scholarly journals HDL and Glut1 inhibition reverse a hypermetabolic state in mouse models of myeloproliferative disorders

2013 ◽  
Vol 210 (2) ◽  
pp. 339-353 ◽  
Author(s):  
Emmanuel L. Gautier ◽  
Marit Westerterp ◽  
Neha Bhagwat ◽  
Serge Cremers ◽  
Alan Shih ◽  
...  
Keyword(s):  
Mouse Models ◽  
Cholesterol Efflux ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Myeloproliferative Disorders ◽  
Tissue Loss ◽  
Human Leukemia ◽  
Glut1 Expression ◽  
Underlying Mechanisms

A high metabolic rate in myeloproliferative disorders is a common complication of neoplasms, but the underlying mechanisms are incompletely understood. Using three different mouse models of myeloproliferative disorders, including mice with defective cholesterol efflux pathways and two models based on expression of human leukemia disease alleles, we uncovered a mechanism by which proliferating and inflammatory myeloid cells take up and oxidize glucose during the feeding period, contributing to energy dissipation and subsequent loss of adipose mass. In vivo, lentiviral inhibition of Glut1 by shRNA prevented myeloproliferation and adipose tissue loss in mice with defective cholesterol efflux pathway in leukocytes. Thus, Glut1 was necessary to sustain proliferation and potentially divert glucose from fat storage. We also showed that overexpression of the human ApoA-I transgene to raise high-density lipoprotein (HDL) levels decreased Glut1 expression, dampened myeloproliferation, and prevented fat loss. These experiments suggest that inhibition of Glut-1 and HDL cholesterol–raising therapies could provide novel therapeutic approaches to treat the energy imbalance observed in myeloproliferative disorders.

scholarly journals Roles of Reconstituted High-Density Lipoprotein Nanoparticles in Cardiovascular Disease: A New Paradigm for Drug Discovery

2020 ◽  
Vol 21 (3) ◽  
pp. 739 ◽  
Author(s):  
Jiansheng Huang ◽  
Dongdong Wang ◽  
Li-Hao Huang ◽  
Hui Huang
Keyword(s):  
Cardiovascular Disease ◽  
High Density Lipoprotein ◽  
Cholesterol Efflux ◽  
Density Lipoprotein ◽  
Inverse Correlation ◽  
Hdl Cholesterol ◽  
High Density ◽  
Atherosclerotic Cardiovascular Disease ◽  
New Paradigm

Epidemiological results revealed that there is an inverse correlation between high-density lipoprotein (HDL) cholesterol levels and risks of atherosclerotic cardiovascular disease (ASCVD). Mounting evidence supports that HDLs are atheroprotective, therefore, many therapeutic approaches have been developed to increase HDL cholesterol (HDL-C) levels. Nevertheless, HDL-raising therapies, such as cholesteryl ester transfer protein (CETP) inhibitors, failed to ameliorate cardiovascular outcomes in clinical trials, thereby casting doubt on the treatment of cardiovascular disease (CVD) by increasing HDL-C levels. Therefore, HDL-targeted interventional studies were shifted to increasing the number of HDL particles capable of promoting ATP-binding cassette transporter A1 (ABCA1)-mediated cholesterol efflux. One such approach was the development of reconstituted HDL (rHDL) particles that promote ABCA1-mediated cholesterol efflux from lipid-enriched macrophages. Here, we explore the manipulation of rHDL nanoparticles as a strategy for the treatment of CVD. In addition, we discuss technological capabilities and the challenge of relating preclinical in vivo mice research to clinical studies. Finally, by drawing lessons from developing rHDL nanoparticles, we also incorporate the viabilities and advantages of the development of a molecular imaging probe with HDL nanoparticles when applied to ASCVD, as well as gaps in technology and knowledge required for putting the HDL-targeted therapeutics into full gear.

Abstract P216: The Association Between Reduction in Inflammation and Changes in Lipoprotein Levels and HDL Cholesterol Efflux Capacity in Rheumatoid Arthritis

Circulation ◽  
2015 ◽  
Vol 131 (suppl_1) ◽  
Author(s):  
Katherine Liao ◽  
Martin Playford ◽  
Michelle Frits ◽  
Jonathan Coblyn ◽  
Christine Iannaccone ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Apparent Paradox ◽  
Cholesterol Efflux Capacity ◽  
Academic Center ◽  
One Year

Background: Potent anti-inflammatory RA treatments are associated with reduced cardiovascular (CV) risk as well as increases in low density lipoprotein (LDL). This apparent paradox may be explained by favorable changes in other lipid measurements. The objective of this study was to determine the longitudinal association between changes in inflammation with advanced lipoprotein measurements and HDL cholesterol efflux capacity. Methods and Results: We conducted this study in a longitudinal RA cohort from a large academic center. We included subjects with hsCRP reduction ≥10mg/L at two time points one year apart. Subjects on statins during the study period or 6 months prior were excluded. We measured total cholesterol (TC), LDL, high density lipoprotein (HDL), apolipoprotein B (apoB), apoA1, and HDL cholesterol efflux capacity at baseline and one year follow-up. We determined the correlations between reduction in hsCRP and change in lipid parameters using the Pearson test. We studied 90 RA subjects, mean age 57 years, 89% female, all subjects were on disease modifying anti-rheumatic drugs; median baseline hsCRP was 28.6mg/L and follow-up 4.3 mg/L (reduction of 85%, p<0.0001). We observed significant correlations between a reduction in hsCRP with increases in LDL (r=0.25,p=0.02, Figure 1a), HDL (r=0.23, p=0.03), apoA1 (r=0.27, p=0.01 and HDL cholesterol efflux capacity (r=0.24, p=0.02), an overall improvement of efflux capacity of 5.7% (p=5x10 -4 , Figure 1b). Conclusion: Reduction in inflammation was associated increased LDL levels, and concomitant increases in HDL, ApoA1, and improvements in HDL cholesterol efflux capacity. These findings provide further insight into lipid modulation and the beneficial effect of reduction in inflammation on lipids in vivo.

scholarly journals Assessing HDL Metabolism in Subjects with Elevated Levels of HDL Cholesterol and Coronary Artery Disease

Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 6862
Author(s):  
William Hancock-Cerutti ◽  
John S. Millar ◽  
Silvia Valentini ◽  
Jason Liu ◽  
Jeffrey T. Billheimer ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Cholesterol Efflux ◽  
Ex Vivo ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Fractional Clearance ◽  
Artery Disease ◽  
Pool Sizes

High-density lipoprotein cholesterol (HDL-C) is thought to be atheroprotective yet some patients with elevated HDL-C levels develop cardiovascular disease, possibly due to the presence of dysfunctional HDL. We aimed to assess the metabolic fate of circulating HDL particles in patients with high HDL-C with and without coronary artery disease (CAD) using in vivo dual labeling of its cholesterol and protein moieties. We measured HDL apolipoprotein (apo) A-I, apoA-II, free cholesterol (FC), and cholesteryl ester (CE) kinetics using stable isotope-labeled tracers (D3-leucine and 13C2-acetate) as well as ex vivo cholesterol efflux to HDL in subjects with (n = 6) and without (n = 6) CAD that had HDL-C levels >90th percentile. Healthy controls with HDL-C within the normal range (n = 6) who underwent the same procedures were used as the reference. Subjects with high HDL-C with and without CAD had similar plasma lipid levels and similar apoA-I, apoA-II, HDL FC, and CE pool sizes with no significant differences in fractional clearance rates (FCRs) or production rates (PRs) of these components between groups. Subjects with high HDL-C with and without CAD also had similar basal and cAMP-stimulated ex vivo cholesterol efflux to HDL. When all subjects were considered (n = 18), unstimulated non-ABCA1-mediated efflux (but not ABCA1-specific efflux) was correlated positively with apoA-I production (r = 0.552, p = 0.017) and HDL FC and CE pool sizes, and negatively with the fractional clearance rate of FC (r = −0.759, p = 4.1 × 10−4) and CE (r = −0.652, p = 4.57 × 10−3). Our data are consistent with the concept that ex vivo non-ABCA1 efflux capacity may correlate with slower in vivo turnover of HDL cholesterol moieties. The use of a dual labeling protocol provided for the first time the opportunity to assess the association of ex vivo cholesterol efflux capacity with in vivo HDL cholesterol metabolic parameters.

scholarly journals High Density Lipoprotein Cholesterol Efflux Capacity and Atherosclerosis in Cardiovascular Disease: Pathophysiological Aspects and Pharmacological Perspectives

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 574
Author(s):  
Maria Pia Adorni ◽  
Nicoletta Ronda ◽  
Franco Bernini ◽  
Francesca Zimetti
Keyword(s):  
High Density Lipoprotein ◽  
Cholesterol Efflux ◽  
Current Knowledge ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
High Density ◽  
Current Evidence ◽  
Endocrine Disorders ◽  
Lifestyle Modifications ◽  
Cholesterol Efflux Capacity

Over the years, the relationship between high-density lipoprotein (HDL) and atherosclerosis, initially highlighted by the Framingham study, has been revealed to be extremely complex, due to the multiple HDL functions involved in atheroprotection. Among them, HDL cholesterol efflux capacity (CEC), the ability of HDL to promote cell cholesterol efflux from cells, has emerged as a better predictor of cardiovascular (CV) risk compared to merely plasma HDL-cholesterol (HDL-C) levels. HDL CEC is impaired in many genetic and pathological conditions associated to high CV risk such as dyslipidemia, chronic kidney disease, diabetes, inflammatory and autoimmune diseases, endocrine disorders, etc. The present review describes the current knowledge on HDL CEC modifications in these conditions, focusing on the most recent human studies and on genetic and pathophysiologic aspects. In addition, the most relevant strategies possibly modulating HDL CEC, including lifestyle modifications, as well as nutraceutical and pharmacological interventions, will be discussed. The objective of this review is to help understanding whether, from the current evidence, HDL CEC may be considered as a valid biomarker of CV risk and a potential pharmacological target for novel therapeutic approaches.

scholarly journals Effect of Dietary Carbohydrate Type on Serum Cardiometabolic Risk Indicators and Adipose Tissue Inflammatory Markers

2018 ◽  
Vol 103 (9) ◽  
pp. 3430-3438 ◽  
Author(s):  
Huicui Meng ◽  
Nirupa R Matthan ◽  
Susan K Fried ◽  
Silvia Berciano ◽  
Maura E Walker ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Cholesterol Efflux ◽  
Cardiometabolic Risk ◽  
Ex Vivo ◽  
Inflammatory Marker ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Risk Indicators ◽  
Dietary Carbohydrate ◽  
Fasting Serum

Abstract Context and Objective Direct comparisons between types of dietary carbohydrate in terms of cardiometabolic risk indicators are limited. This study was designed to compare the effects of an isocaloric exchange of simple, refined, and unrefined carbohydrates on serum cardiometabolic risk indicators, adipose tissue inflammatory markers, and peripheral blood mononuclear cell (PBMC) fractional cholesterol efflux. Design, Participants, and Measures Participants [postmenopausal women and men (N = 11), 65 ± 8 years, body mass index 29.8 ± 3.2 kg/m2, low-density lipoprotein (LDL) cholesterol ≥2.6 mmol/L] were provided with diets (60% energy from total carbohydrate, 15% from protein, 25% from fat) for 4.5 weeks in a randomized crossover design, with 2-week washout periods. The variable component was an isocaloric exchange of simple, refined, or unrefined carbohydrate–containing foods. Serum lipoprotein, glucose, insulin, and inflammatory marker concentrations were measured. Abdominal subcutaneous adipose tissue was aspirated to assess macrophage and inflammatory marker gene expression and ex vivo cytokine secretion, and PBMCs were isolated to assess ex vivo fractional cholesterol efflux. Results Fasting serum LDL and non–high-density lipoprotein (HDL) cholesterol concentrations were higher after the refined compared with simple or unrefined carbohydrate–enriched diets (P &lt; 0.01). Other serum measures, ex vivo fractional cholesterol efflux and adipose tissue gene expression and ex vivo cytokine secretion, were similar between diets. Conclusions Diets enriched in refined compared with simple or unrefined carbohydrate resulted in higher fasting serum LDL and non-HDL cholesterol concentrations but had little effect on other cardiometabolic risk indicators. This small study raises the intriguing possibility that refined carbohydrate may have unique adverse effects on cardiometabolic risk indicators distinct from simple and unrefined carbohydrate.

scholarly journals Fibroblast cholesterol efflux to plasma from metabolic syndrome subjects is not defective despite low high-density lipoprotein cholesterol

2008 ◽  
Vol 158 (1) ◽  
pp. 53-60 ◽  
Author(s):  
Robin P F Dullaart ◽  
Albert K Groen ◽  
Geesje M Dallinga-Thie ◽  
Rindert de Vries ◽  
Wim J Sluiter ◽  
...  
Keyword(s):  
Metabolic Syndrome ◽  
High Density Lipoprotein ◽  
Cholesterol Efflux ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Cholesterol Esterification ◽  
Cellular Cholesterol ◽  
Apo E ◽  
Pltp Activity ◽  
Cellular Cholesterol Efflux

ObjectiveWe tested whether in metabolic syndrome (MetS) subjects the ability of plasma to stimulate cellular cholesterol efflux, an early step in the anti-atherogenic reverse cholesterol transport pathway, is maintained despite low high-density lipoprotein (HDL) cholesterol.DesignIn 76 subjects with and 94 subjects without MetS based on the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria, we determined plasma (apo)lipoproteins, pre-β-HDL formation, phospholipid transfer protein (PLTP) activity, cholesterol esterification (EST), cholesteryl ester transfer (CET), adiponectin, and the ability of plasma from each subject to stimulate cholesterol efflux out of cultured fibroblasts obtained from a single donor.ResultsApo E, PLTP activity, EST, and CET were higher (P=0.04 to <0.001), whereas adiponectin was lower in MetS subjects (P<0.01). Pre-β-HDL and pre-β-HDL formation were not different between subjects with and without MetS. Cellular cholesterol efflux to plasma from MetS subjects was slightly higher versus plasma from subjects without MetS (8.8±1.0 vs 8.5±0.9%,P=0.05), but the difference was not significant after age, sex, and diabetes adjustment. Cellular cholesterol efflux was positively related to pre-β-HDL formation, EST, PLTP activity, and apo E (P<0.05 for all by multiple linear regression analysis), without an independent association with MetS and diabetes status.ConclusionsThe ability of plasma from MetS subjects to promote fibroblast cholesterol efflux is not defective, although HDL cholesterol is decreased. Higher cholesterol esterification, PLTP activity, and apo E levels may contribute to the maintenance of cholesterol efflux in MetS.

scholarly journals Promoter-Specific Roles for Liver X Receptor/Corepressor Complexes in the Regulation of ABCA1 and SREBP1 Gene Expression

2003 ◽  
Vol 23 (16) ◽  
pp. 5780-5789 ◽  
Author(s):  
Brandee L. Wagner ◽  
Annabel F. Valledor ◽  
Gang Shao ◽  
Chris L. Daige ◽  
Eric D. Bischoff ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Hormone Receptors ◽  
Target Genes ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Whole Body ◽  
Abca1 Gene ◽  
Element Binding Protein ◽  
X Receptors

ABSTRACT Liver X receptors (LXRs) regulate the expression of genes involved in cholesterol and fatty acid homeostasis, including the genes for ATP-binding cassette transporter A1 (ABCA1) and sterol response element binding protein 1 (SREBP1). Loss of LXR leads to derepression of the ABCA1 gene in macrophages and the intestine, while the SREBP1c gene remains transcriptionally silent. Here we report that high-density-lipoprotein (HDL) cholesterol levels are increased in LXR-deficient mice, suggesting that derepression of ABCA1 and possibly other LXR target genes in selected tissues is sufficient to result in enhanced HDL biogenesis at the whole-body level. We provide several independent lines of evidence indicating that the repressive actions of LXRs are dependent on interactions with the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoic acid and thyroid hormone receptors (SMRT). While dissociation of NCoR and SMRT results in derepression of the ABCA1 gene in macrophages, it is not sufficient for derepression of the SREBP1c gene. These findings reveal differential requirements for corepressors in the regulation of genes involved in cholesterol and fatty acid homeostasis and raise the possibility that these interactions may be exploited to develop synthetic ligands that selectively modulate LXR actions in vivo.

Abstract 76: MicroRNA-144 Regulates Hepatic ABCA1 and Plasma HDL Following Activation of the Nuclear Receptor FXR

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Thomas Vallim ◽  
Elizabeth Tarling ◽  
Tammy Kim ◽  
Mete Civelek ◽  
Angel Baldan ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Nuclear Receptor ◽  
Molecular Mechanisms ◽  
Lipoprotein Metabolism ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Farnesoid X Receptor ◽  
Abca1 Protein

Rationale The bile acid receptor Farnesoid-X-Receptor (FXR) regulates many aspects of lipid metabolism by various complex and not fully understood molecular mechanisms. We set out to investigate the molecular mechanisms for FXR-dependent regulation of lipid and lipoprotein metabolism. Objective To identify FXR-regulated microRNAs that were subsequently involved in regulating lipid metabolism. Methods and Results ATP binding cassette transporter A1 (ABCA1) is a major determinant of plasma High Density Lipoprotein (HDL)-cholesterol levels. Here we show that activation of the nuclear receptor FXR in vivo increases hepatic levels of miR-144, which in turn lower hepatic ABCA1 and plasma HDL levels. We identified two complementary sequences to miR-144 in the 3’ untranslated region (UTR) of ABCA1 mRNA that are necessary for miR-144-dependent regulation. Overexpression of miR-144 in vitro decreased both cellular ABCA1 protein and cholesterol efflux to lipid-poor apolipoprotein A-I (ApoA-I) protein, whilst overexpression in vivo reduced hepatic ABCA1 protein and plasma HDL- cholesterol. Conversely, silencing miR-144 in mice increased hepatic ABCA1 protein and HDL- cholesterol. In addition, we utilized tissue-specific FXR deficient mice to show that induction of miR-144 and FXR-dependent hypolipidemia requires hepatic, but not intestinal FXR. Finally, we identified functional FXR response elements (FXREs) upstream of the miR-144 locus, consistent with direct FXR regulation. Conclusion In conclusion, we have identified a pathway involving FXR, miR-144 and ABCA1 that together regulate plasma HDL cholesterol. This pathway may be therapeutically targeted in the future in order to increase HDL levels.

Abstract 5: Lipid Droplet Associated Hydrolase: A New Player in Cholesterol Mobilization From Foam Cells

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Younghwa Goo ◽  
Pradip Saha ◽  
Larry Chan ◽  
Antoni Paul
Keyword(s):  
Lipid Droplet ◽  
Cholesterol Efflux ◽  
Bone Marrow Cells ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Foam Cells ◽  
Peritoneal Macrophages ◽  
Cholesterol Homeostasis

Lipid laden macrophages/foam cells are a hallmark of atherosclerotic lesions from early to late stages of development. Macrophages take-up modified low-density lipoprotein (mLDL) particles and store surplus mLDL-derived cholesterol as cholesterol ester (CE) in cytoplasmic lipid droplets (LDs). Accelerating CE hydrolysis from the LDs is a plausible strategy to promote reverse cholesterol transport from the atheroma. However, the identity of the CE hydrolases that function on LDs remains unknown. Previously we identified lipid droplet-associated hydrolase (LDAH) in LDs purified from macrophages and reported that in vitro LDAH regulates CE levels by increasing CE hydrolysis. To determine the relevance of LDAH in atherogenesis, we have generated LDAH knockout (LDAH-/-) mice. Mouse peritoneal macrophages (MPM) isolated from LDAH-/- mice had increased cytoplasmic LDs, increased net CE content, and decreased cholesterol efflux. In atherosclerosis studies, both male and female LDAH-/- mice crossed with apolipoprotein E knockout (apoE-/-) mice fed a Western diet developed larger lesions. Lesions of LDAH-/-/ apoE-/- mice were characterized by increased areas of macrophages containing enlarged cytoplasms with large LDs. Supporting a direct atheroprotective role of LDAH in macrophages, lesions of apoE-/- mice that received bone marrows from LDAH-/-/apoE-/- mice progressed faster than those that received bone marrow cells from LDAH+/+/apoE-/- mice. In qPCR analyses of genes involved in cholesterol homeostasis in macrophages, we found that ABC binding cassette transporters ABCA1 and ABCG1, which mediate cholesterol efflux through the plasma membrane, were consistently decreased in LDAH-/- MPM. Further in vivo gene expression studies on macrophages selectively obtained from lesions using laser capture microdissection are underway. In conclusion, our study suggests that LDAH promotes LD CE hydrolysis and cholesterol efflux from foam cells within the atheroma, and uncovers a potential target to promote reverse cholesterol from arteries as a means of ameliorating atherosclerosis development.

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