PPAR-α and PPAR-γ activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway

Chinetti-Gbaguidi, Giulia; Lestavel, Sophie; Bocher,; At, Remaley; Neve, Bernadette; Torra, IP; Teissier, Elisabeth; Minnich, Anne; Jaye, Michael; Duverger, Nicholas; Hb, Brewer; Jc, Fruchart; Clavey,; Staels, Bart

doi:10.1038/83348

Cited by 1,082 publications

(776 citation statements)

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“…Further intergene expression profile correlations within blood mononuclear cells from subjects of Groups II and IV also revealed significant positive correlation between genes coding for PPARc and LXRa and this phenomenon was accompanied by a significant negative correlation between genes coding for LDLR and PPARc (Figure 3b). These observations are in conformity with the transcriptional regulatory pathways that exist between the genes coding for PPARs (a, c) and LXRa [24]. However, the observed positive correlations between PPARs (a, c) and LDLR is in contrary to the transcriptional regulatory pathways that exist between these genes.…”

Section: Discussionsupporting

confidence: 79%

Importance of blood cellular genomic profile in coronary heart disease

2005

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SummarySince receptor/transcription factor family especially peroxisome proliferator-activated receptors PPARs (a, c) and liver X receptor a (LXRa) have been recognized to play crucial role in both lipid metabolism and inflammation, the present study was addressed to explore the interrelationship between blood cellular genomic expression profile, serum lipid levels and severity of coronary heart disease (CHD) in human subjects. Based upon the demographic and laboratory data, the human subjects were divided into 4 groups. Genomic expression profile in the subjects belonging to these groups was determined by measuring the transcriptional expression of genes coding for PPARs (a, c), CD36, LXRa and low density lipoprotein receptor (LDLR) in their blood mononuclear cells. This genomic expression profile was correlated with serum lipid profile as well as with the severity of CHD (revealed by coronary angiography coupled with modified Gensini score) using standard statistical analytical methods. Further in vitro and in vivo effect of statins on such genomic profile was also explored. Although genes coding for PPARs (a, c), CD36, LDLR showed correlation with the severity of coronary atherosclerosis , blood cellular LXRa genomic profile showed conspicuous negative correlation with the severity of coronary atherosclerosis in subjects with or without hypercholesterolemia. This view was further confirmed in experiments directed to understand the effect of statins on the cellular genomic profile of PPARs (a, c) and LXRa. Based on these reported findings, we propose that blood cellular LXRa genomic profile has a protective effect against the development of CHD and hence may be of importance in devising synthetic therapeutic drugs for CHD in future.

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Section: Discussionsupporting

confidence: 79%

Importance of blood cellular genomic profile in coronary heart disease

2005

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“…The discovery of PPAR-α as the target of fibrate action has opened a renaissance for fibrates to correct the key lipoprotein abnormalities of diabetic dyslipidaemia [169]. The activation of both PPARs α and γ seems to promote the expression of ABCA1 gene via LXR activation and consequently enhance the reverse cholesterol transport [170,171]. This action explains the consistent increase of HDL cholesterol induced by thiazolidinediones (TZDs) [172].…”

Section: New Perspectives Of Lipid Management In Type 2 Diabetesmentioning

confidence: 99%

Diabetic dyslipidaemia: from basic research to clinical practice*

2003

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The recognition that the increase of plasma triglyceride rich lipoproteins (TRLs) is associated with multiple alterations of other lipoproteins species that are potentially atherogenic has expanded the picture of diabetic dyslipidaemia. The discovery of heterogeneity within major lipoprotein classes VLDL, LDL and HDL opened new avenues to reveal the specific pertubations of diabetic dyslipidaemia. The increase of large VLDL 1 particles in Type 2 diabetes initiates a sequence of events that generates atherogenic remnants, small dense LDL and small dense HDL particles. Together these components comprise the atherogenic lipid triad. Notably the malignant nature of diabetic dyslipidaemia is not completely shown by the lipid measures used in clinical practice. The key question is what are the mechanisms behind the increase of VLDL 1 particles in diabetic dyslipidaemia? Despite the advances of recent years, our understanding of VLDL assembly and secretion is still surprisingly incomplete. To date it is still unclear how the liver is able to regulate the amount of triglycerides incorporated into VLDL particles to produce either VLDL 1 or VLDL 2 particles. The current evidence suggests that the machinery driving VLDL assembly in the liver includes (i) low insulin signalling via PI-3 kinase pathway that enhances lipid accumulation into "nascent" VLDL particles (ii) up-regulation of SREBP-1C that stimulates de novo lipogenesis and (iii) excess availability of "polar molecules" in hepatocytes that stabilizes apo B 100. Recent data suggest that all these steps could be fundamentally altered in Type 2 diabetes explaining the overproduction of VLDL apo B as well as the ability of insulin to suppress VLDL 1 apo B production in Type 2 diabetes.Recent discoveries have established the transcription factors including PPARs, SREBP-1 and LXRs as the key regulators of lipid assembly in the liver. These observations suggest these factors as a new target to tailor more efficient drugs to treat diabetic dyslipidaemia. [Diabetologia (2003) 46:733-749]

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“…In macrophages, PPARα also induces the expression of NPC1 and NPC2, which control the transport of free cholesterol from the lysosome to the plasma membrane (Chinetti-Gbaguidi et al, 2005), thus leading to increased cholesterol efflux. In a similar pathway, PPARα and γ induce ABCA1 expression (Chinetti et al, 2001), which also aids cholesterol efflux from macrophages and cholesterol reverse transport.…”

Section: Pparsmentioning

confidence: 99%