Review
PPARα in atherosclerosis and inflammation

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Abstract

Peroxisome proliferator-activated receptor (PPAR)α is a nuclear receptor activated by natural ligands such as fatty acids as well as by synthetic ligands such as fibrates currently used to treat dyslipidemia. PPARα regulates the expression of genes encoding proteins that are involved in lipid metabolism, fatty acid oxidation, and glucose homeostasis, thereby improving markers for atherosclerosis and insulin resistance. In addition, PPARα exerts anti-inflammatory effects both in the vascular wall and the liver. Here we provide an overview of the mechanisms through which PPARα affects the initiation and progression of atherosclerosis, with emphasis on the modulation of atherosclerosis-associated inflammatory responses. PPARα activation interferes with early steps in atherosclerosis by reducing leukocyte adhesion to activated endothelial cells of the arterial vessel wall and inhibiting subsequent transendothelial leukocyte migration. In later stages of atherosclerosis, evidence suggests activation of PPARα inhibits the formation of macrophage foam cells by regulating expression of genes involved in reverse cholesterol transport, formation of reactive oxygen species (ROS), and associated lipoprotein oxidative modification among others. Furthermore, PPARα may increase the stability of atherosclerotic plaques and limit plaque thrombogenicity. These various effects may be linked to the generation of PPARα ligands by endogenous mechanisms of lipoprotein metabolism. In spite of this dataset, other reports implicate PPARα in responses such as hypertension and diabetic cardiomyopathy. Although some clinical trials data with fibrates suggest that fibrates may decrease cardiovascular events, other studies have been less clear, in terms of benefit. Independent of the clinical effects of currently used drugs purported to achieve PPARα, extensive data establish the importance of PPARα in the transcriptional regulation of lipid metabolism, atherosclerosis, and inflammation.

Introduction

Atherosclerosis, the major cause of death from cardiovascular disease in industrialized countries, is characterized by the progressive accumulation of lipid and fibrous depositions in the vessel wall of large arteries [1], [2]. Well-established risk factors for atherosclerosis include hypertension, hypercholesterolemia, and diabetes mellitus. More recent work reveals procoagulant and proinflammatory states can be added as important contributors to the development of atherosclerosis [3], [4], [5]. To an increasing extent, attention has focused on how abnormalities of metabolism – atherogenic dyslipidemia, insulin resistance, visceral adiposity – may promote atherogenesis. Indeed, clinical evidence underscores how parameters such as glucose represent a continuous rather than dichotomous variable in cardiovascular risk, even at levels that do not meet a diagnosis of frank diabetes. Likewise, although debates continue regarding triglycerides as an independent risk factor for cardiovascular events, the presence of hypertriglycemia confers a considerable increase in risk among subjects with otherwise similar ratios of low density lipoprotein (LDL) and high density lipoprotein (HDL).

This evolving view of atherosclerosis as a metabolic complication has directed attention towards peroxisome proliferator-activated receptors (PPARs) as transcriptional regulators involved in lipid metabolism, inflammation, and atherosclerosis. PPARs, as ligand-activated transcription factors belonging to the nuclear hormone receptor family, can regulate multiple target genes. Extensive data establish expression of all three PPAR isotypes – PPARα, -γ, and -δ/β – throughout the vasculature and inflammatory cells [8]. The focus here is on PPARα, which has been strongly implicated in beta oxidation of fatty acids as well as lipid metabolism. Not surprisingly given these effects, PPARα is expressed mainly in higher energy-requiring tissues like skeletal muscle and heart as well as the liver. Activation of PPARα has been reported to improve levels of triglycerides, HDL, and the overall atherogenic plasma lipid profile, while also potentially modulating inflammation as well as insulin resistance itself [6], [7]. PPARα has been reported to be activated by natural ligands such as fatty acids and their derivatives, and contain leukotrienes products [9], [10], as well as by drugs such as the lipid-lowering fibrates [11], [12], [13]. Pharmacological treatment of patients with fibrates has been shown to lower cardiovascular mortality although this dataset is mixed as will be discussed further below.

One of the many lines of evidence that suggest PPARα may play a role in atherosclerosis derives from the data implicating this receptor in limiting inflammation. In the absence of PPARα, mice have a prolonged response to inflammatory stimuli [9]. PPARs have also been found to modulate the acute phase response of the liver as well as mechanisms of inflammation in the vasculature [14], [15]. Aortas from PPARα-deficient mice display an exacerbated inflammatory response to stimulation with lipopolysaccharide. In addition, murine endothelial cells (EC) and hepatocytes that lack PPARα have increased levels of inflammatory targets such as vascular cell adhesion molecule-1 (VCAM-1) and serum amyloid A (SAA) [10], [16].

PPARα's seeming placement at the nexus of lipid metabolism, energy balance, and inflammation, makes its potential as a target for limiting atherosclerosis of obvious interest. This review examines the various mechanisms through which PPARα has been implicated in atherosclerosis and explores the potential importance of PPARα in atherosclerosis. Although inflammation is an important part of the immune response and necessary for organismal defense, chronic inflammatory activation may also have deleterious, maladaptive effects, including promotion of atherosclerosis and its complications. Given the evidence for PPARα's involvement in limiting inflammation under basal conditions and inhibiting inflammatory responses after inflammatory stimuli forces, this issue will be a focus of the discussion here.

Section snippets

PPARα in the regulation of inflammation in the liver

The liver is an integral and often overlooked player in atherosclerosis, including systemic effects through hepatic function as the organ seat for the synthesis of lipoprotein particles — important contributors to cardiovascular risk. The liver is also the site of synthesis for other acute phase reactants such as C-reactive protein (CRP), fibrinogen, and serum amyloid A (SAA). Levels of these proteins all reportedly correlate with cardiovascular disease [17], [18]. The acute phase response is a

PPARα and endothelial reactivity

Development of atherosclerotic lesions is often preceded by abnormalities in vascular wall reactivity [29]. In many ways, this alteration in arterial function stems from changes in endothelial cells, highlighting one of many examples that have re-defined the endothelium as a dynamic, biologically-active organ rather than just a passive arterial lining. The importance of the endothelium in vessel reactivity and subsequent abnormalities of arterial responses has fostered the use of the term

PPARα and the arterial adhesion and entry of leukocytes

Early atherogenesis is characterized by the recruitment and subsequent entry of leukocytes to an injured endothelium. This endothelial damage can derive directly from risk factors such as hypertension (shear stress), hyperglycemia, and hypercholesterolemia. Leukocytes are recruited to these sites of injury by following a chemical gradient of released chemoattractant cytokines, or chemokines, released from the activated endothelial cells and the sub-endothelium. Subsequently, these inflammatory

PPARα and local immune cell responses

T lymphocytes and dendritic cells (DCs) are now recognized as important players in atherosclerosis, with the recruitment, activation, and proliferation of these immune cells contributing to lesion formation and its complications. Activated T lymphocytes and dendritic cells (DC), the most potent antigen-presenting cells, co-localize in atheromata [48]. After their recruitment and entry into the vessel wall, T lymphocytes, consisting of mainly CD4-positive cells, differentiate from naive Th0

PPARα, oxidative modification of lipoproteins, and foam cell formation

Elevated LDL-cholesterol is a well-established risk factor for cardiovascular disease (CAD), as evident from the strong association between genetic disorders of cholesterol metabolism characterized by marked elevated LDL levels and premature CAD; patients with familial hypercholesterolemia can have myocardial infartions as early as 1 to 2 years of age. In more common forms of CAD, LDL confers an increased risk of atherosclerosis across a very wide range of LDL levels. Indeed, as clinical trial

PPARα and plaque stability and thrombogenicity

During the progression from early fatty streaks to a more complex atherosclerotic lesion, SMCs proliferate, migrate, and accumulate in the atherosclerotic plaque. The production of extracellular matrix (ECM) components by SMCs can further expand the lesion and foster a more fibrous plaque. The SMC is also the source of the material that makes up the fibrous cap that separates the necrotic, lipid-rich prothrombotic core and the circulation. Rupture of the fibrous cap, which typically occurs in

Connecting lipoprotein metabolism to PPARα activation in vivo: implications for inflammation and atherosclerosis

Although critical early work established that certain fatty acids could activate all PPAR isotypes, until recently little information existed on how metabolism of lipoproteins might be connected to PPAR responses. Given the complexity of lipid metabolism, such pathways might help explain selective PPAR activation or how abnormalities in lipid metabolism might be defined in part by changes in PPAR activation. Interestingly, many aspects of the PPAR field have been defined by responses to

PPARα activation: good or bad?

Although the bulk of PPARα data argues for PPARα as a mechanism for limiting inflammation and atherosclerosis, it is important to note countering evidence that suggests PPARα may also exert untoward effects. Although mouse bone marrow transplantation experiments using PPARα deficient macrophages support PPARα as decreasing atherosclerosis, crossing PPARα deficient mice with ApoE-deficient mice led to more atherosclerosis rather than decreasing atherosclerosis as might have been predicted if

Conclusion

Atherosclerosis is a chronic disease characterized by lipid and fibrous depositions in the arterial wall in the setting of a chronic pro-coagulant, pro-inflammatory state. The potential importance of PPARα in atherosclerosis is evident by its transcriptional regulation of pathways involved in atherogenic dyslipidemia, extracellular matrix remodeling, cholesterol efflux, thrombogenicity, and inflammation. As such, PPARα may well be involved in all the stages of atherosclerosis, from the earliest

References (101)

  • D.C. Jones et al.

    Nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) is expressed in resting murine lymphocytes. The PPARalpha in T and B lymphocytes is both transactivation and transrepression competent

    J. Biol. Chem.

    (2002)
  • J.J. Genest et al.

    Prevalence of risk factors in men with premature coronary artery disease

    Am. J. Cardiol.

    (1991)
  • I. Lemieux et al.

    A 16-week fenofibrate treatment increases LDL particle size in type IIA dyslipidemic patients

    Atherosclerosis

    (2002)
  • I. Inoue et al.

    The ligands/activators for peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma increase Cu2+,Zn2+-superoxide dismutase and decrease p22phox message expressions in primary endothelial cells

    Metabolism

    (2001)
  • T.B. Rajavashisth et al.

    Inflammatory cytokines and oxidized low density lipoproteins increase endothelial cell expression of membrane type 1-matrix metalloproteinase

    J. Biol. Chem.

    (1999)
  • H. Shu et al.

    Activation of PPARalpha or gamma reduces secretion of matrix metalloproteinase 9 but not interleukin 8 from human monocytic THP-1 cells

    Biochem. Biophys. Res. Commun.

    (2000)
  • W. Eberhardt et al.

    Inhibition of cytokine-induced matrix metalloproteinase 9 expression by peroxisome proliferator-activated receptor alpha agonists is indirect and due to a NO-mediated reduction of mRNA stability

    J. Biol. Chem.

    (2002)
  • G. Chinetti et al.

    Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages

    J. Biol. Chem.

    (1998)
  • J.G. Chen et al.

    Identification of a peroxisome proliferator responsive element (PPRE)-like cis-element in mouse plasminogen activator inhibitor-1 gene promoter

    Biochem. Biophys. Res. Commun.

    (2006)
  • E.D. Korn

    Clearing factor, a heparin-activated lipoprotein lipase. I. Isolation and characterization of the enzyme from normal rat heart

    J. Biol. Chem.

    (1955)
  • L. Li et al.

    Peroxisome proliferator-activated receptor alpha and gamma agonists upregulate human macrophage lipoprotein lipase expression

    Atherosclerosis

    (2002)
  • F.G. Gbaguidi et al.

    Peroxisome proliferator-activated receptor (PPAR) agonists decrease lipoprotein lipase secretion and glycated LDL uptake by human macrophages

    FEBS Lett.

    (2002)
  • W. Haberbosch et al.

    Apolipoprotein C-II deficiency. The role of apolipoprotein C-II in the hydrolysis of triacylglycerol-rich lipoproteins

    Biochim. Biophys. Acta

    (1984)
  • M. Merkel et al.

    Apolipoprotein AV accelerates plasma hydrolysis of triglyceride-rich lipoproteins by interaction with proteoglycan-bound lipoprotein lipase

    J. Biol. Chem.

    (2005)
  • J.F. Berbee et al.

    Severe hypertriglyceridemia in human APOC1 transgenic mice is caused by apoC-I-induced inhibition of LPL

    J. Lipid. Res.

    (2005)
  • T. Shimizugawa et al.

    ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase

    J. Biol. Chem.

    (2002)
  • S. Mandard et al.

    The fasting-induced adipose factor/angiopoietin-like protein 4 is physically associated with lipoproteins and governs plasma lipid levels and adiposity

    J. Biol. Chem.

    (2006)
  • M. Merkel et al.

    Lipoprotein lipase: genetics, lipid uptake, and regulation

    J. Lipid Res.

    (2002)
  • T. Ishida et al.

    Endothelial lipase modulates susceptibility to atherosclerosis in apolipoprotein-E-deficient mice

    J. Biol. Chem.

    (2004)
  • H. Duez et al.

    Reduction of atherosclerosis by the peroxisome proliferator-activated receptor alpha agonist fenofibrate in mice

    J. Biol. Chem.

    (2002)
  • P.G. McGovern et al.

    Recent trends in acute coronary heart disease-mortality, morbidity, medical care, and risk factors. The Minnesota Heart Survey Investigators

    N. Engl. J. Med.

    (1996)
  • L. Wilhelmsen et al.

    Coronary heart disease attack rate, incidence and mortality 1975–1994 in Goteborg, Sweden

    Eur. Heart J.

    (1997)
  • S.M. Grundy et al.

    Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition

    Circulation

    (2004)
  • R. Ross

    Atherosclerosis — an inflammatory disease

    N. Engl. J. Med.

    (1999)
  • P. Libby

    Inflammation in atherosclerosis

    Nature

    (2002)
  • M.H. Frick et al.

    Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease

    N. Engl. J. Med.

    (1987)
  • D. Patsouris et al.

    Peroxisome proliferator activated receptor ligands for the treatment of insulin resistance

    Curr. Opin. Investig. Drugs

    (2004)
  • B. Desvergne et al.

    Peroxisome proliferator-activated receptors: nuclear control of metabolism

    Endocr. Rev.

    (1999)
  • P.R. Devchand et al.

    The PPARalpha-leukotriene B4 pathway to inflammation control

    Nature

    (1996)
  • O. Ziouzenkova et al.

    Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: evidence for an antiinflammatory role for lipoprotein lipase

    Proc. Natl. Acad. Sci. U. S. A.

    (2003)
  • S.A. Kliewer et al.

    Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma

    Proc. Natl. Acad. Sci. U. S. A.

    (1997)
  • B.M. Forman et al.

    Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta

    Proc. Natl. Acad. Sci. U. S. A.

    (1997)
  • G. Krey et al.

    Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay

    Mol. Endocrinol.

    (1997)
  • B. Staels et al.

    Activation of human aortic smooth-muscle cells is inhibited by PPARalpha but not by PPARgamma activators

    Nature

    (1998)
  • C.Y. Han et al.

    Reciprocal and coordinate regulation of serum amyloid A versus apolipoprotein A-I and paraoxonase-1 by inflammation in murine hepatocytes

    Arterioscler. Thromb. Vasc. Biol.

    (2006)
  • P.M. Ridker et al.

    Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women

    JAMA

    (2005)
  • P.M. Ridker et al.

    C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women

    N. Engl. J. Med.

    (2000)
  • J.S. Yudkin et al.

    C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue?

    Arterioscler. Thromb. Vasc. Biol.

    (1999)
  • E. Rizos et al.

    Effect of ciprofibrate on C-reactive protein and fibrinogen levels

    Angiology

    (2002)
  • A. Madej et al.

    Effects of fenofibrate on plasma cytokine concentrations in patients with atherosclerosis and hyperlipoproteinemia IIb

    Int. J. Clin. Pharmacol. Ther.

    (1998)
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