterol ◽  
Farnesoid X Receptor ◽  
Receptor Protein ◽  
Chimeric Mice ◽  
Obeticholic Acid ◽  
Protein Levels ◽  
Mechanistic Basis

Obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist that regulates bile acid and lipid metabolism. FXR activation induces distinct changes in circulating cholesterol among animal models and humans. The mechanistic basis of these effects has been elusive because of difficulties in studying lipoprotein homeostasis in mice, which predominantly package circulating cholesterol in HDLs. Here, we tested the effects of OCA in chimeric mice whose livers are mostly composed (≥80%) of human hepatocytes. Chimeric mice exhibited a human-like ratio of serum LDL cholesterol (LDL-C) to HDL cholesterol (HDL-C) at baseline. OCA treatment in chimeric mice increased circulating LDL-C and decreased circulating HDL-C levels, demonstrating that these mice closely model the cholesterol effects of FXR activation in humans. Mechanistically, OCA treatment increased hepatic cholesterol in chimeric mice but not in control mice. This increase correlated with decreased SREBP-2 activity and target gene expression, including a significant reduction in LDL receptor protein. Cotreatment with atorvastatin reduced total cholesterol, rescued LDL receptor protein levels, and normalized serum LDL-C. Treatment with two clinically relevant nonsteroidal FXR agonists elicited similar lipoprotein and hepatic changes in chimeric mice, suggesting that the increase in circulating LDL-C is a class effect of FXR activation.

Abstract 391: Sterol Efflux Function and Protein Composition of HDL Associates With Recovery From Stroke

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Deanna Plubell ◽  
Alexandra Fenton ◽  
Clark Wayne ◽  
Neil A Zakai ◽  
Joseph F Quinn ◽  
...  
Keyword(s):  
Stroke Risk ◽  
Protein Composition ◽  
Hdl Cholesterol ◽  
Time Dependent ◽  
Stroke Recovery ◽  
Control Group ◽  
Post Stroke ◽  
Dependent Protein ◽  
Meta Analyses ◽  
The Relationship

Background: Prospective cohort studies and meta-analyses examining the relationship between HDL-cholesterol (C) and stroke are discordant and question the value of HDL-C as a marker for stroke risk prediction. Other properties of HDL-C such as cholesterol efflux capacity (CEC) and proteome, are less studied. Methods: We investigated the changes in HDL CEC and proteome to determine if they are associated with improved stroke recovery. Plasma from age- and lipid profile-matched healthy controls (N = 35) and stroke patients were collected at 24 (early, N = 35) and 96 hour (late, N = 20) post stroke, and analyzed with three independent assays to measure macrophage-mediated, ABCA1 and ABCG1-specific sterol efflux, and HDL proteome. Stroke recovery was assessed at 3 months using the Modified Rankin Scores (MRS) and the NIH Stroke Scale (NIHSS). Results: Both macrophage- and ABCG1-mediated CEC were reduced by 50% ( P <0.0001) and 20% ( P <0.038) in early and late post stroke samples, respectively, compared to the control group. Patients who had comparable or increased CEC between the two-time points exhibited lower NIHSS and MRS indicating better recovery. Proteomic analysis of HDL indicated a distinct time-dependent remodeling post stroke. Coagulation complement cascade proteins (FGB, FGA, A2M, C3) significantly increased (FDR>0.01) early and returned to control levels later, inflammation proteins (SAA1, SAA2, PON1, C4B) increased early and continued to increase. Interestingly, platelet adhesion proteins (DSG1, JUP, ITGB1, ITGA2, TUBB, DNAH3, PF4) were abundantly present in only later samples. Conclusion: 1) patients who maintain or improve HDL CEC post stroke exhibit better recovery scores, 2) post stroke HDL proteome remodeling is dynamic with distinct time-dependent protein signatures that may associate with stroke recovery.

scholarly journals The Interaction Network and Signaling Specificity of Two-Component System in Arabidopsis

2020 ◽  
Vol 21 (14) ◽  
pp. 4898
Author(s):  
Ruxue Huo ◽  
Zhenning Liu ◽  
Xiaolin Yu ◽  
Zongyun Li
Keyword(s):  
Signal Transduction ◽  
Molecular Mechanisms ◽  
Interaction Network ◽  
Response Regulators ◽  
Signaling Specificity ◽  
Protein Protein Interaction ◽  
Protein Levels ◽  
Two Component ◽  
Model Plant Arabidopsis Thaliana ◽  
External Signals

Two-component systems (TCS) in plants have evolved into a more complicated multi-step phosphorelay (MSP) pathway, which employs histidine kinases (HKs), histidine-containing phosphotransfer proteins (HPts), and response regulators (RRs) to regulate various aspects of plant growth and development. How plants perceive the external signals, then integrate and transduce the secondary signals specifically to the desired destination, is a fundamental characteristic of the MSP signaling network. The TCS elements involved in the MSP pathway and molecular mechanisms of signal transduction have been best understood in the model plant Arabidopsis thaliana. In this review, we focus on updated knowledge on TCS signal transduction in Arabidopsis. We first present a brief description of the TCS elements; then, the protein–protein interaction network is established. Finally, we discuss the possible molecular mechanisms involved in the specificity of the MSP signaling at the mRNA and protein levels.

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