Nicotinic acid (niacin): new lipid-independent mechanisms of action and therapeutic potentials

Nicotinic acid (niacin) has been used for decades to prevent and treat atherosclerosis. The well-documented antiatherogenic activity is believed to result from its antidyslipidemic effects, which are accompanied by unwanted effects, especially a flush. There has been renewed interest in nicotinic acid owing to the need for improved prevention of atherosclerosis in patients already taking statins. In addition, the identification of a nicotinic acid receptor expressed in adipocytes and immune cells has helped to elucidate the mechanisms underlying the antiatherosclerotic as well as the unwanted effects of this drug. Nicotinic acid exerts its antiatherosclerotic effects at least in part independently of its antidyslipidemic effects through mechanisms involving its receptor on immune cells as well as through direct and indirect effects on the vascular endothelium. Here, we review recent data on the pharmacological effects of nicotinic acid and discuss how they might be harnessed to treat other inflammatory diseases such as multiple sclerosis or psoriasis.     

Nicotinic acid: an old drug with a promising future

Nicotinic acid has been used for decades to treat dyslipidaemic states. In particular its ability to raise the plasma HDL cholesterol concentration has led to an increased interest in its pharmacological potential. The clinical use of nicotinic acid is somewhat limited due to several harmless but unpleasant side effects, most notably a cutaneous flushing phenomenon. With the recent discovery of a nicotinic acid receptor, it has become possible to better understand the mechanisms underlying the metabolic and vascular effects of nicotinic acid. Based on these new insights into the action of nicotinic acid, novel strategies are currently under development to maximize the pharmacological potential of this drug. The generation of both flush-reducing co-medications of nicotinic acid and novel drugs targeting the nicotinic acid receptor will provide future therapeutic options for the treatment of dyslipidaemic disorders.     

Characterization of determinants of ligand binding to the nicotinic acid receptor GPR109A (HM74A/PUMA-G)

The G-protein-coupled receptor GPR109A (HM74A/PUMA-G) has recently been shown to function as a receptor for nicotinic acid (niacin) and to mediate its antilipolytic effects. Nicotinic acid is able to strongly raise plasma levels of high-density lipoprotein cholesterol, a property that distinguishes nicotinic acid from other lipid-lowering drugs. To investigate the structural determinants of GPR109A ligand binding, we performed site-directed mutagenesis of putative ligand binding residues combined with generation of chimeric receptors consisting of GPR109A and its close relative GPR109B, which does not bind nicotinic acid. We could identify Asn86/Trp91 [transmembrane helix (TMH) 2/extracellular loop (ECL) 1], Arg111 (TMH3), Ser178 (ECL2), Phe276 (TMH7), and Tyr284 (TMH7) as amino acid residues critical for binding of nicotinic acid. Together with data from molecular modeling studies, our data suggest that the ligand binding pocket for nicotinic acid of GPR109A is distinct from that of most other group A receptors. Although Arg111 at TMH3 serves as the basic anchor point for the carboxylate ligands, the ring system of nicotinic acid is embedded between Trp91 at the junction TMH2/ECL1 and Phe276/Tyr284 at TMH7. The heterocyclic ring is also bound to Ser178 at ECL2 via an H-bond. These data will facilitate the design of new antidyslipidemic drugs acting via GPR109A.     

What restricts the clinical use of nicotinic acid?

Nicotinic acid is the oldest hypolipidemic agent in use, since 1955. It possesses broad-spectrum lipidmodifying properties including reduction of total cholesterol, low density lipoprotein (LDL) cholesterol and triglycerides. In addition, nicotinic acid is the most potent available hypolipidemic agent for increasing plasma high density lipoprotein (HDL) cholesterol and decreasing lipoprotein (a) levels. Clinical trials have demonstrated that nicotinic acid can decrease cardiovascular morbidity and mortality. However, nicotinic acid is underused in the clinical setting due to its high rate of side effects, including flushing, gastrointestinal disorders, rash, hyperglycemia and hyperuricemia. The nicotinic acid-associated side effects and their management are the focus of this review.     

烟酸受体GPR109A介导的烟酸作用机制研究进展

烟酸作为调脂药物应用于临床已经50多年,相对高剂量的烟酸具有广泛的调脂作用。越来越多的证据表明,烟酸单用或联合降低低密度脂蛋白胆固醇(LDL-C)药物使用能够延缓动脉粥样硬化(AS)的进程和降低发生心血管事件的风险;但它的作用机制一直不是很明确。2003年,三个研究小组同时发现了烟酸受体,使人们对烟酸的作用机制有了进一步认识。烟酸受体GPR109A是一种Gi蛋白偶联受体,主要表达于白色、棕色脂肪组织、脾和免疫细胞。研究表明,烟酸受体主要介导以下作用:①烟酸作用于脂肪细胞的烟酸受体,抑制脂肪组织甘油三酯(TG)的水解,降低血浆游离脂肪酸(FFA);②烟酸作用于皮肤角质细胞和朗格汉细胞的烟酸受体诱导前列腺素分泌,引起皮肤血管舒张,引发潮红;③激活烟酸受体还可增加脂联素分泌,诱导中性粒细胞凋亡,上调过氧化物酶体增殖激活受体γ表达。     

Nicotinic acid-induced flushing is mediated by activation of epidermal langerhans cells

The antidyslipidemic drug nicotinic acid (niacin) has been used for decades. One of the major problems of the therapeutical use of nicotinic acid is a strong cutaneous vasodilation called flushing, which develops in almost every patient taking nicotinic acid. Nicotinic acid-induced flushing has been shown to be mediated by the nicotinic acid receptor GPR109A and to involve the formation of vasodilatory prostanoids. However, the cellular mechanisms underlying this short-term effect are unknown. Here, we show that epidermal Langerhans cells are essential for the cutaneous flushing response induced by nicotinic acid. Langerhans cells respond with an increase in [Ca(2+)](i) to nicotinic acid and express prostanoid synthases required for the formation of the vasodilatory prostanoids prostaglandin E(2) and prostaglandin D(2). Depletion of epidermal Langerhans cells but not of macrophages or dendritic cells abrogates nicotinic acid-induced flushing. These data unexpectedly identify epidermal Langerhans cells as essential mediators of nicotinic acid-induced flushing and may help to generate new strategies to suppress the unwanted effects of nicotinic acid. In addition, our results suggest that Langerhans cells besides their immunological roles are also involved in the local regulation of dermal blood flow.     

Acyl hydroxypyrazoles as novel agonists for high-affinity nicotinic acid receptor GPR109A: WO2008051403

Background: Acyl hydroxypyrazoles were discovered and claimed by Merck as novel agonists for the high-affinity nicotinic acid receptor, G-protein coupled receptor 109A (GPR109A). The fused bicyclic core contains a hydroxypyrazole that mimics the anthranilide moiety described in their earlier patents and patent publications. Objective: This article evaluates new GPR109A receptor agonists disclosed by Merck in the recent patent WO2008051403. Conclusion: The aim of this invention was to provide potential therapy to reduce free fatty acids (FFA), low-density lipoprotein cholesterol (LDL-C), total cholesterol, and serum triglycerides (TG), and to raise high-density lipoprotein cholesterol (HDL-C). Thus, these agonists could – potentially – be used to treat dyslipidemia, atherosclerosis, and metabolic syndromes such as diabetes.     

烟酸调脂治疗临床应用现状和进展

烟酸具有降低血浆总胆固醇、三酰甘油、低密度脂蛋白胆固醇和脂蛋白(a),升高高密度脂蛋白胆固醇的作用,但是普通制剂有众多的不良反应大大限制了它的使用。随着烟酸缓释剂型的问世,其不良反应明显降低,为临床调脂治疗和联合用药提供了一种更安全、有效的选择。     

Pharmacological evaluation of the efficacy of <Emphasis Type="Italic">Dysoxylum binectariferum</Emphasis> stem bark and its active constituent rohitukine in regulation of dyslipidemia in rats

The antidyslipidemic effect of the ethanolic extract of Dysoxylum binectariferum stem bark and its major active constituent rohitukine was evaluated in a high fat diet (HFD)-fed dyslipidemic rat model. Chronic feeding of ethanolic extract (200 mg/kg) in HFD-fed rats showed significant lipid lowering activity. The bioassay guided fractionation of ethanolic extract resulted in the identification of known alkaloid rohitukine as major active constituent. Rohitukine (50 mg/kg) significantly decreased the plasma levels of total cholesterol (24 %), phospholipids (25 %), triglycerides (27 %), very low density lipoprotein (27 %) and low density lipoprotein (32 %) accompanied with an increase in high density lipoprotein (21 %). The present study demonstrated that ethanolic extract of Dysoxylum binectariferum stem bark and its major constituent rohitukine both have antidyslipidemic as well as antioxidant potentials. The antidyslipidemic activity of rohitukine can be correlated to its effect on enzymes involved in lipid metabolism.     

International Union of Basic and Clinical Pharmacology. LXXXII: Nomenclature and Classification of Hydroxy-carboxylic Acid Receptors (GPR81, GPR109A, and GPR109B)

The G-protein-coupled receptors GPR81, GPR109A, and GPR109B share significant sequence homology and form a small group of receptors, each of which is encoded by clustered genes. In recent years, endogenous ligands for all three receptors have been described. These endogenous ligands have in common that they are hydroxy-carboxylic acid metabolites, and we therefore have proposed that this receptor family be named hydroxy-carboxylic acid (HCA) receptors. The HCA(1) receptor (GPR81) is activated by 2-hydroxy-propanoic acid (lactate), the HCA(2) receptor (GPR109A) is a receptor for the ketone body 3-hydroxy-butyric acid, and the HCA(3) receptor (GPR109B) is activated by the β-oxidation intermediate 3-hydroxy-octanoic acid. HCA(1) and HCA(2) receptors are found in most mammalian species, whereas the HCA(3) receptor is present only in higher primates. The three receptors have in common that they are expressed in adipocytes and are coupled to G(i)-type G-proteins mediating antilipolytic effects in fat cells. HCA(2) and HCA(3) receptors are also expressed in a variety of immune cells. HCA(2) is a receptor for the antidyslipidemic drug nicotinic acid (niacin) and related compounds, and there is an increasing number of synthetic ligands mainly targeted at HCA(2) and HCA(3) receptors. The aim of this article is to give an overview on the discovery and pharmacological characterization of HCAs, and to introduce an International Union of Basic and Clinical Pharmacology (IUPHAR)-recommended nomenclature. We will also discuss open questions regarding this receptor family as well as their physiological role and therapeutic potential.     

Discovery of a Potent Nicotinic Acid Receptor Agonist for the Treatment of Dyslipidemia

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Management of hyperlipidaemia associated with heart transplantation

The past 20 years have seen considerable advances in the field of organ transplantation that have together led to a notable increase in survival rates and a reduction in postoperative morbidity of transplant recipients. However, these advances have been accompanied by the appearance of other complications of transplantation, such as post-transplant hyperlipidaemia, hypertension and graft coronary vasculopathy (GCV). GCV is an accelerated form of atherosclerosis in transplanted hearts that has proven to be one of the most important late complications of heart transplantation and is the single most limiting factor for long-term survival. The most important factors favouring the development of hyperlipidaemia after heart transplantation are inappropriate diet in combination with reduced physical activity, adverse effects of immunosuppressive therapy (ciclosporin [cyclosporin], corticosteroids) and polygenic hypercholesterolaemia in combination with ischaemic cardiomyopathy. The treatment of hyperlipidaemia in heart transplant recipients results in a variety of complications and side effects. In particular, interactions between lipid-lowering drugs and immunosuppressive therapy have been observed. Early attempts at treatment with bile acid binding agents and nicotinic acid derivatives often proved insufficiently effective, and led to unacceptable adverse effects and significant disturbances of ciclosporin metabolism. Fibric acid derivatives provided moderate reductions in triglyceride and total cholesterol levels that were mostly--with the exception of gemfibrozil--accompanied by significant impairment of renal function. Probucol achieved only an unsatisfactory reduction in low-density lipoprotein (LDL) cholesterol. Omega-3 fatty acids lower cholesterol levels and improve endothelial function in heart transplant recipients; however, the significance of these effects is still under discussion. As in the general patient population, use of HMG-CoA reductase inhibitors (statins) achieved significant reductions in cholesterol levels. Use of these substances has resulted in significantly extended long-term survival times, significantly less GCV and fewer severe graft rejections. Selective cholesterol absorption inhibitors, administered with or without statins, could provide another treatment option for heart transplant patients with hypercholesterolaemia. In severe familial hypercholesterolaemia, which is rarely observed in heart transplant recipients, treatment with statins can be combined with extracorporeal cholesterol elimination procedures such as heparin induced extracorporeal LDL cholesterol precipitation (HELP). HELP enables total cholesterol levels to be kept within any desired target range, and has been used successfully and without adverse effects in heart transplant recipients.     

Current, new and future treatments in dyslipidaemia and atherosclerosis

The new therapeutic options available to clinicians treating dyslipidaemia in the last decade have enabled effective treatment for many patients. The development of the HMG-CoA reductase inhibitors (statins) have been a major advance in that they possess multiple pharmacological effects (pleiotropic effects) resulting in potent reductions of low density lipoproteins (LDL) and prevention of the atherosclerotic process. More recently, the newer fibric acid derivatives have also reduced LDL to levels comparable to those achieved with statins, have reduced triglycerides, and gemfibrozil has been shown to increase high density lipoprotein (HDL) levels. Nicotinic acid has been made tolerable with sustained-release formulations, and is still considered an excellent choice in elevating HDL cholesterol and is potentially effective in reducing lipoprotein(a) [Lp(a)] levels, an emerging risk factor for coronary heart disease (CHD). Furthermore, recent studies have reported positive lipid-lowering effects from estrogen and/or progestogen in postmenopausal women but there are still conflicting reports on the use of these agents in dyslipidaemia and in females at risk for CHD. In addition to lowering lipid levels, these antihyperlipidaemic agents may have directly or indirectly targeted thrombogenic, fibrinolytic and atherosclerotic processes which may have been unaccounted for in their overall success in clinical trials. Although LDL cholesterol is still the major target for therapy, it is likely that over the next several years other lipid/lipoprotein and nonlipid parameters will become more generally accepted targets for specific therapeutic interventions. Some important emerging lipid/lipoprotein parameters that have been associated with CHD include elevated triglyceride, oxidised LDL cholesterol and Lp(a) levels, and low HDL levels. The nonlipid parameters include elevated homocysteine and fibrinogen, and decreased endothelial-derived nitric oxide production. Among the new investigational agents are inhibitors of squalene synthetase, acylCoA: cholesterol acyltransferase, cholesteryl ester transfer protein, monocyte-macrophages and LDL cholesterol oxidation. Future applications may include thyromimetic therapy, cholesterol vaccination, somatic gene therapy, and recombinant proteins, in particular, apolipoproteins A-I and E. Non-LDL-related targets such as peroxisome proliferator-activating receptors, matrix metalloproteinases and scavenger receptor class B type I may also have clinical significance in the treatment of atherosclerosis in the near future. Before lipid-lowering therapy, dietary and lifestyle modification is and should be the first therapeutic intervention in the management of dyslipidaemia. Although current recommendations from the US and Europe are slightly different, adherence to these recommendations is essential to lower the risk of atherosclerotic vascular disease, more specifically CHD. New guidelines that are expected in the near future will encompass global opinions from the expert scientific community addressing the issue of target LDL goal (aggressive versus moderate lowering) and the application of therapy for newer emerging CHD risk factors.     

烟酸制剂临床调脂治疗评价

目的：探讨烟酸制剂对多种高脂血症的效应。方法：参阅烟酸的药理作用机制及近年来国外烟酸缓释制剂和包含烟酸在内的联合制剂临床应用的报道。结果：适用于混合型高脂血症、高三酰甘油酯血症、低高密度脂蛋白血症及高脂蛋白（a）血症，同时具有升高高密度脂蛋白胆固醇的作用，对Ⅱb和Ⅳ型最好。结论：普通制剂有众多的不良反应大大限制了它的使用，随着烟酸缓释制荆的出现，其不良反应明显降低，而且长期大规模应用观察认为能减少冠心病的发作和死亡率，从而为临床调血脂治疗和联合用药提供了一种更安全、有效的选择。     

Nicotinic acid: new/old drug. Immediate or sustained release: too risky for a drug with no proven benefit

(1) For patients with hypercholesterolaemia requiring primary or secondary prevention, pravastatin, simvastatin and atorvastatin have a proven benefit in terms of mortality and/or morbidity. Gemfibrozil and cholestyramine have a proven impact on morbidity. (2) The lipid-lowering properties of immediate-release nicotinic acid have been known for about 50 years, as have its frequent and sometimes severe adverse effects. About 70% of patients experience cutaneous flushing, and 20-30% develop gastrointestinal adverse effects. Hepatotoxic effects occur in about 2% of patients, especially in those using high daily doses or sustained-release formulations. (3) The clinical evaluation of immediate-release nicotinic acid is mainly based on two comparative placebo-controlled trials. One, involving 5000 patients monitored on average for 15 years, showed no effect on survival. One trial suggested that immediate-release nicotinic acid reduced the risk of recurrent myocardial infarction. (4) Sustained-release nicotinic acid has not been evaluated in terms of its effect on morbidity or mortality. It has been shown to lower LDL cholesterol and triglyceride levels and to raise the HDL cholesterol level. (5) This new pharmaceutical formulation has a profile and frequency of known adverse effects similar to those of immediate-release nicotinic acid. (6) When hypercholesterolaemia persists despite an appropriate diet, it is best to use one drug with a proven preventive impact on mortality and/or morbidity. This is not the case for sustained-release nicotinic acid. (7) When statin therapy is inadequate, it remains to be shown whether adding another cholesterol-lowering drug is beneficial in terms of morbidity and mortality. If, in rare cases, combination with a statin is envisaged, it is best to use gemfibrozil or cholestyramine. Note that gemfibrozil should only be combined with a statin with the greatest caution.     

Pharmacological profile of SMP-797, a novel acyl-coenzyme a: cholesterol acyltransferase inhibitor with inducible effect on the expression of low-density lipoprotein receptor

We investigated the pharmacological profile of SMP-797, a novel hypocholesterolemic agent. SMP-797 showed inhibitory effects on acyl-coenzyme A: cholesterol acyltransferase (ACAT) activities in various microsomes and in human cell lines, and hypocholesterolemic effects in rabbits fed a cholesterol-rich diet and hamsters fed a normal diet. In hamsters, the reduction of total cholesterol level by SMP-797 was mainly due to the decrease of low-density lipoprotein (LDL) cholesterol level rather than that of very low-density lipoprotein (VLDL) cholesterol level. Interestingly, SMP-797 increased the hepatic low-density lipoprotein receptor expression in vivo when it decreased the low-density lipoprotein cholesterol level. SMP-797 also increased low-density lipoprotein receptor expression in HepG2 cells like atorvastatin, an HMG-CoA reductase inhibitor, although other acyl-coenzyme A: cholesterol acyltransferase inhibitor had no effect. In addition, SMP-797 had no effect on cholesterol synthesis in HepG2 cells. These results suggested that the increase of low-density lipoprotein receptor expression by SMP-797 was independent of its acyl-coenzyme A: cholesterol acyltransferase inhibitory action and did not result from the inhibition of hepatic cholesterol synthesis. In conclusion, these results suggest that SMP-797 is a novel hypocholesterolemic agent showing a cholesterol-lowering effect in which the increase of hepatic low-density lipoprotein receptor expression as well as the inhibition of acyl-coenzyme A: cholesterol acyltransferase is involved.     

Pharmacotherapy for dyslipidaemia--current therapies and future agents

Current lipid-altering agents that lower low density lipoprotein cholesterol (LDL-C) primarily through increased hepatic LDL receptor activity include statins, bile acid sequestrants/resins and cholesterol absorption inhibitors such as ezetimibe, plant stanols/sterols, polyphenols, as well as nutraceuticals such as oat bran, psyllium and soy proteins; those currently in development include newer statins, phytostanol analogues, squalene synthase inhibitors, bile acid transport inhibitors and SREBP cleavage-activating protein (SCAP) activating ligands. Other current agents that affect lipid metabolism include nicotinic acid (niacin), acipimox, high-dose fish oils, antioxidants and policosanol, whilst those in development include microsomal triglyceride transfer protein (MTP) inhibitors, acylcoenzyme A: cholesterol acyltransferase (ACAT) inhibitors, gemcabene, lifibrol, pantothenic acid analogues, nicotinic acid-receptor agonists, anti-inflammatory agents (such as Lp-PLA(2) antagonists and AGI1067) and functional oils. Current agents that affect nuclear receptors include PPAR-alpha and -gamma agonists, while in development are newer PPAR-alpha, -gamma and -delta agonists, as well as dual PPAR-alpha/gamma and 'pan' PPAR-alpha/gamma/delta agonists. Liver X receptor (LXR), farnesoid X receptor (FXR) and sterol-regulatory element binding protein (SREBP) are also nuclear receptor targets of investigational agents. Agents in development also may affect high density lipoprotein cholesterol (HDL-C) blood levels or flux and include cholesteryl ester transfer protein (CETP) inhibitors (such as torcetrapib), CETP vaccines, various HDL 'therapies' and upregulators of ATP-binding cassette transporter (ABC) A1, lecithin cholesterol acyltransferase (LCAT) and scavenger receptor class B Type 1 (SRB1), as well as synthetic apolipoprotein (Apo)E-related peptides. Fixed-dose combination lipid-altering drugs are currently available such as extended-release niacin/lovastatin, whilst atorvastatin/amlodipine, ezetimibe/simvastatin, atorvastatin/CETP inhibitor, statin/PPAR agonist, extended-release niacin/simvastatin and pravastatin/aspirin are under development. Finally, current and future lipid-altering drugs may include anti-obesity agents which could favourably affect lipid levels.     

Hypolipidemic Effects of 2-Furoic Acid in Sprague-Dawley Rats

2-Furoic acid was shown to be effective in lowering both serum cholesterol and serum triglyceride levels significantly in rats with an elevation of HDL cholesterol level at 20 mg/kg/day orally. LDL receptor activity was reduced in hepatocytes, aorta foam cells, small intestinal epithelium cells and fibroblasts. HDL receptor activity was elevated in the rat hepatocytes and small intestinal cells. These activities were correlated with inhibition of acyl CoA cholesterol acyl transferase activity. Neutral cholesterol ester hydrolase activity was elevated in rat hepatocytes and human fibroblasts. Thus, 2-furoic acid appears to interfere directly with activity of intracellular enzymes rather than affecting high affinity-mediated lipoprotein membrane receptors. In vivo treatment with 2-furoic acid led to reduction in the liver and small intestine ATP dependent citrate lyase, acetyl CoA synthetase, acyl CoA cholesterol acyl transferase, sn-glycerol 3-phosphate acyl transferase, phosphatidylate phosphohydrolase and heparin induced lipoprotein lipase activities. 2-Furoic acid reduced biliary cholesterol levels but the agent increased bile salts which are lithogenic. Acute toxicity studies in mice suggest that the agent has some hepatic toxicity effects. The LD⁵⁰ was relatively low at 250 mg/kg IP in mice.     

HDL as a target in the treatment of atherosclerotic cardiovascular disease

Lipid abnormalities are among the key risk factors for cardiovascular disease. Indeed, lipid-modifying drugs - in particular, the statins, which primarily lower plasma levels of low-density lipoprotein (LDL) cholesterol - considerably reduce the risk of cardiovascular events, leading to their widespread use. Nevertheless, it seems that there might be limits to the degree of benefit that can be achieved by lowering LDL-cholesterol levels alone, which has led to increased interest in targeting other lipid-related risk factors for cardiovascular disease, such as low levels of high-density lipoprotein (HDL) cholesterol. In this article, we first consider the mechanisms that underlie the protective effect of HDL cholesterol, and then discuss several strategies that have recently emerged to increase levels of HDL cholesterol to treat cardiovascular disease, including nuclear receptor modulation, inhibition of cholesteryl ester transfer protein and infusion of apolipoprotein/phospholipid complexes.     

Paradoxical effects of fenofibrate and nicotinic acid in apo E-deficient mice

Atherosclerosis is a complex vascular disease initiated by abnormal accumulation of plasma lipoproteins in the subendothelial space. Elevated levels of plasma triglycerides (TG) and low-density lipoprotein (LDL)-cholesterol as well as low concentrations of high-density lipoprotein (HDL) play a causal role in the development and progression of atherosclerotic lesions. We have shown that apolipoprotein E-deficient (apo E-KO) mice have elevated triglyceride levels plus diminished HDL concentrations. Drugs such as fenofibrate and nicotinic acid are well known to reduce TG and increase HDL levels in humans. In this study, we investigated the beneficial effects of fenofibrate and niacin on lipid profile and atherogenesis in apo E-KO mice and their wild-type counterparts. Animals were fed with a cholesterol-enriched diet supplemented with fenofibrate (0.1% wt/wt, n = 8) or nicotinic acid (0.5% wt/wt, n = 8) for 14 weeks. Body weights were recorded weekly, and plasma lipid profiles were determined at 4-week intervals. The hearts and aortas were collected and fixed for histologic and morphometric evaluations of atherosclerotic lesions. Fenofibrate treatment in apo E-KO mice paradoxically increased total cholesterol and TG by 65% and 44%, respectively, and decreased HDL-cholesterol levels by 35% as compared with controls. Similar effects of fenofibrate on cholesterol levels, but not on TG concentrations, were observed in C57BL/6 mice. Fenofibrate-treated mice had lower body weight as compared with controls. Niacin had no effect on body weight gain but failed to decrease TG or to increase HDL levels in either apo E-KO mice or their wild-type counterparts. Neither fenofibrate nor niacin significantly influenced atherogenesis in apo E-KO mice as compared with controls. In conclusion, this study shows that neither niacin nor fenofibrate has beneficial lipid-modifying and antiatherosclerosis activities in mice. Identification of mechanisms underlying paradoxical effects of fenofibrate on lipoprotein metabolisms in apo E-KO mice merits further investigation.