Hyperlipidemias: Duriez P

Fruchart JC, Duriez P. · Lipoprotein and Atherosclerosis Research Unit, INSERM--Unité de Recherche sur l'Arthérosclérose and Lille University 2 U545, Pasteur Institute of Lille, Lille, France. · Drugs Today (Barc). · Pubmed #16511610 No free full text.

Abstract: Epidemiological studies have shown that hypertriglyceridemia and low HDL-cholesterol were both associated with an increased risk of coronary heart disease. Furthermore, hypertriglyceridemia is now recognized as an independent risk factor for coronary artery disease. Secondary prevention trials (e.g., LOCAT, BECAIT, BIP and DAIS) in coronary artery disease with drugs acting primarily on triglycerides (e.g., the PPAR-alpha activators bezafibrate, fenofibrate and gemfibrozil) have shown that reducing triglycerides and increasing HDL-cholesterol, without significantly affecting LDL-cholesterol, slows down coronary artery luminal narrowing. Furthermore, the VA-HIT study recently showed that gemfibrozil decreased coronary artery disease mortality in secondary prevention trials, partly by increasing HDL-cholesterol. The peroxisome proliferator-activated receptors (PPARs) (i.e., PPAR-alpha, -beta(delta) and -gamma) form a subfamily of the nuclear receptor gene family. Whereas all PPARs are, albeit to differing extents, activated by fatty acids and derivatives, PPAR-alpha binds the hypolipidemic fibrates. PPAR-alpha activation mediates changes in lipoprotein metabolism. Moreover, PPAR-alpha activators increase hepatic uptake and esterification of free fatty acids, in addition to increasing mitochondrial free fatty acid uptake and the resulting free fatty acid oxidation. The effect of fibrates on the metabolism of triglyceride-rich lipoproteins is due to a PPAR-alpha-dependent stimulation of lipoprotein lipase and of apolipoprotein (apo)A-V and to an inhibition of apoC-III expression, whereas the increase in plasma HDL-cholesterol depends partly on an overexpression of apoA-I and apoA-II. PPARs are also expressed in atherosclerotic lesions.

de Groot E, Hovingh GK, Wiegman A, Duriez P, Smit AJ, Fruchart JC, Kastelein JJ. · Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands. · Circulation. · Pubmed #15198964 links to  free full text

Abstract: Large observational studies and atherosclerosis regression trials of lipid-modifying pharmacotherapy have established that intima-media thickness of the carotid and femoral arteries, as measured noninvasively by B-mode ultrasound, is a valid surrogate marker for the progression of atherosclerotic disease. To exploit fully the potential of ultrasound imaging in atherosclerosis research, standardized and strictly implemented imaging protocols should be used in both observational studies and applied clinical research. This article describes such a protocol developed at the Academic Medical Center of the University of Amsterdam, the Netherlands. Results are presented from a study that estimated atherosclerosis progression from childhood into old age by measuring intima-media thickness in subjects with familial hypercholesterolemia compared with healthy controls.

Fruchart JC, Nierman MC, Stroes ES, Kastelein JJ, Duriez P. · Departement de Recherche sur les Lipoproteines et l'Atherosclerose,Pasteur de Lille, Inserm U545 et Faculté de Pharmacie, Université du Droit et de la Santé de Lille 2, Lille, France. · Circulation. · Pubmed #15198961 links to  free full text

Abstract: Advances in our understanding of the ways in which the traditional cardiovascular risk factors, including standard lipid (eg, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol) and nonlipid (eg, hypertension) risk factors, interact to initiate atherosclerosis and promote the development of cardiovascular disease have enhanced our ability to assess risk in the individual patient. In addition, the ongoing identification and understanding of so-called novel risk factors may further improve our ability to predict future risk when these are included along with the classic risk factors in assessing the global risk profile. This review briefly summarizes the evidence that some newer risk factors, including impaired fasting glucose, triglycerides and triglyceride-rich lipoprotein remnants, lipoprotein(a), homocysteine, and high-sensitivity C-reactive protein, contribute to an increased risk of coronary and cardiovascular diseases.

Bordet R, Gelé P, Deplanque D, Duriez P. · EA 1046 Laboratoire de Pharmacologie, Faculté de Médecine, Université Lille 2, Lille, France. · Therapie. · Pubmed #12822203 No free full text.

Abstract: Statins and fibrates have been demonstrated to prevent both cardiovascular events and stroke. While this preventive effect was initially thought to be related to their lipid-lowering effects, in particular hypocholesterolaemic effect, analysis of primary and secondary prevention trials suggest that these preventive effects could be partly independent of their effects on lipid disorders. The pleiotropic effects, such as vascular, anti-inflammatory or anti-oxidants effects, were described for both the statins and fibrates. In addition to the preventive effects, these pleiotropic effects could partially explain the decrease in myocardial or cerebral ischemia consequences in experimental models. These cellular protective effects may have a therapeutic interest to decrease severity of stroke or coronary acute syndrome. They could also explain the drugs' lipid-lowering preventive effects independent of the treatment of lipid disorders. Beyond vascular pathologies, the pleiotropic effects of lipid-lowering drugs could explain their potentially beneficial effect in different diseases, such as dementia or cancer.

Duriez P. · Département d'Athérosclérose, Inserm U545, Institut Pasteur, 1 rue du Professeur Calmette, BP 245, 59019 Lille, France. · Expert Opin Pharmacother. · Pubmed #11825316 No free full text.

Abstract: Primary and secondary prevention trials for coronary heart disease (CHD) in hyperlipidaemic or so-called 'normolipidaemic' patients with drugs affecting lipid metabolism have clearly confirmed that even slight alterations in lipoprotein metabolism are major risk factors for CHD. The global cardiovascular risk must be determined before deciding to treat patients with drugs affecting lipid metabolism. Screening for dyslipidaemia consists of determining cholesterol (C), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C) and triglyceride (TG) plasma levels and the decision to treat depends mainly on LDL-C plasma levels. Furthermore, secondary dyslipidaemia must be diagnosed and primary disease must be adequately treated. There are four classes of available lipid-regulating drugs: HMG-CoA reductase inhibitors (statins), bile acid sequestrants (resins), peroxisome proliferator-activated receptor-alpha (PPAR- alpha) activators (fibrates) and nicotinic acid. All four will be discussed in this review. Clinical trials have shown that drugs improving lipid metabolism reduce CHD relative risk from 24% (secondary prevention) to 37% (primary prevention) and the absolute risk from 2% (primary prevention) to 8.5% (secondary prevention). These studies indicate that the number of patients needed to be treated to economise one clinical event ranges from 12 (secondary prevention) to 50 (primary prevention). Clinical trials are currently testing the hypothesis that 'lower LDL-C is better'.

Fruchart JC, Staels B, Duriez P. · Unité de Recherche sur les Lipoprotéines et l'Athérosclérose, Faculté de Pharmacie, Inserm U545, Institut Pasteur et Université de Lille 2, Lille, France. · Pharmacol Res. · Pubmed #11712864 No free full text.

Abstract: PPAR-alpha belongs to the family of nuclear receptors. Activated PPAR-alpha stimulates the expression of genes involved in fatty acid and lipoprotein metabolism. PPAR-alpha activators, such as the normolipidaemic fibric acids, decrease triglyceride concentrations by increasing the expression of lipoprotein lipase and decreasing apo C-III concentration. Furthermore, they increase HDL-cholesterol by increasing the expression of apo A-I and apo A-II. PPAR-alpha activation by fibric acids improves insulin sensibility, and decreases thrombosis and vascular inflammation. PPAR-alpha activators (gemfibrozil) decrease the risk of coronary heart disease in patients with normal LDL-cholesterol and low HDL-cholesterol (VA-HIT) and they slow the progression of premature coronary atherosclerosis (BECAIT) (bezafibrate), particularly in patients with type 2 diabetes (DAIS) (fenofibrate).

Duriez P, Fruchart JC. · Département d'Athérosclérose - U325 INSERM, Institut Pasteur et Faculté de Pharmacie, Université de Lille II, 1 rue du Professeur Calmette, 59019 Lille cedex, France. · Curr Atheroscler Rep. · Pubmed #11122689 No free full text.

Abstract: Hypertriglyceridemia is now recognized as an independent risk factor of coronary artery disease (CAD). A recent secondary prevention study of CAD with a statin suggested that it may be prudent to target fasting triglycerides to less than 150 mg/dL. Secondary prevention trials of CAD with drugs acting primarily on triglycerides (fibrates) have shown that reducing triglycerides and increasing high-density lipoprotein (HDL) cholesterol, without significantly affecting low-density lipoprotein cholesterol slows down coronary artery luminal narrowing (Lopid Coronary Angiography Trial [LOCAT], Bezafibrate Coronary Atherosclerosis Intervention Trial [BECAIT], Bezafibrate Infarction Prevention [BIP]). Furthermore, Veterans Administration-HDL Intervention Trial (VA-HIT) and Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto-1 (GISSI) studies recently showed that gemfibrozil and fish oils, respectively, decreased CAD mortality in secondary prevention trials. Statins are also capable of significantly reducing high triglyceride levels. Further clinical studies are necessary to confirm in terms of mortality the beneficial effect of reducing triglycerides and increasing high-density lipoprotein cholesterol in secondary CAD prevention; whereas, in primary prevention the beneficial effect of drastically reducing triglycerides by the way of pharmacology needs to be proved.

Boullier A, Hennuyer N, Tailleux A, Furman C, Duverger N, Caillaud JM, Castro G, Fievet C, Fruchart JC, Duriez P. · Department of Atherosclerosis, Pasteur Institute, INSERM U325 and University of Lille II, Lille, France. · Clin Sci (Lond). · Pubmed #11222122 No free full text.

Abstract: High levels of high-density lipoprotein (HDL) cholesterol have been reported to protect against the development of atherosclerosis in humans by increasing reverse cholesterol transport and inhibiting the oxidation of low-density lipoprotein (LDL) due to the paraoxonase content of HDL. The purpose of the present study was to assess if there are any relationships between in vivo increases in serum levels of immunological LDL oxidation markers [autoantibodies against oxidized LDL, autoantibodies against malondialdehyde-modified LDL, LDL immune complexes and anti-cardiolipin autoantibodies], paraoxonase activity and the development of atherosclerosis in control rabbits and in transgenic rabbits expressing human apolipoprotein (apo) A-I. A total of 13 apo A-I transgenic rabbits and 18 non-transgenic littermates were fed on a cholesterol-rich diet (0.4%, w/w) for 14 weeks, and were monitored at weeks 0, 2, 6, 10 and 14. Aortic atherosclerotic lesions were measured at the end of this period. Human apo A-I transgenic rabbits with high HDL cholesterol levels were not protected against the development of atherosclerosis when they were fed on a cholesterol-rich diet which induced dramatic hypercholesterolaemia. Immunological markers of LDL oxidation increased and serum paraoxonase activity decreased similarly in control and transgenic rabbits. In conclusion, the present study demonstrates that high HDL cholesterol levels are ineffective in inhibiting increases in immunological markers of LDL oxidation and the development of atherosclerosis in a mammal with severe hypercholesterolaemia.

Rugeri L, Susen S, Bard JM, Corseaux D, Gavériaux V, Devos P, Lecerf JM, Duriez P, Jude B. · Laboratoire d'Hématologie, Centre Hospitalier Régional Universitaire and Institut Pasteur Lille, France. · Thromb Res. · Pubmed #10593431 No free full text.

Abstract: Monocytes are potent regulators of blood coagulation through the expression of tissue factor (TF) on stimulation and of tissue factor pathway inhibitor (TFPI), a selective inhibitor of TF pathway. As hyperlipidemia can modify some monocyte functions, we compared the TF and TFPI expression by circulating monocytes and the plasma TFPI levels between 65 healthy normolipemic controls and 38 nontreated hyperlipemic patients. TF and TFPI relationships with plasma lipoproteins are also examined. TF and TFPI expression were evaluated in peripheral mononuclear cells after isolation from blood by density gradient centrifugation and after short culture with or without lipopolysaccharide (LPS). TF and TFPI activity and antigen were measured in mononuclear cell lysates using amidolytic assay and enzyme-linked immunosorbent assay, respectively. TFPI activity and antigen were measured in plasma using the same methods. Plasma factor VII (FVII) activity and antigen were also determined. LPS-stimulated monocyte TF activity and antigen were lower in hyperlipidemic patients than in controls (0.0001<p<0.03). This decrease of monocyte TF expression in hyperlipidemic patients was not related to an increase of monocyte TFPI. Monocyte TF activity was negatively correlated to atherogenic fractions and positively correlated to protective fractions, specially after ex vivo LPS stimulation. Increased TFPI and FVII plasma levels were found in hyperlipidemic patients compared to controls. These results indicate an impairment of TF production by circulating monocytes from hyperlipidemic subjects, which is linked to the increase of atherogenic lipoprotein fractions. Further studies are required to elucidate the mechanism of this inhibition.

Fruchart JC, Duriez P. · Département d'Athérosclérose, U325 INSERM, Institut Pasteur et Université de Lille II. · Ann Endocrinol (Paris). · Pubmed #10520406 No free full text.

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Fruchart JC, Duriez P. · Unité de Recherche sur les Lipoprotéines et l'Athérosclérose, Institut Pasteur de Lille, Inserm U545, Faculté de Pharmacie, Université de Lille II, 1, rue du Professeur Calmette, BP 245, F59019 Lille. · Ann Pharm Fr. · Pubmed #14747768 No free full text.

Abstract: Statins and fibrates constitute the two major families of lipid-lowering agents. Statins are widely used for the treatment of pure hypercholesterolaemia while fibrates are used for the treatment of hypertriglyceridemia. Both drugs are also used for the treatment of mixed dyslipidemia. Some fibrates efficiently lower serum LDL-cholesterol. Statins inhibit HMG-CoA reductase and decrease cellular cholesterol synthesis. The resulting lower intracellular cholesterol concentration induces the activation of SREBP thus inducing the over expression and transcription of the LDL receptor gene. This over expression of the LDL receptor in the liver increases the clearance of circulating LDL thus decreasing the LDL-cholesterol plasma levels. The effects of fibrates on lipid metabolism are entirely due to their capacity to activate PPAR-alpha and to induce the over expression of genes containing a PPRE in their promoter. Fibrates decrease triglyceride concentrations by increasing the beta-oxidation of fatty acids in the liver and by decreasing triglyceride-VLDL synthesis. Fibrates also decrease triglycerides by increasing the hydolysys of triglycerides in chylomicron and VLDL through their capacity to increase and to decrease the lipoprotein lipase and the apo C-III transcription, respectively. Fibrates could decrease triglycerides partly by inducing apo A-V over-expression. These molecules increase HDL-cholesterol by increasing apo A-I and apo A-II transcription. Therefore the mechanisms of action of statins and fibrates depend on their capacity to modulate the expression of genes controlling lipoprotein metabolism.