Elsevier

Physiology & Behavior

Volume 94, Issue 2, 23 May 2008, Pages 187-197
Physiology & Behavior

Review
Peroxisome proliferator-activated receptors and the metabolic syndrome

https://doi.org/10.1016/j.physbeh.2007.11.053Get rights and content

Abstract

The prevalence of the metabolic syndrome is rapidly increasing. This syndrome is characterized by metabolic disturbances, such as abnormal lipid and carbohydrate metabolism and a low-grade inflammatory state. PPARs play an important role in these metabolic processes, which makes them effective targets for treatment and prevention of the metabolic syndrome. Synthetic PPAR agonists, such as fibrates and thiazolidinediones are already used to treat hyperlipidemia and diabetes mellitus, respectively. Besides synthetic ligands, dietary fatty acids and fatty acid derivatives can also bind to an activate PPARs. As demonstrated with ligand-binding assays, PPARs have a clear preference of binding polyunsaturated fatty acids. Monounsaturated fatty acids are also very effective in binding PPARs, whereas saturated fatty acids are poor PPAR binders. However, ligand binding does not necessarily mean transcriptional activation. Therefore, it is important to investigate transactivation properties of dietary fatty acids as PPAR agonists and their role in metabolic reactions. Furthermore, human intervention studies comparing the effects of natural versus synthetic ligands side-by-side may reveal specific fatty acids that exert beneficial PPAR-mediated metabolic effects. The ability of PPARs to sense fatty acids and to mediate lipid metabolism, glucose metabolism and the inflammatory state makes them excellent targets for dietary modulation in order to prevent and treat the metabolic syndrome and associated diseases. This review discusses the role and function of PPARs and their ligands in light of the metabolic syndrome.

Introduction

There is an increasing incidence of diet-related diseases, such as cardiovascular diseases (CVD) and type II diabetes mellitus (T2D). Obesity is a major risk factor for developing these metabolic diseases, and the incidence has reached global epidemic proportions [1]. CVD and T2D are often linked with the metabolic syndrome (MS), which refers to a cluster of metabolic disturbances, such as abnormal lipid and carbohydrate metabolism and a pro-inflammatory state of the body [2].

Potential molecular targets to treat and prevent these metabolic disturbances are peroxisome proliferator-activated receptors (PPARs). PPARs are one of the central regulators of nutrient–gene interactions and are able to regulate lipid, carbohydrate, and inflammatory pathways, hereby maintaining homeostasis [3], [4], [5]. In fact, PPARα agonists (fibrates) and PPARγ agonists (thiazolidinediones) are already used to improve serum lipoprotein profiles and glucose metabolism, respectively [6], [7]. PPARs are able to sense the presence of fatty acids [8]. Upon binding with fatty acids or a synthetic agonist, PPARs bind as a heterodimer with the retinoid X receptor (RXR) to a PPAR response element (PPRE) in enhancer sites of regulated genes to increase gene transcription [9]. Furthermore, phosphorylation status and the presence of co-factors are important in regulating PPAR-dependent gene transcription [10], [11].

Fatty acids derived from the diet can modulate the activity of PPARs, but the type of fatty acid differs in its capacity to activate PPAR-dependent gene transcription [12], [13], [14]. Activation of PPARs by fatty acids has been investigated in previous studies, which almost exclusively focused on ligand-binding assays [14], [15]. Ligand binding, however, does not necessarily mean transcriptional activation. Here we will present an overview of the current knowledge of PPARs and their ability to sense fatty acids, their synthetic agonists, and their ability to modify gene transcription in light of the metabolic syndrome. First, we elaborate on the role and function of PPAR isotypes and their tissue distribution. Second, the ability of natural and synthetic ligands to transactivate PPARs is discussed. Finally, the influences of PPARs on lipid metabolism, glucose metabolism and inflammation are described and the importance of these effects in relation to the metabolic syndrome is discussed.

Section snippets

PPAR isotypes, chromosomal location and tissue distribution in humans

PPARs form a subclass of the nuclear hormone receptor superfamily. First, the PPAR subclasses are described, followed by the general structure of PPARs, their chromosomal localization, and their variation in tissue-specific expression. So far, three PPAR isotypes are identified in vertebrates: PPARα, PPARβ (also designated as PPARδ) and PPARγ. These isotypes were first discovered as a group in Xenopus laevis [16]. Based on sequence homology, the mammalian PPARα and -γ were easily identified,

PPAR ligands

Fatty acids are important dietary components and participate in the regulation of gene expression upon nutritional changes. Hereby, fatty acids influence transport, mobilization, utilization and the availability of lipids and glucose. Many effects of fatty acids are regulated via PPARs, as these receptors are lipid-sensing transcription factors [8]. Fatty acids are only one class of compounds that are known to activate PPARs. PPARs can also be activated by the hypolipidemic drugs (e.g.

Lipid and lipoprotein metabolism

Dyslipidemia in the metabolic syndrome is characterized by elevated triglyceride levels and reduced HDL cholesterol levels and associated with increased LDL cholesterol levels [53], [54]. In addition, obesity, diabetes, CVD, and fasting are associated with elevated levels of plasma free fatty acids [55], [56], [57]. PPARs are thought to play a prominent role to prevent dyslipidemia and maintain metabolic homeostasis as PPARs are the major regulators of lipid and fatty acid metabolism that

References (109)

  • P. Cronet et al.

    Structure of the PPARalpha and -gamma ligand binding domain in complex with AZ 242; ligand selectivity and agonist activation in the PPAR family

    Structure

    (2001)
  • K. Mochizuki et al.

    Selectivity of fatty acid ligands for PPARalpha which correlates both with binding to cis-element and DNA binding-independent transactivity in Caco-2 cells

    Life Sci

    (2006)
  • Z. Wang et al.

    Critical roles of the p160 transcriptional coactivators p/CIP and SRC-1 in energy balance

    Cell Metab

    (2006)
  • H.I. Kim et al.

    Transcriptional activation of SHP by PPAR-gamma in liver

    Biochem Biophys Res Commun

    (2007)
  • G. Krey et al.

    Xenopus peroxisome proliferator activated receptors: genomic organization, response element recognition, heterodimer formation with retinoid X receptor and activation by fatty acids

    J Steroid Biochem Mol Biol

    (1993)
  • J. Kasuga et al.

    Design, synthesis, and evaluation of potent, structurally novel peroxisome proliferator-activated receptor (PPAR) delta-selective agonists

    Bioorg Med Chem

    (2007)
  • S. Seber et al.

    The effect of dual PPAR alpha/gamma stimulation with combination of rosiglitazone and fenofibrate on metabolic parameters in type 2 diabetic patients

    Diabetes Res Clin Pract

    (2006)
  • K. Schoonjans et al.

    Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression

    J Lipid Res

    (1996)
  • K. Schoonjans et al.

    Induction of the acyl-coenzyme A synthetase gene by fibrates and fatty acids is mediated by a peroxisome proliferator response element in the C promoter

    J Biol Chem

    (1995)
  • E. Bruckert et al.

    Ciprofibrate therapy normalises the atherogenic low-density lipoprotein subspecies profile in combined hyperlipidemia

    Atherosclerosis

    (1993)
  • B. Staels et al.

    Regulation of apo A-I gene expression by fibrates

    Atherosclerosis

    (1998)
  • Y.X. Wang et al.

    Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity

    Cell

    (2003)
  • M. Kabine et al.

    Peroxisome proliferator-activated receptors as regulators of lipid metabolism; tissue differential expression in adipose tissues during cold acclimatization and hibernation of jerboa (Jaculus orientalis)

    Biochimie

    (2004)
  • J.N. van der Veen et al.

    Reduced cholesterol absorption upon PPARdelta activation coincides with decreased intestinal expression of NPC1L1

    J Lipid Res

    (2005)
  • E. Esteve et al.

    Dyslipidemia and inflammation: an evolutionary conserved mechanism

    Clin Nutr

    (2005)
  • M.S. Kipnes et al.

    Pioglitazone hydrochloride in combination with sulfonylurea therapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, placebo-controlled study

    Am J Med

    (2001)
  • B. Verges

    Clinical interest of PPARs ligands

    Diabetes Metab

    (2004)
  • G. Martin et al.

    Coordinate regulation of the expression of the fatty acid transport protein and acyl-CoA synthetase genes by PPARalpha and PPARgamma activators

    J Biol Chem

    (1997)
  • K. Motojima et al.

    Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor alpha and gamma activators in a tissue- and inducer-specific manner

    J Biol Chem

    (1998)
  • G. Chinetti et al.

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

    J Biol Chem

    (1998)
  • P. Tontonoz et al.

    PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL

    Cell

    (1998)
  • S. Kersten

    Peroxisome proliferator activated receptors and obesity

    Eur J Pharmacol

    (2002)
  • P. Raman et al.

    Role of glucose and insulin in thiazolidinedione-induced alterations in hepatic gluconeogenesis

    Eur J Pharmacol

    (2000)
  • R. Ross

    Atherosclerosis is an inflammatory disease

    Am Heart J

    (1999)
  • P. Delerive et al.

    Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1

    J Biol Chem

    (1999)
  • G. Rizzo et al.

    PPARs and other nuclear receptors in inflammation

    Curr Opin Pharmacol

    (2006)
  • U. Salmenniemi et al.

    Multiple abnormalities in glucose and energy metabolism and coordinated changes in levels of adiponectin, cytokines, and adhesion molecules in subjects with metabolic syndrome

    Circulation

    (2004)
  • P. Delerive et al.

    Peroxisome proliferator-activated receptors in inflammation control

    J Endocrinol

    (2001)
  • F.M. Martens et al.

    Metabolic and additional vascular effects of thiazolidinediones

    Drugs

    (2002)
  • Y. Miyazaki et al.

    Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone

    Diabetes Care

    (2001)
  • B. Staels et al.

    Mechanism of action of fibrates on lipid and lipoprotein metabolism

    Circulation

    (1998)
  • P.A. Grimaldi

    Lipid sensing and lipid sensors: peroxisome proliferator-activated receptors as sensors of fatty acids and derivatives

    Cell Mol Life Sci

    (2007)
  • B. Desvergne et al.

    Peroxisome proliferator-activated receptors: nuclear control of metabolism

    Endocr Rev

    (1999)
  • 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)
  • 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)
  • J.C. Hanselman et al.

    Expression of the mRNA encoding truncated PPAR alpha does not correlate with hepatic insensitivity to peroxisome proliferators

    Mol Cell Biochem

    (2001)
  • D. Auboeuf et al.

    Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans: no alteration in adipose tissue of obese and NIDDM patients

    Diabetes

    (1997)
  • P. Gervois et al.

    A truncated human peroxisome proliferator-activated receptor alpha splice variant with dominant negative activity

    Mol Endocrinol

    (1999)
  • W. Su et al.

    Differential expression, distribution, and function of PPAR-gamma in the proximal and distal colon

    Physiol Genomics

    (2007)
  • D.J. Mangelsdorf et al.

    Characterization of three RXR genes that mediate the action of 9-cis retinoic acid

    Genes Dev

    (1992)
  • Cited by (70)

    • Inhibition of PPARα attenuates vimentin phosphorylation on Ser-83 and collapse of vimentin filaments during exposure of rat Sertoli cells in vitro to DBP

      2014, Reproductive Toxicology
      Citation Excerpt :

      Immunocytochemistry and CHIP-qPCR results showed that PPARα was transferred to the nucleus after 24 h of DBP exposure and activated the PPRE transcription factor, which demonstrated the activation of PPARα. Besides the transportation to nucleus and promotion of the transcription of target genes, PPARα is also associated with kinase-dependent processes in the cytoplasm (non-genomic effects) [61,62]. PPARα is involved in many of the kinase-dependent processes, such as the mitogen-activated protein kinase (MAPKs) signal cascade [63,64], transforming growth factor (TGF)-β pathway [65], and the protein kinase C (PKC) signal pathway [66].

    • Free fatty acids as modulators of the NLRP3 inflammasome in obesity/type 2 diabetes

      2014, Biochemical Pharmacology
      Citation Excerpt :

      PPARs regulate distinct biochemical events required for lipid homeostasis. After binding of their ligand, they mediate transcriptional activation of genes carrying the PPAR response element [18]. The effects of FAs as signaling molecules can also be explained by receptor binding at the cell surface.

    View all citing articles on Scopus
    View full text