Peroxisome proliferator-activated receptor gamma (PPARγ) and its ligands: A review
Introduction
Nuclear receptors are integral regulators of gene transcription and intracellular function (see reviews [1], [2]). The nuclear receptor superfamily includes members such as the estrogen; thyroid and glucocorticoid receptors as well as the subfamily of peroxisome proliferator-activated receptors (PPARs; Fig. 1A). Nuclear receptors are ligand-activated transcription factors that regulate diverse biologic events ranging from cell differentiation and development to lipid metabolism and energy homeostasis. Steroids, fatty acids, hormones, and vitamins A and D are among the natural lipophilic ligands that bind to this superfamily of receptors.
The PPAR subfamily of nuclear hormone receptors include distinct genes that code for several PPAR isoforms denoted: PPARα, β/δ and γ [3]. The PPARγ gene contains three promoters that yield three RNA isoforms, γ1, γ2, and γ3 by alternative promoter usage and splicing [4], [5], [6], [7]. The PPARγ1 and γ3 RNA transcripts both translate into PPARγ1 protein. Expression of PPARs is tissue dependent [8]. PPARα is highly expressed in liver, cardiac myocytes, enterocytes and proximal tubule of the kidney. PPARβ/δ is ubiquitously expressed, whereas PPARγ is highly expressed in adipose tissue and the immune system. PPARγ1 is expressed (in relatively low abundance) in many tissues, whereas PPARγ2 is predominantly expressed in adipocytes.
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PPAR: key regulators of gene transcription
PPARγ, like other members of the nuclear receptor superfamily, is characterized by three general functional domains: the N-terminal domain (a site for functional regulation by phosphorylation; [9], [10], [11], [12], [13]), the DNA binding domain and the ligand binding domain (see Fig. 1B). The processes by which PPAR bind DNA and regulate transcription have been extensively reviewed (see [14], [15]). Briefly, ligand binds to the PPAR molecule, causing a conformational change in the AF2
PPARγ ligands
Although there are a number of naturally occurring agents that activate PPARγ (Fig. 3, [21]), the identity of the true natural ligand of this receptor is still a mystery. Various polyunsaturated acids activate PPARγ in micromolar concentrations [22], [23]. Since free fatty acids circulate within human plasma in micromolar levels [24], it is not unrealistic to consider the possibility of their functioning as the receptor’s natural ligand. However, concentration of unsaturated fatty acids within
PPARγ: a pivotal regulator of adipocyte differentiation
Adipogenesis refers to the process of differentiation of preadipocyte precursor cells into adipocytes that are capable of lipid filling as well as the expression and secretion of myriad hormones and cytokines. Adipogenesis occurs prenatally and postnatally, both in response to normal cell turnover and to support excess energy storage [48]. The program of adipocyte differentiation and associated induction of adipocyte gene expression has been extensively studied (see review [49]). PPARγ (coupled
Regulation of PPARγ gene expression
Although considerable data exist which quantify effects of PPARγ activation (primarily via treatment with thiazolidinediones), there is a relative paucity of data that describe the regulation of expression of PPARγ, especially the differential regulation of expression of the various PPARγ isoforms.
In livestock, the PPARγ gene has been cloned in pigs [61], [62] and cattle [63]. The porcine PPARγ gene has been mapped to porcine chromosome 13 [64], and the nucleic acid sequence of porcine PPARγ is
Nutritional regulation of gene expression: PPARγ as a fatty acid receptor
Dietary fat (fatty acid profile and total fat consumption) regulates gene expression in metabolic tissues; often effects are observed in a tissue-specific manner. For example, consumption of high fat diets leads to whole-body insulin resistance in rodents, and the mechanisms underlying this insulin resistance involve the insulin responsive glucose transporter, GLUT4. Increased dietary fat (but not caloric) consumption down-regulates GLUT4 protein expression in adipose tissue but not skeletal
Role of PPARγ in nutritional regulation of gene expression
In addition to regulating the expression of PPARγ RNA and protein, dietary fatty acids are also able to activate PPARs and promote diet-induced changes in gene expression in metabolically important tissues. Many fatty acids activate the various PPAR isoforms (see review [76]), and PPAR isoforms are implicated in mediating the anti-cancer effects of diverse fatty acids such as conjugated linoleic acids (CLAs).
CLA is a group of geometric and positional isomers of linoleic acid found in ruminant
Role of PPARγ in the pathophysiology of diabetes, cancer and inflammation
PPARγ and its ligands have now been implicated in the pathology and/or treatment of numerous diseases in man including obesity, diabetes, atherosclerosis and cancer. As several of these pathologies are also prevalent in companion animals, a review of the clinical and pharmaceutical literature follows.
PPARγ ligands are insulin sensitizers
Non-insulin dependent diabetes mellitus (NIDDM), otherwise known as Type II diabetes, is characterized by defects in peripheral glucose uptake and utilization, hepatic glucose production and pancreatic β-cell dysfunction (see Fig. 6, [86]). Peripheral insulin resistance (skeletal muscle and adipose tissue) and hyperinsulinemia often precede the development of hyperglycemia and frank diabetes.
Pharmaceutical ligands for PPARγ, including the TZD class of drugs, are potent insulin sensitizers that
PPAR gamma and beta cell function
An important component in the development of hyperglycemia and glucose intolerance in diabetic patients and animal models of NIDDM is reduced pancreatic beta cell function and/or mass. PPARγ ligands may have therapeutic efficacy in preventing the loss of β-cell function as it has recently been reported that PPARγ is expressed in normal human islet cells [92] and several studies conducted with ZDF rats report that treatment of prediabetic animals with thiazolidinediones prevented beta cell loss
Mutations in hPPARγ gene impact insulin action
A commonly occurring mutation in the human PPARγ2 gene is the proline to alanine exchange in codon 12 (Pro12Ala). This mutation is associated with reduced transcriptional activity when assayed in vitro [97]. Furthermore, the Pro12Ala polymorphism in humans is associated with lower fasting insulin concentrations [97] improved insulin sensitivity [98], [99], increased antilipolytic insulin sensitivity [100] and reduced risk of Type II diabetes [101], [102]. Recently, Stefan et al. [103] provided
PPARγ in inflammation
PPARγ has been implicated in the regulation of multiple inflammatory processes (see reviews [14], [15], [109], [110]). Furthermore, PPARγ ligands have been proposed as possible therapeutics for inflammatory disease processes including inflammatory bowel disease and arthritis.
PPARγ is expressed throughout the immune system in rodents, humans and pigs [3], [62], [111], [112] and PPARγ expression is induced during monocyte to macrophage differentiation in vitro [110], [113]. Multiple studies have
PPARγ and cancer
The ability of PPARγ to regulate cell differentiation and proliferation has inspired a number of researchers to explore the use of PPARγ agonists as chemotherapeutic agents [117], [118], [119]. PPARγ is highly expressed in human lipocarcinomas [120] and various other human tumors including breast [121], [122], lung [123], [124], colon [125], [126], prostate [127], bladder [128] and gastric [129]. Furthermore, prostaglandin 15d-PGJ2 and/or troglitazone induce apoptosis and growth inhibition of
Summary
PPARγ is a nuclear receptor that plays a pivotal role in the regulation of gene transcription and cellular differentiation. Furthermore, it appears to link lipid and glucose metabolism and is being pursued as a therapeutic target for diverse pathophysiological states in humans including diabetes, cancer and inflammation. Although a considerable amount is known about the regulation of PPARγ action in rodents and humans, there is a paucity of data examining PPARγ expression and function in
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