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Biomedical subjects

Jean-Charles Fruchart

Publications and source records attributed to Jean-Charles Fruchart.

116 records · Page 7Linked to original sources
PubMed2002

Increased ABCA1 activity protects against atherosclerosis.

The ABC transporter ABCA1 plays a key role in the first steps of the reverse cholesterol transport pathway by mediating lipid efflux from macrophages. Previously, it was demonstrated that human ABCA1 overexpression in vivo in transgenic mice results in a mild elevation of plasma HDL levels and increased efflux of cholesterol from macrophages. In this study, we determined the effect of overexpression of ABCA1 on atherosclerosis development. Human ABCA1 transgenic mice (BAC(+)) were crossed with ApoE(-/-) mice, a strain that spontaneously develop atherosclerotic lesions. BAC(+)ApoE(-/-) mice developed dramatically smaller, less-complex lesions as compared with their ApoE(-/-) counterparts. In addition, there was increased efflux of cholesterol from macrophages isolated from the BAC(+)ApoE(-/-) mice. Although the increase in plasma HDL cholesterol levels was small, HDL particles from BAC(+)ApoE(-/-) mice were significantly better acceptors of cholesterol. Lipid analysis of HDL particles from BAC(+)ApoE(-/-) mice revealed an increase in phospholipid levels, which was correlated significantly with their ability to enhance cholesterol efflux.

ATP Binding Cassette Transporter 1↗
PubMed2002

Identification of Rev-erbalpha as a physiological repressor of apoC-III gene transcription.

Elevated serum levels of triglyceride-rich remnant lipoproteins (TRL) are a major risk factor predisposing a subject to atherosclerosis. Apolipoprotein C-III (apoC-III) is a major constituent of TRL that impedes triglyceride hydrolysis and remnant clearance and, as such, may exert pro-atherogenic activities. In the present study, transient cotransfection experiments in rat hepatocytes in primary culture and rabbit kidney RK13 cells demonstrated that overexpression of Rev-erbalpha specifically decreases basal and HNF-4 stimulated human apoC-III promoter activity. A Rev-erbalpha response element was mapped by promoter deletion, mutation analysis, and gel-shift experiments to a AGGTCA half-site located at position -23/-18 (downstream of the TATA box) in the apoC-III promoter. Finally, Rev-erbalpha-deficient mice displayed elevated serum and liver mRNA levels of apoC-III together with increased serum VLDL triglycerides. Taken together, our data identify Rev-erbalpha as a regulator of apoC-III gene expression, providing a novel, physiological role for this nuclear receptor in the regulation of lipid metabolism.

Animals↗
PubMed2002

DNA binding-independent induction of IkappaBalpha gene transcription by PPARalpha.

PPARs are ligand-activated transcription factors that regulate energy homeostasis. In addition, PPARs furthermore control the inflammatory response by antagonizing the nuclear factor-kappaB (NF-kappaB) signaling pathway. We recently demonstrated that PPARalpha activators increase IkappaBalpha mRNA and protein levels in human aortic smooth muscle cells. Here, we studied the molecular mechanisms by which PPARalpha controls IkappaBalpha expression. Using transient transfection assays, it is demonstrated that PPARalpha potentiates p65-stimulated IkappaBalpha transcription in a ligand-dependent manner. Site-directed mutagenesis experiments revealed that PPARalpha activation of IkappaBalpha transcription requires the NF-kappaB and Sp1 sites within IkappaBalpha promoter. Chromatin immunoprecipitation assays demonstrate that PPARalpha activation enhances the occupancy of the NF-kappaB response element in IkappaBalpha promoter in vivo. Overexpression of the oncoprotein E1A failed to inhibit PPARalpha-mediated IkappaBalpha promoter induction, suggesting that cAMP response element binding protein-binding protein/p300 is not involved in this mechanism. By contrast, a dominant-negative form of VDR-interacting protein 205 (DRIP205) comprising its two LXXLL motifs completely abolished PPARalpha ligand-mediated activation. Furthermore, cotransfection of increasing amounts of DRIP205 relieved this inhibition, suggesting that PPARalpha requires DRIP205 to regulate IkappaBalpha promoter activity. By contrast, DRIP205 is not involved in PPARalpha-mediated NF-kappaB transcriptional repression. Taken together, these data provide a molecular basis for PPARalpha-mediated induction of IkappaBalpha and demonstrate, for the first time, that PPARalpha may positively regulate gene transcription in the absence of functional PPAR response elements.

Animals↗
PubMed2002

Characterization of the human PPARalpha promoter: identification of a functional nuclear receptor response element.

PPARalpha is a nuclear receptor that controls lipid and glucose metabolism and exerts antiinflammatory activities. The factors regulating human PPARalpha (hPPARalpha) gene expression remain largely unexplored. To study the mechanisms controlling hPPARalpha expression, the hPPARalpha gene promoter was identified and characterized. First, an alternatively spliced exon within the 5'-untranslated region of the hPPARalpha gene was identified by RT-PCR. Next, the transcription start site was mapped and the hPPARalpha gene promoter was cloned and functionally analyzed. Because PPARalpha levels are elevated in tissues expressing the hepatocyte nuclear factor-4 (HNF4), such as liver, the regulation of hPPARalpha by HNF4 was examined. Transient transfections in HepG2 and Cos cells showed that HNF4 enhances hPPARalpha promoter activity. 5'-Deletion and mutation analysis of the hPPARalpha promoter identified a regulatory element (RE) consisting of a degenerate hexamer repeat with a single nucleotide spacer (direct repeat 1), termed alphaHNF4-RE. Gel shift assays demonstrated that HNF4 binds to this alphaHNF4-RE. Furthermore, HNF4 increased the activity of a heterologous promoter driven by two copies of the alphaHNF4-RE. The nuclear receptor COUP-TFII also bound this site and down-regulated basal as well as HNF4-induced hPPARalpha promoter activity. Finally, PPARalpha was shown to bind the alphaHNF4-RE, leading to an induction of PPARalpha expression in hepatocytes. In summary, the organization of the 5'-flanking and untranslated region of the hPPARalpha gene was characterized and the hPPARalpha promoter region has been identified. Furthermore, these data demonstrate that the hPPARalpha gene is regulated by nuclear receptors, such as HNF-4, COUP-TFII, and PPARalpha.

5' Untranslated Regions↗
PubMed2002

[Role of the peroxisome proliferator-activated receptors (PPARS) in the regulation of lipids and inflammation control].

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor family. The hypolipidemic fibrates and the antidiabetic glitazones are synthetic ligands for PPAR alpha and PPAR gamma, respectively. Furthermore, fatty acids and eicosanoids are natural PPAR ligands. PPARs function as regulators of lipid and lipoprotein metabolism and glucose homeostasis and influence cellular proliferation, differentiation and apoptosis. PPAR alpha is highly expressed in tissues such as liver, muscle, kidney and heart, where it stimulates the beta-oxidative degradation of fatty acids. PPAR alpha furthermore mediates the action of the hypolipidemic drugs of the fibrate class on plasma lipoprotein metabolism. PPAR gamma is predominantly expressed in intestine and adipose tissue. PPAR gamma triggers adipocyte differentiation and promotes lipid storage. In addition, PPARs play a role in inflammation control. PPAR activators inhibit the activation of inflammatory response genes by negatively interfering with the NF-kappa B and AP-1 signalling pathways. PPAR activators exert these anti-inflammatory activities in different immunological and vascular wall cell types such as monocyte-macrophages, endothelial, epithelial and smooth muscle cells in which PPARs are expressed. These findings indicate a modulatory role for PPARs in the control of the inflammatory response with potential therapeutic applications in inflammation-related diseases, such as atherosclerosis.

Animals↗
PubMedDate not supplied

Paraoxonase 1 and platelet-activating factor acetylhydrolase activities in patients with low hdl-cholesterol levels with or without primary hypertriglyceridemia.

BACKGROUND: Previous studies have shown that high density lipoprotein (HDL)-deficient states are associated with reduced paraoxonase 1 (PON1) activity. However, HDL reduction caused by primary hypertriglyceridemia has not been fully explored. The aim of the present study was to evaluate whether PON1 and platelet-activating factor acetylhydrolase (PAF-AH), two antioxidant enzymes, were altered in patients with low HDL-cholesterol levels with or without primary hypertriglyceridemia in comparison with control normolipemic subjects. METHODS: We studied 24 patients with low HDL-cholesterol levels with (n=12) or without (n=12) primary hypertriglyceridemia in comparison with 12 control subjects who presented normal HDL-cholesterol and triglyceride levels. Paraoxon and phenylacetate were used as substrate for measuring PON1 activities and 1-hexadecyl-2-[3H]acetyl-glycero-3-phosphocholine for platelet-activating factor acetylhydrolase (PAF-AH) activity. Double substrate method was used to assign phenotypes. Lipid, lipoprotein, apolipoprotein, and lipoprotein particles were determined by standardized methods. RESULTS: Both PON1 activities were significantly reduced in patients with low HDL-cholesterol levels. This reduction could be selectively attributed to the hypertriglyceridemic subgroup. PAF-AH activity was not different between hypoalphalipoproteinemic patients and controls. PON1 activities correlated positively and significantly with HDL-cholesterol, HDL2-cholesterol, HDL3-cholesterol, HDL-phospholipids, apo A-I, apo A-II, and LpA-I:A-II. PAF-AH correlated positively and significantly with total and low density lipoprotein-cholesterol. CONCLUSIONS: Data from this study would suggest that in hypoalphalipoproteinemic syndrome, particularly when associated with hypertriglyceridemia, there is impairment in enzymatic antioxidant activity exclusively related with HDL.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMedDate not supplied

[Pharmacology of PPARalpha, PPARgamma and dual PPARalpha/gamma agonists in clinical development].

Cardiovascular diseases (CVD) remain the leading cause of mortality in the western societies. Several risk factors predispose to CVD including diabetes, obesity, insulin resistance, dyslipidemia and hypertension. Various pharmacological therapies have been developed to control the risk factors associated to CVD. Fibrates are able to correct dyslipidemia, therefore decreasing CVD risk. Thiazolidinediones (TZD) or glitazones by increasing insulin sensitivity decrease plasma glucose levels in diabetic patients. Both fibrates and TZD activate the peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors that play a central role in the control of lipid and glucose metabolism. In this review, we will discuss the mode of action of fibrates and TZD and we will present an overview on PPAR ligands under development.

Cardiovascular Diseases↗