Hyperlipidemias: Staels B

Caron S, Staels B. · No affiliation provided · Circ Res. · Pubmed #19059836 No free full text.

This publication has no abstract.

Staels B. · Universite Lille Nord de France, Inserm U545, UDSL, Lille, France. · Postgrad Med. · Pubmed #19494475 No free full text.

Abstract: Clinical evidence has demonstrated that bile acid sequestrants reduce glucose levels in patients with type 2 diabetes mellitus (T2DM). This effect has been confirmed in multiple double-blind, placebo-controlled clinical studies with the bile acid sequestrant colesevelam hydrochloride (HCl). Colesevelam HCl was approved by the US Food and Drug Administration in January 2008 as an adjunctive therapy for patients with T2DM to improve glycemic control. However, the mechanism of action for the glucose-lowering effect of bile acid sequestrants is unclear. Bile acid sequestrants are nonsystemic pharmacological agents that bind bile acids in the gastrointestinal tract, thereby diverting bile acids from the enterohepatic circulation. This, in turn, upregulates bile acid synthesis (via cholesterol 7-alpha-hydroxylase), which utilizes cholesterol, resulting in reduced low-density lipoprotein cholesterol levels. Recent research has revealed that bile acids are tightly controlled signaling molecules that have metabolic effects beyond their primary role in bile to aid in the digestion of lipids and fat. Bile acids signal via various membrane and nuclear receptors. Therefore, bile acid sequestrants may exert glycemic effects by altering the interaction of these bile acid pathways. This article reviews the role for bile acids in glucose regulation and discusses the potential mechanism(s) of action for the glycemic effects of bile acid sequestrants.

Staels B, Maes M, Zambon A. · Department of Atherosclerosis, Institut Pasteur de Lille, UMR545 Inserm, University of Lille 2, Lille, France. · Nat Clin Pract Cardiovasc Med. · Pubmed #18628776 No free full text.

Abstract: Statins lower cardiovascular risk in patients with diabetes; however, as these patients are at higher risk than other cardiovascular patients, statins merely decrease coronary event rates to the level seen in untreated nondiabetic individuals at risk for cardiovascular disease, indicating the existence of substantial residual risk. One reasonable explanation resides in the fact that statins have only limited effectiveness on hypertriglyceridemia and low HDL cholesterol, and they do not normalize the LDL size-distribution pattern. Peroxisome proliferator-activated receptor (PPAR)alpha agonists, which include fibrates, normalize this atherogenic lipid profile, as well as several cardiovascular risk markers associated with the metabolic syndrome and type 2 diabetes. In particular, hypertriglyceridemia and the ratio of small dense:large buoyant LDL particles are significantly improved. Outcome trials of PPARalpha agonists have demonstrated reductions in cardiovascular morbidity in patients with diabetes and in those with the metabolic syndrome; plaque progression is diminished, diabetic nephropathy and retinopathy are counteracted and amputation-risk decreased. The combination of fibrates with statins improves overall lipoprotein profile further. PPARalpha agonists seem particularly indicated in patients with diabetes who have residual dyslipidemia (high triglyceride and/or low HDL) despite receiving statin therapy, and patients who are nondiabetic, overweight, insulin-resistant and who have hypertriglyceridemia and/or low HDL cholesterol and chronic inflammation.

Staels B, Fruchart JC. · Department of Atherosclerosis, Unité INSERM 545-Institut Pasteur, 1, rue du Professeur Calmette, 59019 Lille Cedex, France. · Diabetes. · Pubmed #16046315 links to  free full text

Abstract: Peroxisome proliferator-activated receptors (PPARs) play key roles in the regulation of energy homeostasis and inflammation, and agonists of PPARalpha and -gamma are currently used therapeutically. Fibrates, first used in the 1970s for their lipid-modifying properties, were later shown to activate PPARalpha. These agents lower plasma triglycerides and VLDL particles and increase HDL cholesterol, effects that are associated with cardiovascular benefit. Thiazolidinediones, acting via PPARgamma, influence free fatty acid flux and thus reduce insulin resistance and blood glucose levels. PPARgamma agonists are therefore used to treat type 2 diabetes. PPARalpha and -gamma agonists also affect inflammation, vascular function, and vascular remodeling. As knowledge of the pleiotropic effects of these agents advances, further potential indications are being revealed, including roles in the management of cardiovascular disease (CVD) and the metabolic syndrome. Dual PPARalpha/gamma agonists (currently in development) look set to combine the properties of thiazolidinediones and fibrates, and they hold considerable promise for improving the management of type 2 diabetes and providing an effective therapeutic option for treating the multifactorial components of CVD and the metabolic syndrome. The functions of a third PPAR isoform, PPARdelta, and its potential as a therapeutic target are currently under investigation.

Gervois P, Fruchart JC, Staels B. · Départment d'Athérosclérose, Institut Pasteur de Lille and Faculté de Pharmacie, Université de Lille II, Lille, France. · Int J Clin Pract Suppl. · Pubmed #16035393 No free full text.

Abstract: Cardiovascular disease (CVD) remains the leading cause of mortality in developed countries. Several risk factors are associated with CVD, including type 2 diabetes, obesity, insulin resistance, dyslipidaemia and hypertension. Different pharmacological therapies have been developed to control these risk factors. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, which belong to the nuclear receptor superfamily that controls lipid and glucose metabolism as well as inflammatory risk factors for CVD. PPARalpha agonists, such as the fibrates, correct dyslipidaemia, thus decreasing CVD risk. PPARgamma agonists, such as the glitazones, increase insulin sensitivity and decrease plasma glucose levels in patients with diabetes. Moreover, both PPARalpha and PPARgamma agonists exert anti-inflammatory activities in liver, adipose and vascular tissues. In this review, we focus on the mode of action of PPARalpha and PPARalpha agonists, illustrating the potential of the newly developed dual PPAR agonists for the treatment of global risk in patients with the metabolic syndrome or type 2 diabetes.

Claudel T, Sturm E, Kuipers F, Staels B. · Unité de Recherche 545, Institut National de la Santé et de la Recherche Médicale, Département d'Athérosclérose, Institut Pasteur de Lille and the Faculté de Pharmacie, Université de Lille II, Lille, France. · Expert Opin Investig Drugs. · Pubmed #15330745 No free full text.

Abstract: Bile acids are end products of cholesterol metabolism. They are exclusively synthesised by the liver and subsequently secreted via the bile duct into the intestine to facilitate the absorption of dietary fat and fat-soluble vitamins. Nuclear receptors are ligand-activated transcription factors. The farnesoid X receptor (FXR) has recently been identified as a bile acid-activated nuclear receptor. FXR controls bile-acid synthesis, conjugation and transport, as well as lipid metabolism. Recent advances in FXR biology demonstrate that FXR may represent a valuable target for the identification of novel drugs to treat dyslipidaemia and cholestasis. However, for therapeutic purposes the development of selective FXR modulators, which only activate or inhibit specific FXR target genes and as such induce specific responses, will be required.

Tailleux A, Torpier G, Mezdour H, Fruchart JC, Staels B, Fiévet C. · Unité de Recherche INSERM 545, Département d'Athérosclérose, Institut Pasteur de Lille, France. · Trends Pharmacol Sci. · Pubmed #14559405 No free full text.

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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).

Staels B. · Département d'Athérosclérose, INSERM U325, Institut Pasteur de Lille, i rue Calmette, 59019 Lille, France. · J Am Acad Dermatol. · Pubmed #11606948 No free full text.

Abstract: Retinoids are small vitamin A-derived lipophilic compounds that influence a wide variety of developmental and metabolic processes. Retinoids exert their action by activating transcription factors belonging to the retinoic acid receptor (RAR) and retinoid X receptor (RXR) subfamilies of nuclear receptors. Therapeutically, retinoids are used for the treatment of dermatological disorders and certain cancers. Dyslipidemia is a common side-effect of therapy with the currently available retinoids. This review summarizes our current understanding of the molecular mechanisms of regulation of lipid and lipoprotein metabolism by retinoids.

Pineda Torra I, Gervois P, Staels B. · Département d'Athérosclérose, Institut Pasteur de Lille, France. · Curr Opin Lipidol. · Pubmed #10327283 No free full text.

Abstract: Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors which are activated by fatty acids and derivatives. The PPAR alpha form has been shown to mediate the action of the hypolipidemic drugs of the fibrate class on lipid and lipoprotein metabolism. PPAR alpha activators furthermore improve glucose homeostasis and influence body weight and energy homeostasis. It is likely that these actions of PPAR alpha activators on lipid, glucose and energy metabolism are, at least in part, due to the increase of hepatic fatty acid beta-oxidation resulting in an enhanced fatty acid flux and degradation in the liver. Moreover, PPARs are expressed in different immunological and vascular wall cell types where they exert anti-inflammatory and proapoptotic activities. The observation that these receptors are also expressed in atherosclerotic lesions suggests a role in atherogenesis. Finally, PPAR alpha activators correct age-related dysregulations in redox balance. Taken together, these data indicate a modulatory role for PPAR alpha in the pathogenesis of age-related disorders, such as dyslipidemia, insulin resistance and chronic inflammation, predisposing to atherosclerosis.

Duez H, Lefebvre B, Poulain P, Torra IP, Percevault F, Luc G, Peters JM, Gonzalez FJ, Gineste R, Helleboid S, Dzavik V, Fruchart JC, Fiévet C, Lefebvre P, Staels B. · UR545INSERM, Département d'Athérosclérose, Institut Pasteur Lille and Faculté de Pharmacie, Université de Lille2, France. · Arterioscler Thromb Vasc Biol. · Pubmed #15618549 links to  free full text

Abstract: OBJECTIVE: The objective of this trial was to study the effects of fenofibrate (FF) and gemfibrozil (GF), the most commonly used fibrates, on high-density lipoprotein (HDL) and apolipoprotein (apo) A-I. METHODS AND RESULTS: In a head-to-head double-blind clinical trial, both FF and GF decreased triglycerides and increased HDL cholesterol levels to a similar extent, whereas plasma apoA-I only increased after FF but not GF. Results in human (h) apoA-Itransgenic (hA-ITg) peroxisome proliferator-activated receptor (PPAR) alpha-/- mice demonstrated that PPARalpha mediates the effects of FF and GF on HDL in vivo. Although plasma and hepatic mRNA levels of hapoA-I increased more pronouncedly after FF than GF in hA-ITgPPARalpha+/+ mice, both fibrates induced acylCoAoxidase mRNA similarly. FF and GF transactivated PPARalpha with similar activity and affinity on a DR-1 PPAR response element, but maximal activation on the hapoA-I DR-2 PPAR response element was significantly lower for GF than for FF. Moreover, GF induced recruitment of the coactivator DRIP205 on the DR-2 site less efficiently than did FF. CONCLUSIONS: Both GF and FF exert their effects on HDL through PPARalpha. Whereas FF behaves as a full agonist, GF appears to act as a partial agonist due to a differential recruitment of coactivators to the promoter. These observations provide an explanation for the differences in the activity of these fibrates on apoA-I.

Hofker M, Calabresi L, Jauhiainen M, Nimpf J, Rudling M, Talmud P, Mooser V, Dallinga-Thie G, von Eckardstein A, Staels B, Karpe F, Kuipers F. · Department of Molecular Genetics, University of Maastricht, The Netherlands. · Atherosclerosis. · Pubmed #15195815 No free full text.

This publication has no abstract.

MacDonald ML, van Eck M, Hildebrand RB, Wong BW, Bissada N, Ruddle P, Kontush A, Hussein H, Pouladi MA, Chapman MJ, Fievet C, van Berkel TJ, Staels B, McManus BM, Hayden MR. · Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, and Child & Family Research Institute, 980 West 28th Avenue, Vancouver, BC, Canada V5Z 4H4. · Arterioscler Thromb Vasc Biol. · Pubmed #19095997 No free full text.

Abstract: OBJECTIVE: Absence of stearoyl-CoA desaturase-1 (SCD1) in mice reduces plasma triglycerides and provides protection from obesity and insulin resistance, which would be predicted to be associated with reduced susceptibility to atherosclerosis. The aim of this study was to determine the effect of SCD1 deficiency on atherosclerosis. METHODS AND RESULTS: Despite an antiatherogenic metabolic profile, SCD1 deficiency increases atherosclerosis in hyperlipidemic low-density lipoprotein receptor (LDLR)-deficient mice challenged with a Western diet. Lesion area at the aortic root is significantly increased in males and females in two models of SCD1 deficiency. Inflammatory changes are evident in the skin of these mice, including increased intercellular adhesion molecule (ICAM)-1 and ulcerative dermatitis. Increases in ICAM-1 and interleukin-6 are also evident in plasma of SCD1-deficient mice. HDL particles demonstrate changes associated with inflammation, including decreased plasma apoA-II and apoA-I and paraoxonase-1 and increased plasma serum amyloid A. Lipopolysaccharide-induced inflammatory response and cholesterol efflux are not altered in SCD1-deficient macrophages. In addition, when SCD1 deficiency is limited to bone marrow-derived cells, lesion size is not altered in LDLR-deficient mice. CONCLUSIONS: These studies reinforce the crucial role of chronic inflammation in promoting atherosclerosis, even in the presence of antiatherogenic biochemical and metabolic characteristics.

Wouters K, van Gorp PJ, Bieghs V, Gijbels MJ, Duimel H, Lütjohann D, Kerksiek A, van Kruchten R, Maeda N, Staels B, van Bilsen M, Shiri-Sverdlov R, Hofker MH. · Department of Molecular Genetics, Physiology and Electron Microscopy Unit, Nutrition and Toxicology Research and Cardiovascular Research, Institutes of Maastricht University, Maastricht, The Netherlands. · Hepatology. · Pubmed #18666236 No free full text.

Abstract: Nonalcoholic steatohepatitis (NASH) involves liver lipid accumulation (steatosis) combined with hepatic inflammation. The transition towards hepatic inflammation represents a key step in pathogenesis, because it will set the stage for further liver damage, culminating in hepatic fibrosis, cirrhosis, and liver cancer. The actual risk factors that drive hepatic inflammation during the progression to NASH remain largely unknown. The role of steatosis and dietary cholesterol in the etiology of diet-induced NASH was investigated using hyperlipidemic mouse models fed a Western diet. Livers of male and female hyperlipidemic (low-density lipoprotein receptor-deficient [ldlr(-/-)] and apolipoprotein E2 knock-in [APOE2ki]) mouse models were compared with livers of normolipidemic wild-type (WT) C57BL/6J mice after short-term feeding with a high-fat diet with cholesterol (HFC) and without cholesterol. Whereas WT mice displayed only steatosis after a short-term HFC diet, female ldlr(-/-) and APOE2ki mice showed steatosis with severe inflammation characterized by infiltration of macrophages and increased nuclear factor kappaB (NF-kappaB) signaling. Remarkably, male ldlr(-/-) and APOE2ki mice developed severe hepatic inflammation in the absence of steatosis after 7 days on an HFC diet compared with WT animals. An HFC diet induced bloated, "foamy" Kupffer cells in male and female ldlr(-/-) and APOE2ki mice. Hepatic inflammation was found to be linked to increased plasma very low-density lipoprotein (VLDL) cholesterol levels. Omitting cholesterol from the HFC diet lowered plasma VLDL cholesterol and prevented the development of inflammation and hepatic foam cells. CONCLUSION: These findings indicate that dietary cholesterol, possibly in the form of modified plasma lipoproteins, is an important risk factor for the progression to hepatic inflammation in diet-induced NASH.

MacDonald ML, Singaraja RR, Bissada N, Ruddle P, Watts R, Karasinska JM, Gibson WT, Fievet C, Vance JE, Staels B, Hayden MR. · Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada. · J Lipid Res. · Pubmed #17960025 links to  free full text

Abstract: A combination of the interrelated metabolic risk factors obesity, insulin resistance, dyslipidemia, and hypertension, often described as the "metabolic syndrome," is known to increase the risk of developing cardiovascular disease and diabetes. Stearoyl-coenzyme A desaturase (SCD) activity has been implicated in the metabolic syndrome, but detailed studies of the beneficial metabolic effects of SCD deficiency have been limited. Here, we show that absence of the Scd1 gene product reduces plasma triglycerides and reduces weight gain in severely hyperlipidemic low density lipoprotein receptor (LDLR)-deficient mice challenged with a Western diet. Absence of SCD1 also increases insulin sensitivity, as measured by intraperitoneal glucose and insulin tolerance testing. SCD1 deficiency dramatically reduces hepatic lipid accumulation while causing more modest reductions in plasma apolipoproteins, suggesting that in conditions of sustained hyperlipidemia, SCD1 functions primarily to mediate lipid stores. In addition, absence of SCD1 partially ameliorates the undesirable hypertriglyceridemic effect of antiatherogenic liver X receptor agonists. Our results demonstrate that constitutive reduction of SCD activity improves the metabolic phenotype of LDLR-deficient mice on a Western diet.

Shiri-Sverdlov R, Wouters K, van Gorp PJ, Gijbels MJ, Noel B, Buffat L, Staels B, Maeda N, van Bilsen M, Hofker MH. · Department of Molecular Genetics, University Maastricht, UNS40/11 P.O. Box 16, 6200 MD, Maastricht, The Netherlands. · J Hepatol. · Pubmed #16466828 No free full text.

Abstract: BACKGROUND/AIMS: The molecular mechanisms leading to Non-Alcoholic Steatohepatitis (NASH) are not fully understood. In mice, NASH can be inhibited by fenofibrate, a synthetic agonist for the nuclear receptor peroxisome proliferator activated receptor alpha, which regulates hepatic triglyceride metabolism. This study aimed to elucidate the relation between steatosis and inflammation in NASH in a human-like hyperlipidemic mouse model. METHODS: Liver phenotype and gene expression were assessed in APOE2 knock-in mice that were fed a western-type high fat diet with or without co-administration of fenofibrate. RESULTS: In response to a western diet, APOE2 knock-in mice developed NASH characterized by steatosis and inflammation. Strikingly, macrophage accumulation in the liver preceded the steatosis during progression of the disease. This phenotype was in line with gene expression patterns, which showed regulation of two major groups of genes, i.e. inflammatory and lipid genes. Fenofibrate treatment decreased hepatic macrophage accumulation and abolished steatosis. Moreover, a marked reduction in the expression of inflammatory genes occurred immediately after fenofibrate treatment. CONCLUSIONS: These data indicate that inflammation might play an instrumental role during the development of NASH in this mouse model. Inhibition of NASH by fenofibrate may be due, at least in part, to its inhibitory effect on pro-inflammatory genes.

Beghin L, Capps N, Duhal N, Davies J, Staels B, Luc G. · Dept of Atherosclerosis, INSERM U 325, Institut Pasteur de Lille, France. · Ann Clin Biochem. · Pubmed #10456219 No free full text.

This publication has no abstract.

Bowyer D, Dallinga-Thie G, von Eckardstein A, Hofker M, Jauhiainen M, Mooser V, Nimpf J, Rudling M, Staels B, Talmud P. · No affiliation provided · Atherosclerosis. · Pubmed #12618281 No free full text.

This publication has no abstract.