Potent peroxisome proliferator-activated receptor-  agonist treatment increases cholesterol efflux capacity in humans with the metabolic syndrome

Khera, Amit; Millar, John S.; Ruotolo, Giacomo; Wang, Ming Dauh; Rader, Daniel J.

doi:10.1093/eurheartj/ehv291

Cited by 31 publications

(19 citation statements)

References 8 publications

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“…Interestingly, under treatment with LY518674 the changes in ABCA1-mediated cholesterol efflux capacity and apoA-I production were found to correlate with one another. 179 In mice transgenic for human apoA-I, treatment with gemfibrozil or fenofibrate increased the reverse transport from macrophages to feces. 185 The effect of fibrate treatment on the anti-oxidative, anti-inflammatory, or endothelial functionality of HDL has been less extensively investigated.…”

Section: Fibratesmentioning

confidence: 99%

“…178 Also in the absence of statins, this subgroup appears to benefit over-proportionately from treatment with bezafibrate or gemfibrozil. 178 Treatment of patients with fenofibrate, bezafibrate, ciprofibrate, or the potent and selective PPAR-α agonist LY518674 increased the capacity of total or apoB-free plasma to release cholesterol from macrophages in some studies, [179][180][181][182][183] but not in others. 170,184 Potential reasons are differences in patient populations and cholesterol efflux assays.…”

Section: Fibratesmentioning

confidence: 99%

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Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

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Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary heart disease. HDL mediates cholesterol efflux from macrophages for reverse transport to the liver and elicits many anti-inflammatory and anti-oxidative activities which are potentially antiatherogenic. Nevertheless, HDL has not been successfully targeted by drugs for prevention or treatment of cardiovascular diseases. One potential reason is the targeting of HDL cholesterol which does not capture the structural and functional complexity of HDL particles. Hundreds of lipid species and dozens of proteins as well as several microRNAs have been identified in HDL. This physiological heterogeneity is further increased in pathologic conditions due to additional quantitative and qualitative molecular changes of HDL components which have been associated with both loss of physiological function and gain of pathologic dysfunction. This structural and functional complexity of HDL has prevented clear assignments of molecules to the functions of normal HDL and dysfunctions of pathologic HDL. Systematic analyses of structure-function relationships of HDL-associated molecules and their modifications are needed to test the different components and functions of HDL for their relative contribution in the pathogenesis of atherosclerosis. The derived biomarkers and targets may eventually help to exploit HDL for treatment and diagnostics of cardiovascular diseases.

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Section: Fibratesmentioning

confidence: 99%

Section: Fibratesmentioning

confidence: 99%

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

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“…Our observation that GLP-1 decreased miR-19b and enhanced ABCA1 mRNA and protein levels suggests that the peptide regulates cholesterol homeostasis in multiple ways. PPAR-α, an important transcriptional regulator of genes involved in lipid metabolism [45,46], was not affected by GLP-1, suggesting that PPAR-α expression cannot account for the alteration of ABCA1 with GLP-1 treatment.…”

Section: Discussionmentioning

confidence: 97%

Glucagon-Like Peptide-1 Modulates Cholesterol Homeostasis by Suppressing the miR-19b-Induced Downregulation of ABCA1

Yao¹,

Li²,

Wang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Abnormal regulation of cholesterol homeostasis is associated with type 2 diabetes mellitus (T2DM) and multiple other diseases. Glucagon-like peptide-1 (GLP-1) has unique effects on modulating hepatic lipid metabolism. However, the mechanism behind these is largely unknown. The aim of this study was to investigate the effects of GLP-1 on cholesterol-induced lipotoxicity in hepatocytes and examine the underlying mechanisms. Methods: Cell viability was determined by CCK-8. Caspase-3 detection was used to assess the effects of GLP-1 on cholesterol-induced apoptosis. TNF-α and IL-6 as the inflammatory markers were measured by ELISA. The alterations of miR-19b and ATP-binding cassette transporter A1 (ABCA1) resulting from high-fat diet/cholesterol incubation or GLP-1 were detected by real-time PCR and western blot. Results: GLP-1 markedly up-regulated the expression of ABCA1 protein, but didn’t affect peroxisome proliferator-activated receptor α (PPAR-α) protein. The miR-19b levels were significantly down-regulated in GLP-1-treated groups. The inhibition and overexpression of miR-19b were established to explore the effects of a GLP-1-mediated alteration in miR-19b. Cholesterol transport assays revealed that treatment with GLP-1 alone or together with miR-19b inhibitor significantly enhanced ABCA1-dependent cholesterol efflux, resulting in reduced total cholesterol. Further, histological examination was used to detect lipid accumulation. Cholesterol significantly attenuated cell viability, promoted hepatic cell apoptosis, and facilitated lipid accumulation, and these effects could be reversed by GLP-1. Conclusion: GLP-1 may affect cholesterol homeostasis by regulating the expression of miR-19b and ABCA1.

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“…Most importantly, therapies that improve CEC, such as reconstituted HDL, 35,36 apoA-I mimetic peptides or fibrates, 37 may benefit cardiac transplant patients through both lipid and immune-modulating mechanisms. Prospective studies are needed to elucidate the specific mechanisms by which increasing CEC may protect this vulnerable group of patients.…”

Section: Discussionmentioning

confidence: 99%

Cholesterol efflux capacity of high-density lipoprotein correlates with survival and allograft vasculopathy in cardiac transplant recipients

Javaheri

Molina

Zamani

et al. 2016

The Journal of Heart and Lung Transplantation

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BACKGROUND Cardiac allograft vasculopathy (CAV) is a major cause of mortality after cardiac transplantation. High-density lipoprotein (HDL) cholesterol efflux capacity (CEC) is inversely associated with coronary artery disease. In 2 independent studies, we tested the hypothesis that reduced CEC is associated with mortality and disease progression in CAV. METHODS We tested the relationship between CEC and survival in a cohort of patients with CAV (n = 35). Multivariable Cox proportional hazard models demonstrated that higher levels of CEC were associated with improved survival (hazard ratio 0.26, 95% confidence interval 0.11 to 0.63) per standard deviation CEC, p = 0.002). To determine whether reduced CEC is associated with CAV progression, we utilized samples from the Clinical Trials in Organ Transplantation 05 (CTOT05) study to determine the association between CEC and CAV progression and status at 1 year (n = 81), as assessed by average change in maximal intimal thickness (MIT) on intravascular ultrasound. RESULTS Patients who developed CAV had reduced CEC at baseline and 1-year post-transplant. We observed a significant association between pre-transplant CEC and the average change in MIT, particularly among patients who developed CAV at 1 year (β = −0.59, p = 0.02, R2 = 0.35). CONCLUSION Reduced CEC is associated with disease progression and mortality in CAV patients. These findings suggest the hypothesis that interventions to increase CEC may be useful in cardiac transplant patients for prevention or treatment of CAV.

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Potent peroxisome proliferator-activated receptor- agonist treatment increases cholesterol efflux capacity in humans with the metabolic syndrome

Cited by 31 publications

References 8 publications

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Glucagon-Like Peptide-1 Modulates Cholesterol Homeostasis by Suppressing the miR-19b-Induced Downregulation of ABCA1

Cholesterol efflux capacity of high-density lipoprotein correlates with survival and allograft vasculopathy in cardiac transplant recipients

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