Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Peroxisome Proliferator-Activated Receptor-γ

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101879

Synonyms

Historical Background

As cardiovascular pathology and its complications are associated with metabolic and immunoregulative disorders, there is a more urgent need to understand the molecular basis of obesity, atherogenesis, and immune inflammation (Mangelsdorf 1995). The identification of peroxisome proliferator-activated receptor gamma (PPARγ) as a nuclear receptor, which has pleiotropic function in inflammation, cell growth and differentiation, apoptosis, and carbohydrate and fat metabolism, has offered new opportunities to understand and manipulate several key mechanisms of atherogenesis (Spiegelman et al. 1996; Clark 2002; Chen et al. 2003). The regulation of PPAR γ-dependent metabolic pathways and immune inflammation has enormous role in cardiovascular disease, metabolic syndrome, diabetes, and malignancy. It can also be important in immunological diseases like inflammatory bowel diseases, rheumatoid arthritis, multiple sclerosis, and psoriasis.

Peroxisome Physiology

Peroxisomes are present in the cytoplasm of the cell in its microsomal fraction. They are cellular organelles of 0.5 mm size and are bounded by a membrane. The matrix of peroxisomes contains more than 40 different enzymes. They are concerned with various anabolic and catabolic functions. The bounding membrane contains a number of proteins which function to transport various substances in and out of peroxisome. Peroxisome replicates first by enlarging and then by dividing. They can arise from endoplasmic reticulum too.

Peroxisome contains enzymes which help the cell to neutralize the toxic peroxides. They contain enzymes like catalase, D-amino acid oxidase, and uric acid oxidase. Uric acid oxidase is absent in humans, so uric acid cannot be oxidized in humans. Thus, if uric acid level is raised it can lead to gout.

A Brief Review of Nuclear Receptors

Nuclear receptors are a class of intracellular transcription factors activated by ligands. Their function is the direct interaction with DNA and transcription control. The pleiotropic effect of nuclear receptors on cell biology and metabolism is realized by the means of different genes activation. Nuclear receptors become active when they detect a certain ligand in the cellular environment. They are protein molecules found within cells and mediate the activity of hormones and other substances such as certain vitamins.

The nuclear receptor’s binding to a ligand results in a conformational change in the receptor. This results in activation of the receptor. They are different from other classes of receptors in their ability to directly interact with and control the expression of DNA.

Structure of Nuclear Receptor

A nuclear receptor contains the following portions.
  • N-terminal region

  • DBD or DNA-binding domain

  • Hinge region

  • LBD or ligand-binding domain

  • C-terminal region

Both the DBD and LBDs are conserved, the others are variable.

DNA-binding domain – This domain contains two zinc fingers which bind to hormone response elements of the DNA (Fig. 1).
Peroxisome Proliferator-Activated Receptor-γ, Fig. 1

PPAR-gamma primary structure. PPAR-gamma primary structure is composed of six domains and contains approximately 500 amino-acids. The N-terminal domain (A/B domain) is variable: PPARγ1 variant and PPARγ2 variant with 30 additional amino acids. The molecular function of this domain is specific contact with coactivators. This process is regulated by the ligand-independent transactivation segment (AF-1, Activation Function-1). The C domain is DNA-binding domain. Its molecular chain is double folding and in the center of the structure two zinc atoms interact with four cysteine residuals. The main functions of D domain are binding of the shaperone protein to the receptor and DNA binding. Shaperone proteins repress the activity and conformational changes of PPARγ. The E domain is ligand-binding domain and is involved in receptor dimerization. The ligand-dependent protein, named activation function-2 (AF-2) has different structure and affinity in the three subtypes of PPARs

HINGE region – This region connects DNA-binding domain with the ligand-binding domain. Its role is to facilitate transport and distribution within the cell.

LIGAND binding domain – which binds to specific ligands that activate the receptors. It recognizes the hormones and determines its action.

They may stay in the cytosol or nucleus.

This receptor stays in the cytosol bound to heat-shock protein. When ligand binds to it, heat-shock protein dissociates from it. The receptor homodimerizes and translocates into nucleus. In the nucleus, the homodimer binds to hormone response elements. Type 1 receptor binds to two half sites; the second half site has a sequence inverted from the first, also called inverted repeats. The nuclear receptor/DNA complex then recruits other proteins which transcripts downstream from the HRE into messenger RNA and eventually to protein.

Examples of these types of nuclear receptors are glucocorticoid receptor, estrogen receptor, progesterone receptor, and androgen receptor (Marika et al. 2004).

Another type of nuclear receptors stays in the nucleus as a heterodimer with Retinoid X Receptor or RXR to DNA. They are in inactive form bound to corepressor protein. Ligand binding to nuclear receptor dissociates corepressors and recruits coactivators.

Examples are retinoic acid receptor, thyroid hormone receptor, and retinoid X receptor. Others include orphan receptors. The natural ligands of these receptors are not known. In humans, there are 48 known nuclear receptors. They are divided into different subfamilies.

Peroxisome Proliferator-Activated Receptor

Peroxisome proliferator-activated receptor was named and discovered in 1990 (Issemann and Green 1990). They are the members of orphan receptors and can bind to physiological ligands. Activation of PPARs leads to the formation of heterodimers with 9-cis retinoid – X receptors. These heterodimers bind to DNA-specific sequences called peroxisome proliferators-response elements, thus initiating or stimulating the transcription of target genes (Fig. 2).
Peroxisome Proliferator-Activated Receptor-γ, Fig. 2

PPARγ target gene associations. PPARγ regulate target gene associations of: (1) Adipoogenesis: Signal transducer and activator of transcription 1 (STAT1), STAT5A (2) Lipid metabolism: lipoprotein lipase (LPL), muscle carnitine palmitoyl transferase-1 (mCPT1), fatty acid-binding protein (FABP), carnitine acylcarnitine transferase (CACT) (3) Carbohydrate metabolism: glucose transporter-4 (GLUT4), Phosphatidylinositol-4,5-bisphosphate 3-kinase(p13K), c-Cbl-associated protein (CAP), insulin receptor substrate-1 (IRS-1)

The PPAR subfamily consists of three members: They are PPARα, PPARα/β and PPARγ (Novac 2004).

PPARα is expressed in liver, kidney, heart, and skeletal muscle.

PPARδ is expressed in many tissues and recent studies have suggested that it may be an important regulator of cholesterol transport in macrophages.

PPAR gamma is found predominantly in liver, adipose tissue, and vessel wall. PPAR gamma regulates genes involved in fatty acid uptake and storage, inflammation, and glucose homeostasis.

PPAR Gamma Gene Polymorphism

The gene for PPAR gamma is localized to chromosome 3, band 3p25 (Beamer 1997). It was first cloned in 1993. There are three mRNA isoforms.

PPARγ1 and PPARγ3 mRNA encode the same protein product.

PPARγ gene consists of at least 11 exons, which can give nine transcript variants. The regulation of function of PPARγ is context dependent and is due to the complexity of processing. This leads to its pleiotropic functions (Sabatino and Casamassimi 2005).

Proteins produced from PPARγ2 contain an additional NH2-terminal region, composed of 30 amino acids. The proteins derived from PPARγ1 and γ3 mRNA are similar. PPARγ2 is mainly expressed in adipose tissue, whereas PPARγ1 is more widely expressed (Desvergne and Wahli 1999).

Liu and coworkers suggested that PPARγ C161T polymorphism was associated with CAD in a Chinese population. The T allele of the PPARγ gene might have a protective effect on the progression of CAD and might reduce the onset of ACS, which might associate with the decreased expression of MMP-9 and TNF-α in patients with CAD.

Posttranslational modification regulates the transactivation potential of PPARγ.

The identities of the endogenous ligand(s) for PPARγ remain undecided. So they are classified as an “orphan receptor.” There are several naturally occurring compounds which have been shown to be capable of activating the receptor at concentrations comparable to physiological levels. These include a variety of polyunsaturated fatty acids (e.g., linoleic acid, linolenic acid, and arachidonic acid) and eicosanoids (e.g., prostaglandin J2 derivatives; Forman et al. 1995; Kliewer et al. 1998).

Synthetic ligands, e.g., TZDs and tyrosine agonists are now the most potent known activators of PPARγ.

Tissue Distribution

PPARγ1 has widespread expression at low levels. They can be found in heart, muscle, spleen, colon, kidney, and pancreas.

PPARγ2 and PPARγ3 are highly expressed in white and brown adipose tissue; these receptors are also expressed in vascular endothelium and vascular smooth muscle. In addition, PPARγ3 is expressed in large intestine and macrophages.

PPARγ is widely expressed in cells of the immune system. These include monocyte/macrophages, granulocytes (neutrophils, eosinophils, basophils), mast cells, dendritic cells, T cells, B cells, and human platelets.

PPARγ Ligands

PPAR ligands control the transcription of the PPAR receptors.

These can be natural and synthetic ligands.

Natural ligands are derived from diet and from intracellular sources.

The natural ligands include polyunsaturated fatty acids, e.g., linoleic acid, linolenic acid, arachidonic acid, and eicosanoids, e.g., prostaglandin J2 derivatives, nitrolinoleic acid, lysophosphatidic acid, 9- and 13- HODE (HydroxyOctaDecadiEnoic acids), and 15- HETE (HydroxyEicosaTetraEnoic acids).

Members of the cyclooxygenase, prostaglandin pathways, or eicosanoids act also as natural ligands (Kliewer et al. 1995). These include PGD2 and PGJ2.

15d- PGJ2 is derived from the PGD2 by a series of reactions and is thought to be the most potent endogenous ligand for PPAR (Forman et al. 1995).

Synthetic ligands of PPAR includes TZDs or thiazolidinediones and non- TZDs.

TZDs include pioglitazone, rosiglitazone, ciglitazone, and troglitazone. TZD that act on both alpha and gamma receptors include TZD 18. Troglitazone was the first synthetic PPAR-γ ligand but was withdrawn because of incidences of serious hepatotoxicity (Zang et al. 2006).

Non TZD PPAR ligands are GW-7845, GW-1929, diindolymethane analogs, CDDO (2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid), and others. Non TZD dual agonist CG301360 alleviates insulin resistance and lipid dysregulation in db/db Mice (Jeong et al. 2010).

Selective PPAR modulators can modulate the therapeutic potential and side effects. The large ligand-binding site of the PPAR allows different modulators to bind in different orientation. This allows selective modulation of the action without changing side effects.

Examples of selective modulation (SPPAR y M):

CDDO induces apoptosis more than TZDs. TZDs release coactivators more effectively than CDDO which release corepressors more effectively. So, the understanding of coregulators (coactivators and corepressors) is important in understanding the function of different PPAR ligands (Ulivieri and Baldari 2007).

PPARα/γ dual agonists are currently under development and hold considerable promise in the management of type 2 diabetes, metabolic syndrome and provide an effective therapeutic area for prevention and treating the multifactorial metabolic and inflammatory components of CVD (Staels and Fruchart 2005). Several experimental and clinical evidences elucidated the beneficial effects of PPAR ligands in prevention and treatment of various forms of metabolic syndrome CVD (Balakumar et al. 2007).

There are some reports of differences of activity between the thiazolidinediones. Pioglitazone appears to have a beneficial effect on cardiovascular disease, whereas rosiglitazone increases cardiovascular risk. The difference in lipid profile after treatment can be the reason for the superiority of pioglitazone over rosiglitazone (Rodriguez et al. 2010).

Function

All the three PPARs are activated by normally occurring fatty acids and their metabolites. They are like body’s fatty acid sensor. Three-dimensional structure of PPARs shows that their ligand-binding pockets are much larger than other nuclear receptors. This makes them more accessible to different molecules (Kliewer et al. 2001).

The receptor exerts many of its effects by regulating target gene transcription in a ligand-dependent manner like other nuclear receptors. After attaching to PPARγ-RXR heterodimer to specific DNA sequences or response elements – PPREs located in the target gene promoter, binding of ligands mediates cofactor recruitment, which in turn leads to transcriptional regulation.

The receptor plays a critical role in fat cell differentiation, inducing the expression of adipocyte-specific genes, and promoting the formation of mature lipid-laden adipocytes (Tontonoz et al. 1994a, b; Fajas et al. 1998).

It plays critical role in the development of both white and brown adipocytes in vivo in mice (Kubota et al. 1999).

In studies with the clinical phenotypes of subjects with PPARγ gene mutations suggest a similar role in the regulation of human adipose tissue mass (Chatterjee 2001).

At first, a novel transcription factor, ARF6 was identified as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. To identify the components of ARF6, it was purified from nuclear extract of HIB-1B brown adipocytes. Further analyses identified the ARF6 complex as a heterodimer of the retinoid X receptor α (RXRα) and the peroxisome proliferator activated receptor γ (PPARγ). These results suggest PPARγ as an important regulator of adipocyte-specific gene expression (Tontonoz et al. 1994).

PPARγ transfection into fibroblasts was important to direct those cells toward an adipocyte-like differentiation. The role of PPARγ was also established in the lack of white fat in PPARγ-deficient mice, adipokine expression, interaction with other key adipocyte proteins, and the association of a PPARγ dominant-negative polymorphism with lipodystrophy (Chawla et al. 1994).

It was observed that Rosiglitazone fail to reduce glucose or insulin levels in A-ZIP/F-1 mice, which lack white adipose tissue. A-ZIP/F-1 phenotype resembles human with severe lipoatrophic diabetes, with the lack of fat, hyperlipidemia, fatty liver, marked insulin resistance and hyperglycemia. This indicates that white adipose tissue is required for the antidiabetic effects of PPARγ ligands (Chao et al. 2000).

PPARγ also regulates genes of LPL, acyl-coenzyme A synthetase, glucose transporter GLUT4, and phosphoenolpyruvate carboxykinase, in addition to adipogenesis (Lehrke and Lazar 2005).

Both in vivo and in vitro, PPARγ agonists increase the expression and secretion of adiponectin, a hormone exclusively produced by the adipocyte (Maeda et al. 2001).

Though the role of PPARγ as a regulator of lipid and glucose metabolism is well established, PPARγ has also been implicated in malignancy. Ligands for PPARγ can have positive and negative effects on cell proliferation and hence on malignancy. Development of colorectal cancer is influenced by prostaglandins and fatty acids. Peroxisome proliferator-activated receptor gamma (PPAR gamma), which is highly expressed in the colon can act as a transcriptional mediator for prostaglandins and fatty acids. In C57BL/6 J–APCMin/+ mice, which is susceptible to intestinal neoplasia, PPAR gamma activation modifies the development of colon tumors (Lefebvreet al. 1998) (Fig. 3).
Peroxisome Proliferator-Activated Receptor-γ, Fig. 3

PPARγ regulates a number of cellular processes that affect glucose homeostasis, endothelial function, and vessel wall inflammation, as well as protecting against cardiovascular and kidney complications that occur in diabetes. On cellular level PPARγ activation negatively regulate the expression of proinflammatory genes, improve insulin sensitization, and lipid metabolism

Peroxisome proliferator-activated receptors (PPARs) are involved in diverse processes such as steroidogenesis, angiogenesis, tissue remodeling, cell cycle, apoptosis, and lipid metabolism (Klinge Bodenner 1997; Gosset et al 2001; Garg 2004). These processes are required for normal ovarian function. The expression of PPAR gamma is limited principally to granulosa cells in developing follicles, and is regulated by luteinizing hormone (LH) (Komar 2005).

PPARγ and Immune Function

Earlier studies by Greene et al. found a truncated PPARγ expression in peripheral blood lymphocytes (Greene et al. 1995). However, the evidence of the role of PPARs in inflammation was provided by Gilroy et al. and an anti-inflammatory effect of PGD2 and 15d–PGJ2 and PPARγ in rat model of pleural inflammation (Gilroy et al. 1999).

Finally, in relating PPARs to inflammation, Gilroy and colleagues, studying COX-2 inhibitors in a rat model of carrageenan-induced pleural inflammation, presented evidence for an anti-inflammatory role of PGD2 and 15d–PGJ2, suggesting a possible role for PPARγ in inflammation.

PPARγ expression has been widely observed in different immune cells. Its ligands have an anti-inflammatory effect on both innate and acquired immune systems (Clark 2002).

In macrophages of the atherosclerosis, PPARγ plays an important role (Han et al. 2000; Chawla et al. 2001). PPAR ligands inhibit macrophage activation and production of inflammatory cytokines like TNF-alpha, IL-1 beta, and IL- 6 and nitrous oxide synthase (NOS) (Jiang et al. 1998). PPARγ activation can modify the macrophage differentiation into more anti-inflammatory phenotype. Proinflammatory cytokines are mediated by the PPARγ at the transcriptional level (Liu et al. 2010).

PPARγ also affects T-lymphocyte function. PPARγ activation can inhibit the proliferation of T lymphocyte and reduce production of IFNγ, TNF-alpha, and IL-2 (Clark et al. 2000). The effect is mediated by NFAT (Nuclear Factor of Activated T Cells). PPARγ is also expressed in B lymphocytes. Certain PPARγ ligands can inhibit B-cell proliferation and induce apoptosis (Padilla et al. 2002).

Role in Disease Process

PPARγ plays a role in pathophysiology of diseases like diabetes, obesity, atherosclerosis, and cancer. Modulation of receptor action in these diseases by specific ligands is of therapeutic value, e.g., thiazolidinediones in the treatment of diabetes mellitus. Thiazolidinediones is a high-affinity PPARγ ligand used as insulin sensitizing agent for the treatment of type 2 diabetes mellitus. Study of polymorphism of PPARγ receptor has enabled the understanding of the role of PPARγ in glucose homeostasis, lipid metabolism, and regulation of fat mass. Study of naturally occurring human genetic variants with several different clinical phenotypes emphasizes diverse roles of this receptor in normal physiology of PPARγ.

PPAR Gamma and Its Role in Dyslipidemia

PPARγ agonists lowered the circulating levels of triglycerides, cholesterol, and nonesterified fatty acids in animal models of dyslipidemia. These effects have also been found in modest degree in humans. PPAR gamma agonists modulate lipid metabolism by regulating genes lipoprotein lipase, CD36, and ABCA1. Clinical trials have demonstrated that TZD decreased serum levels of LDL-cholesterol and triglycerides and increased serum levels of HDL-cholesterol in type 2 diabetes (Komatsu and Node 2010).

There are reported differences between different PPAR gamma agonists in lipid modulating effect. Rosiglitazone has been observed to lower FFA and possibly triglycerides while raising LDL levels, with variable effects reported on HDL cholesterol (Willson et al. 1996). Pioglitazone, on the other hand, lowers triglycerides and LDL cholesterol while increasing HDL levels (Boyle 2002). PPAR gamma activation regulates endothelial function, proliferation and migration of vascular smooth muscle cells, and activation of macrophages.

Dysregulation of the AMP-activated protein kinase (AMPK) signaling pathway leads to disturbances in cellular FFA metabolism and causes ectopic lipid accumulation, cellular dysfunction, and inflammation. The common factor for the development of the metabolic syndrome, insulin resistance, hypertension, and endothelial and pancreatic ß-cell dysfunction can be this AMPK pathway (Ruderman and Prentki 2004). AMPK activation induces FFA oxidation and increases insulin sensitivity (Fisher et al. 2002). A number of the beneficial effects of the thiazolidinediones could be mediated via AMPK pathway. AMP-activated protein kinase (AMPK) is activated in response to multiple stresses leading to an increase in the intracellular AMP:ATP ratio. Incubation of muscle cells with thiazolidinedione and rosiglitazone highly increases this ratio with the concomitant activation of AMPK (Fryer et al. 2002). Other studies have also shown that TZDs activate AMPK activity both in vitro and in vivo. Those altogether suggest that AMPK might be a mediator of the insulin-sensitizing effects of TZD (Saha et al. 2004).

PPAR Gamma and Its Role in Atherosclerosis

PPARγ regulates the CD36 expression and uptake of oxidized LDL in macrophage. Observation of Tontonoz and colleagues raised speculation that uptake of oxidized LDL might lead to accumulation of lipids in the foam cells and exacerbation of atherosclerosis (Tontonoz et al. 1998). Increased CD36 expression leads to increase intracellular accumulation of oxidized LDL cholesterol. This cholesterol would be metabolized to produce 9-hydroxyoctadecadienoic acid (9-HODE) and (13-HODE). These enoic acids could further activate the receptor and lead to a vicious cycle of increased oxidized LDL uptake (Ricote et al. 1998). Subsequent works provided evidence that in addition to PPARγ activation of oxLDL uptake by its ligands, PPARγ regulates the efflux of cholesterol from macrophages (Chawla et al. 2010). Ligand activation of PPAR gamma leads to activation of LXR alpha. Activation of LXR alpha leads to induction of ABCA1 which leads to cholesterol efflux. From these observations, it appears that PPAR gamma coordinates a process of oxidized LDL uptake, processing, and efflux.

Matrix metalloproteinases are implicated in the development of unstable plaque (Plutzky 1999). MMP-9 levels are increased in type 2 diabetic patients with coronary artery disease. Studies have found treatment with PPAR gamma ligand rosiglitazone reduces MMP-9, tumor necrosis factor-α, and SAA serum levels. This study shows that PPAR gamma activation exerts an anti-inflammatory and antiatherogenic effect in patients with in type 2 diabetic patients with coronary artery disease (Marx et al. 2003a, b).

In nondiabetic subjects with coronary artery disease, modification of transcription within the vessel wall by PPAR gamma ligand rosiglitazone decreases the levels of markers of endothelial cell activation and acute phase reactants. Treatment with rosiglitazone in this group of patients reduces the levels of E-selectin, von Willebrand factor, C-reactive protein and fibrinogen (Sidhu et al. 2003, 2004).

PPARγ agonist has been shown to slow the progression of intima-media thickness in carotid artery in both diabetic and nondiabetic CAD patients (Sidhu et al. 2004). Combination therapy with PPAR ligands, pioglitazone, and fenofibrate, improves vascular function due to the improvement of insulin resistance, inflammation, and oxidative stress in patients with the metabolic syndrome (Watanabe et al. 2006).

Serum levels of soluble CD40L are elevated in acute coronary syndromes and have been associated with increased cardiovascular risk. Interaction of CD40L with CD40 receptor is associated with its inflammatory role in atherosclerosis. PPARγ-agonist thiazolidinedione rosiglitazone reduces sCD40L serum levels in patients with type 2 diabetes and CAD thus indicating the role of PPAR gamma in inflammation and atherosclerosis (Marx et al. 2003b).

ApoE genotype ε4 is an independent risk factor for coronary artery disease. The apoE ε4 carriers have significant higher LDL-C levels than other apoE carriers. Polymerase chain reaction-restricted fragments length polymorphism was used to determine the relationship between apoE genotype and PPAR gamma C161 → T substitution in coronary artery disease. The relationship of CAD to apoE genotype was attenuated by PPARγ C161 → T variant genotype (Peng et al. 2003). While PPAR gamma C161 → T variant genotype has been associated with reduction in CAD, the same has not been established with PPAR gamma P12A. Studies suggest that the A12 allele is associated with increased insulin sensitivity and reduced risk of type 2 diabetes; however, data on the risk of coronary artery heart disease (CHAD) is controversial (Pischon 2005). In other studies, comparison of the risk of early onset CAD with any or all of the four genetic factors like PPARγ2 Pro12/Pro12, ENOS T-786C, BChE-K, and APOE ε4 was taken. Mutation of any single gene causes only a mildly increased LR (none >1.7); the risk of early-onset CAD increased to 2.78 with combined four mutations. Thus, the genetics of early-onset CAD appear to be multifactorial or polygenic (Nassar et al. 2006).

Peroxisome proliferator-activated receptor-γ improves the impaired coronary arteriolar dilation by reducing oxidative stress by a mechanism unrelated to its effect on hyperglycemia and hyperinsulinemia in Type 2 DM (db/db) mice. Treatment with rosiglitazone, a PPARγ agonist, increases NO mediated coronary arteriolar dilations by reduction of vascular NAD(P)H oxidase-derived superoxide production and enhancement of catalase activity. This antioxidant action of rosiglitazone may protect coronary arteriolar function in Type 2 DM.

It is known that PPAR-γ agonists inhibit vascular smooth muscle proliferation and migration and improve endothelial function. But it has also been observed that PPARγ agonists modulate bone marrow (BM)-derived angiogenic progenitor cells (APCs) promote endothelial lineage differentiation and early reendothelialization after vascular intervention. In experiments with C57/BL6 mice following femoral angioplasty, treatment with PPARγ agonist, rosiglitazone promoted the differentiation of APCs toward the endothelial lineage in mouse. Adult BM and peripheral blood contain APCs that are bipotential and able to differentiate into endothelial and smooth muscle lineages. The PPARγ agonist rosiglitazone promotes differentiation of these APCs toward the endothelial lineage, inhibits differentiation toward the smooth muscle cell lineage and thus decreases restenosis after angioplasty (Takagi et al. 2003; Choi et al. 2004; Kipshidze et al. 2004; Wang et al. 2004). A similar result was observed with pioglitazone. In randomized, placebo-controlled, double-blind trial, 6-month pioglitazone therapy significantly reduced neointima volume after coronary stent implantation in nondiabetic patients (Marx et al. 2005).

Toll-like receptor 4 (TLR4) activates the expression of proinflammatory cytokines which are involved in the formation of atherosclerosis. PPARγ agonist rosiglitazone inhibits the Ang II-induced proinflammatory responses in vascular smooth muscle cells (VSMCs) through TLR4-dependent signaling pathway. Rosiglitazone reduces Ang II-induced proinflammatory mediators like matrix metalloproteinase-9 and tumor necrosis factor-α, and increases the production of anti-inflammatory mediators PPARγ and 6-keto-PGF1α (Ji 2009).

PPAR Gamma and Insulin-Resistance

PPAR gamma stimulation (troglitazone as a ligand) results in adipocyte differentiation to generate small forms with high-insulin sensitivity (Chawla et al. 1994; Okuno et al. 1998). In adults under a HF diet, however, adipocyte hypertrophy and hence the size of adipocytes is dependent upon the amount of PPAR gamma (Kubata et al. 1999).

Rosiglitazone failed to reduce glucose or insulin levels in mice, which lack white adipose tissue, suggesting that white adipose tissue is required for the antidiabetic effects of PPARγ ligands.

Both resistin and TNF-alpha induce insulin resistance. Expression of resistin and TNF-alpha is reduced by PPAR gamma ligands, which indicates that the insulin-sensitizing effect of PPARγ agonists is related to its anti-inflammatory properties (Steppan et al. 2001).

With the improvement of insulin resistance, the metabolic syndrome, including dyslipidemia and hypertension, also improve with rosiglitazone or TZD treatment than with Glyburide treatment (Sutton et al. 2002; Boyle et al. 2002).

PPAR Gamma and Its Role in Vascular Remodeling

Vascular remodeling is now established as a key contributory factor in cardiovascular continuum and its complications. Different investigators in experimental studies have shown that PPAR gamma activation by thiazolidendiones inhibits the proliferation, hypertrophy, and migration of vascular smooth muscle cells (Dubey et al. 1993; Law et al. 1996; de Dios et al. 2003; Marx et al. 1998; Law et al. 2000; Desouza et al. 2003; Hsueh et al. 2001). It was a good experimental basis for recent clinical studies. The PPAR gamma agonists also reduce the progression of intima-media thickness that commonly occurs in patients with type 2 diabetes and atherosclerosis (Minamikawa et al.1998). In recent years, the attention was concentrated on secondary prophylactic of carotid atherosclerosis by the means of PPAR gamma agonists in patients with coronary heart disease without diabetes (Sidhu et al. 2004). This vascular remodeling effect of PPAR-gamma receptors could be caused by interference with the mitogen-activated protein–kinase pathway (Graf et al. 1997). Zhang et al. (2010) concluded that PPAR gamma inhibits VSMC phenotypic modulation through inhibiting phosphoinositide 3-kinase/protein kinase B signaling. In aortas of SHR (spontaneously hypertensive rat) and VSMCs derived from SHR showed impaired PPAR-gamma expression. There are reduced contractile proteins, α-smooth muscle actin (α-SMA) and smooth muscle 22α (SM22α), and enhanced proliferation and migration. Activation of PPAR gamma using rosiglitazone increased aortic α-SMA and SM22α expression and decreased aortic remodeling in SHRs. Increased phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) activity was seen in SHR-derived VSMCs which was counteracted by PI3K inhibitor. This can be an important therapeutic target for hypertension and vascular disorders (Zhang et al. 2010).

PPARγ activation has antiatherogenic effects. PPAR-gamma is expressed in macrophage foam cells of human atherosclerotic lesions. PPAR gamma activation has anti-inflammatory effects by negatively regulating the expression of proinflammatory genes, inhibiting gene expression and migration in human vascular smooth muscle cells (Ji et al. 2009). Treatment with the PPAR gamma agonist troglitazone decreased carotid intima-media thickness. A substitution of cytosine to guanine in the PPAR gamma 2 gene leads to an exchange of proline (Pro) to alanine (Ala) in exon B (codon 12) of this gene. A study of the impact of this polymorphism on atherosclerosis has shown significant influence. In a study in the Department of Molecular Diagnostics, National Research Center, Moscow, among 588 Russian T2D patients and 597 normoglycaemic controls, the Pro/Pro genotype showed increased levels of fasting insulin in nondiabetic controls and elevated serum triglycerides in T2D patients. Carriers of the Pro12 allele and subjects homozygous for Pro/Pro had significantly increased the risk of developing T2D. Nondiabetic and diabetic subjects homozygous for Pro/Pro had a significantly higher HOMA-IR score and reduced ISI value. This study supports the strong association of PPARg gamma Pro12Ala polymorphism in insulin resistance and T2D in a Russian population (Chistiakov et al. 2010).

However, in one Indian study, no such significant association was detected with CAD and PPAR gamma Pro12Ala polymorphism. Though PPAR gamma alleles were not associated with CAD among Indians, proline carriers had significantly higher levels of HDL-cholesterol among CAD patients (Ashok Kumar et al. 2010). The study among 278 CAD patients has demonstrated that 12Ala PPAR-γ allelic variant influence the predisposition for CAD and was associated with the risk of myocardial infarction at the age 45 years and younger in the population of North-West region of Russian Federation (Sergeeva et al. 2017).

In a Danish study too the investigators think that it is possible that the observed associations were due to chance. In case-cohort study involving 1031 ACS cases and a sub-cohort of 1703 persons were taken within the population-based prospective study Diet, Cancer, and Health of 57,053 individuals. Homozygous male variant allele carriers of PPARgamma2 Pro12Ala were found to be at higher risk of ACS (HR = 2.12, 95% CI: 1.00–4.48) than homozygous carriers of the Pro-allele. The association was observed among homozygous variant allele carriers only. The associations were obtained in subgroups of small numbers of cases (Vogel 2009), in some populations (Gao et al. 2010).

Schneider and colleagues demonstrated that 12Ala allele in PPARγ2 correlates with a significantly increased CAD extent in men. CAD extent was related with the extent of insulin resistance too (Schneider 2009).

Thus, PPARγ regulates on transcriptional level different gene associations with pleiotropic metabolic effects (Touyz Schriffin 2006). Management of PPARγ activity may be an important therapeutic target for cardiovascular and metabolic disorders.

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.I.P. Pavlov 1st Saint Petersburg State Medical UniversitySt. PetersburgRussia
  2. 2.Federal Almazov North-West Research CentreSt. PetersburgRussia