INTRODUCTION:

The peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, protein), and tumorigenesis of higher organisms. Three types of PPARs have been identified: alpha, gamma, and delta (beta): (alpha) – expressed in liver, kidney, heart, muscle, adipose tissue, and others ß/d (beta/delta) – expressed in many tissues but markedly in brain, adipose tissue, and skin γ (gamma) – although transcribed by the same gene, this PPAR through alternative splicing is expressed in three forms: γ1 – expressed in virtually all tissues, including heart, muscle, colon, kidney, pancreas, and spleen γ2 – expressed mainly in adipose tissue (30 amino acids longer) γ3 – expressed in macrophages, large intestine, white adipose tissue.

PPAR biology

PPARs contain 5 modular domains: a ligand-binding domain (LBD) in which the specific PPAR agonist binds, a transactivating domain which, in response to ligand binding, undergoes a permissive conformational change required for transcriptional activation; and a DNA-binding domain, which interacts with specific PPAR response elements (PPRE) in the promoter region of PPAR-regulated target genes.

Three PPAR isotypes have been identified: PPARγ, PPARα, and PPARδ. Despite unique attributes of each PPAR isotype, these receptors also share a common biology. PPAR activation is initiated by the binding of a cognate ligand to the LBD of a specific PPAR isotype Ligand binding and activation function 2 movement allow PPAR heterodimerization with the retinoid X receptor (RXR), another nuclear receptor activated by its own ligand (purportedly 9 cis-retinoic acid), which is required for transcriptional PPAR activity. RXR also can dimerize with itself or other specific nuclear receptor partners. Through their respective DNA binding domains, the PPAR/RXR complex binds to DNA at sequence-specific regions in gene promoters known as PPREs, which consist of direct repeats of DNA separated by a single nucleotide.

Transcriptional PPAR responses also depend heavily on ligand-induced recruitment or release of small accessory molecules known as coactivators and corepressors, respectively. These cofactors, a large, diverse family involving multiple members such as nuclear corepressor, PPAR-binding protein, PPARγ coactivator, and cAMP response element-binding protein are critical determinants of the cellular PPAR response. This multiprotein complex induces transcription by chromatin remodeling and interaction with the basal transcriptional machinery. In contrast to the positive regulation of target genes described earlier, PPAR activation also can repress transcription. This is a common but less-well-understood theme in PPAR-mediated repression of inflammation.

PPARs Role in Lipid metabolism and Energy Homeostasis

PPARs in the digestive tract

Triglycerides and phospholipids from the diet are mainly absorbed in the duodenum and jejunum, while cholesterol is mainly absorbed in the ileum. In these intestinal regions, the high PPARα and PPARβ expression correlates with the expression of the enterocytic fatty acid binding protein (FABPs) genes, the I-FABP and L-FABP, and of the cellular retinol binding protein genes. A strong positive regulation of the L-FABP gene occurs upon dietary intake of long-chain fatty acids or direct ileal infusion of linoleic acid or a-bromopalmitate, which are PPARα and PPARβ ligands, whereas I-FABP was unaffected. A clofibrate-enriched diet also induces LFABP gene expression and further suggests a relationship between PPAR and FABP expression in the gut.¹

PPAR, circulating lipoproteins, and cholesterol metabolism.

Cholesterol is an essential component of cell membranes and is the molecule from which steroids are synthesized and which serves as precursor for bile acid synthesis. The main source of cholesterol is the diet. If this supply is insufficient, then cholesterol synthesis is induced mainly in liver cells but also in many other cells. Two transcription factors are currently known to have a strong impact on intracellular cholesterol metabolism: SREBP and LXRa. Little is known about the putative role of the different PPAR isotypes with respect to regulation of cholesterol, except that cellular cholesterol levels in preadipocyte influence PPARγ expression. This effect is mediated by adipocyte determination and differentiation factor 1 (ADD1)/SREBP1, which is preferentially involved in fatty acid synthesis, whereas SREBP2 plays a role in intracellular cholesterol metabolism. Such functional interactions between transcription factors suggest interconnected regulations of cholesterol and fatty acid metabolism. In addition to intracellular cholesterol metabolism, the regulation of circulating cholesterol levels has a high physiopathological relevance since, qualitatively and quantitatively, it is a risk factor for atherosclerosis and its associated diseases. The cholesterol-enriched low density lipoprotein (LDL) particles are formed by release of the triglyceride content of VLDL via the action of lipoprotein lipase (LPL). The released fatty acids are either stored in the adipose tissue or oxidized to generate ATP in different tistissues, especially muscle. High density lipoprotein (HDL), in contrast to LDL, is considered as a “good” cholesterol-containing lipoprotein particle as it has a protective effect on atherosclerosis development. Indeed, it is instrumental in removing excess cholesterol from extrahepatic cells and in transporting it to the liver and steroidogenic organs, where it is taken up via the scavenger receptor BI. The role of PPARs in this general picture is reflected by the therapeutic benefits of fibrates, which are the first efficient lipid-lowering drugs to be used. Fibrate treatment both enhances catabolism of triglyceride-rich particles and reduces VLDL production. Furthermore, it stimulates HDL apolipoprotein expression.

One other important mechanism of the fibrate lipidlowering effect is believed to be an increased LPL activity through PPAR-mediated activation of LPL gene expression. LDL and HDL blood levels also depend in part on the synthesis, mainly by the liver, of the apolipoproteins required for their assembly. Several of these apolipoproteins are regulated by fibrates via PPARs. Fibrates down-regulate the production of apoCIII, an atherogenic component of apoBcontaining lipoproteins, which inhibits LPL activity andimpairs the uptake by the liver of triglyceride-rich lipoproteins. Direct support for these apoCIII effects is provided by transgenic animal studies showing a correlation between liver apoCIII expression and plasma triglyceride levels. Consequently, down-regulation of hepatic apoCIII production by PPARa appears to be beneficial since lipolysis of VLDL particles is increased and the resulting LDL is efficiently removed from the plasma. In humans, apolipoprotein AI and AII, which are the major HDL apolipoproteins, are up-regulated by PPAR through transcriptional control, while ApoAI expression is down-regulated in rodents.²

Pleiotropic roles of PPARα in the liver

Regardless of the fate of fatty acids in the liver, two first steps fatty acid transport across the cell membrane and activation into an acyl-CoA are required for further processing of the fatty acids. These two steps are facilitated through the induction of a fatty acid transporter protein (FATP) and FAT by ligand-activated PPARα as well as by the up-regulation at the transcriptional level of the long-chain fatty acid ACS gene. Formation of fatty acyl-CoA by ACS precedes either their incorporation into triglycerides (the anabolic pathway) or their oxidation (the catabolic pathway) by two major pathways: peroxisomal β-oxidation and mitochondrial β -oxidation. For each of these pathways, the expression of some key enzymes is up-regulatedby PPARα.

PPARα and peroxisomal β-oxidation

Peroxisome proliferation, which can be triggered in rodents but not in humans,corresponds to an increase in the volume density of peroxisomes and of the peroxisomal fatty acid β -oxidation activity. This activity is inducible by signals such as exposure to cold, high-fat diet, and thyroid hormone, but also by a wide variety of compounds collectively called peroxisome proliferators that includes certain hypolipidemic drugs.

PPARα and mitochondrial β -oxidation

Mitochondrial β -oxidation greatly contributes to energy production via oxidative phosphorylation generating ATP. The role of PPARα in energy homeostasis is linked to the extent with which PPARα regulates this pathway. As far as energy conservation is concerned, mitochondrial β -oxidation is approximately twice as efficient as peroxisomal β -oxidation. The first limiting step in mitochondrial b-oxidation is the entry flux of fatty acids into the mitochondria, which is controlled by a carnitine-dependent facilitated transport system. This control is not only quantitative but also qualitative since it excludes the very-long-chain fatty acids. One of its critical components, the carnitine palmitoyl transferase I (CPT I), catalyzes the formation of fatty acyl carnitine for translocation across the inner mitochondrial membrane. This enzyme is strongly induced by peroxisome proliferators and fatty acids, and a functional PPRE has been characterized in the promoter sequence of the muscle-type CPTI gene. PPARα further regulates the mitochondrial β -oxidative spiral by modulating the expression of the medium- chain acyl-CoA dehydrogenase (MCAD) gene.³

PPARs and control of inflammatory responses

Lipid mediators, particularly eicosanoids such as prostaglandins, leukotrienes, thromboxanes, and lipoxins, are involved in a variety of physiological processes including stimulation or inhibition of inflammation. Therapeutic control of an inflammatory response can be achieved either by blocking the membrane receptors mediating the action of inflammatory molecules or by modulating their metabolic fate through inhibition of their synthesis or stimulation of their breakdown. The first indication of a role of PPAR in controlling inflammation was the demonstration that LTB4, a potent chemotactic inflammatory eicosanoid whose activity is mediated by a membrane receptor (333), also binds to PPARα and induces transcription of genes of the v- and b-oxidation pathways that can neutralize and degrade LTB4 itself. In agreement with the above, dietary n-3 fatty acids and clofibrate, which also bind PPARα, have been reported to accelerate catabolism of LTB4 in granulocytes and macrophages. Conversely, PPARα-deficient mice show a proprolonged inflammatory response when challenged with LTB4 or its precursor arachidonic acid, possibly due to the absence of stimulation of the catabolic pathways, hence, the increased duration of the inflammation. Inhibition of the synthesis of proinflammatory molecules such as interleukin 6 (IL-6) and prostaglandins by activated smooth muscle cells also appears to participate in PPARα-mediated control of inflammation via a decreased activity of NF-kB, a transcription factor regulating cytokine production.

Recent studies demonstrate that PPARγ too may have an important impact on inflammation, as treatment of activated macrophages with high doses of the PPARγ ligand 15-deoxy- D12,14-PGJ2 provokes a resting phenotype and inhibits the production of the inducible form of nitric oxide synthase and therefore nitric oxide, as well as that of gelatinase B and scavenger receptor A. This inhibition is due to an antagonizing activity of PPARα directed toward the activity of the transcription factors AP-1, STAT, and NF-kB, which are known to control cytokine gene expression. As an interesting complement to these observations, fenofibrate treatment administered to hyperlipidemic patients not only lowers blood lipid values as previously discussed, but leads to a decrease in the blood of acute-phase proteins, whose levels of expression reflect systemic inflammation. This observation suggests that diets that modify PPAR activity and circulating lipid levels might also have a regulatory effect on inflammatory processes.⁴

PPARs and atherosclerosis

Atherosclerosis is a pathological process that ultimately leads to the localized obstruction of an artery due to the progressive build-up in the arterial wall of an atheromatous plaque. At least three pathological processes participate in plaque formation: foam cell differentiation, inflammatory reaction, and cell proliferation. The passage of monocytes from the luminal endothelial surface to the subendothelial space where they differentiate into macrophages is the initial step. The presence of these resident macrophages in the intima of the vascular wall and high levels of LDL in the blood favor a modification of the LDL particles through oxidation or other poorly defined processes. Endocytosis of these particles by macrophages is then mediated by scavenger receptors. In contrast to the LDL receptor, these receptors are not down-regulated by the intracellular cholesterol content and thus allow an excessive accumulation of intracellular lipids resulting in the formation of lipid-laden foam cells. Cytokines produced by these activated macrophage/ foam cells include the macrophage-colony stimulating factor, IL-1, and TNFa, which form the basis of the inflammatory component of the atherosclerotic lesion and promote proliferation of smooth muscle cells. Necrosis of macrophages and lipid-loaded foam cells releases their intracellular contents, resulting in an accumulation of extracellular components that form the fibrous cap of the atheromatous lesion. Eventually, the rupture of this plaque leads to the acute arterial obstruction.

Many aspects of these pathological processes might be modulated by PPARs. The role of PPAR in the adipose differentiation program, present similarities with the formation of foam cells. In addition, attention has recently been given, using THP1 cells, to the activation of the monocyte-macrophage transition and the concomitant up-regulation of the CD36 scavenger receptor, whose gene is a direct PPAR target. Both phenomenons are under the positive control of PPAR which is itself up-regulated by oxidized LDL Furthermore, expression of PPAR has indeed been demonstrated in mouse and human atherosclerotic lesions. In contrast to this apparently proatherosclerotic action of PPAR, inhibition of inflammatory cytokine production by the activated receptor might explain the beneficial effect of TZD in preventing atherosclerotic plaque progression. Similarly, inhibition of the macrophage activities by oxidized LDL whose 9-HODE (9-hydroyxyoctadecadienoic acid) and 13-HODE components are PPARγ ligands, has been observed. Obviously, further studies are needed to determine the exact role of PPARγ in the development of atherosclerosis. Proliferation of aortic smooth muscle cells, which express both PPARα and PPAR, also likely contributes to both atherogenesis and restenosis processes. Activation of PPAR in these cells leads to a beneficial decrease of the phorbol 12-myristate 13-acetate-induced matrix metalloproteinase gene expression.⁵

PPARs and the development of the fetal epidermal permeability barrier

Nuclear receptors which interact with the retinoid X receptor are involved in the regulation of epidermal differentiation and development. Cutaneous development in utero was affected by peroxisome proliferator-activated receptor or farnesoid X-activated receptor activators, or by an activator of another retinoid X receptor partner, liver X receptor. Peroxisome proliferator-activated receptor- and - and liver X receptor- and - mRNAs were detected in fetal epidermis by reverse transcriptase–polymerase chain reaction and northern analyses. The presence of these receptors and the ability of their activators to stimulate epidermal barrier and stratum corneum development suggest a physiologic role for peroxisome proliferator-activated receptor and liver X receptor and their endogenous ligands in the regulation of cutaneous development.⁶

PPARs, carcinogenesis, and control of the cell cycle

Studies based on tumor cell lines have implicated PPAR in cell cycle withdrawal. One of the first pieces of evidence implicating PPAR in the control of cell cycle came from the observation that PPAR activation decreased the binding of the E2F/DP heterodimers to its target genes. This decrease in E2F/DP activity is in part mediated by PPAR through the down-regulation of the PP2A protein phosphatase Inhibition of E2F/DP activity can also be achieved via activation of RB. Interestingly, PPAR ligands were shown to inhibit phosphorylation of RB in vascular smooth muscle cells, therefore contributing to maintain RB in its active form. Consequently, the G1/S transition in these cells was abrogated. Another suggested mechanism involving PPAR gamma in the mediation of cell cycle arrest was provided by the study of Morrison and Farmer (1999), who suggested a role of PPAR in up-regulating the cyclin-dependent kinase inhibitors p18 and p21 during adipogenesis. PPAR hence could control the expression not only of genes involved in the acquisition of a differentiated phenotype but also of genes involved in the negative regulation of cell cycle.⁷

Pharmaceutical Drugs Targeting PPAR- Fibrates and Thiazolidinediones

Fibrates and Cholesterol

Fibrates, fibric acid derivatives, are cholesterol-lowering drugs that work by decreasing the amount of circulating plasma cholesterol and triglycerides. Most fibrates also increase HDL levels. The potential side effects of fibrates have limited their use, but they have been shown to be successful in controlling cholesterol levels.

Two fibrates will be examined here:

· Bezafibrate

· Gemfibrozil

Bezafibrate

Bezafibrate is primarily a PPAR-alpha agonist, but also has some interaction with PPAR-beta. The intervention of bezafibrate was shown to decrease plasma fibrinogen (involved in blood clotting) levels, reduce plasma cholesterol and triglyceride levels, and increase HDL levels, all of which worked to stop or reverse atherosclerosis progression. Results showed that bezafibrate treatment reduced plasma triglycerides by 21% and increased HDL levels by 18%. Bezafibrate treatment was a safe and effective way to reduce plasma triglyceride levels and increase HDL levels.

Gemfibrozil

Like bezafibrate, gemfibrozil has been shown to decrease cholesterol and plasma triglyceride levels while increasing HDL levels. Gemfibrozil reduced the risk of CHD by 34% in the experimental group by decreasing cholesterol, plasma triglycerides, and LDL levels while increasing HDL levels. Because of fibrates effectiveness in treating dyslipidemia and CHD by increasing HDL levels, their use has been combined with the use of statins, drugs that decrease LDL levels by interrupting cholesterol formation. Statins, if not eliminated, can be myotoxic. Use of gemfibrozil with statins increases the risk of myotoxicity due to inhibition statin elimination. Therefore, the combination is not recommended.

Thiazolidinediones and Insulin Sensitivity

Type II diabetes usually results from obesity or inactivity, specifically though, visceral obesity. Normally, insulin has an antilipolytic effect on fat cells, though some fat cells seem to be "dysfunctional" in that they do not respond to insulin. These dysfunctional fat cells release fatty acids even in the presence on insulin, leading to elevated plasma free fatty acid (FFA) levels, which then results in insulin resistance in the liver and skeletal muscle. In addition to this, these fat cells over-secrete the cytokines interleukin-6 (IL-6), resistin, and tumor necrosis factor-alpha (TNF-alpha) and under-secrete adiponectin (an insulin-sensitizing cytokine), all of which contribute to the further progression of insulin resistance, atherosclerosis, and inflammation.

PPAR-gamma activation results in FFA uptake and storage in subcutaneous adipose tissue over visceral adipose tissue. Decreasing plasma FFA levels will reduce insulin resistance. In addition to decreasing plasma FFA levels, PPAR-gamma activation has been also shown to increase GLUT-1 and GLUT-4 receptors on skeletal muscle and the liver in rats, increase adiponectin secretion and decrease TNF-alpha secretion resulting in decreased blood glucose levels. Two thiazolidinediones will be examined here:

· troglitazone

· pioglitazone.

Troglitazone

The study found troglitazone to decrease plasma fatty acid levels, fasting plasma glucose, triglycerides, and fasting plasma insulin levels in type 2 diabetics, resulting in increased insulin sensitivity. The PPAR-gamma agonist troglitazone has been shown to be effective in treating type-2 diabetes and insulin resistance, but it has been removed from the market due to cases of hepatotoxicity.

Pioglitazone

Pioglitazone has been shown to result in similar changes in fasting plasma FFA, triglycerides, and fasting plasma glucose levels as troglitazone, except pioglitazone caused these changes without affecting fasting or glucose-stimulated insulin levels.pioglitazone decreasing the fat content of the liver. Pioglitazone has also been shown to increase HDL levels in patients with type-2 diabetes and dyslipidemia.

Natural Dietary Supplements Targeting PPAR -Lignans and Fatty Acids

Due to the potential side effects associated with the current pharmaceutical drugs that target PPAR receptors, safe alternatives are being searched for. New research is being done with various lignans and fatty acids to measure their ability to activate the PPAR receptors.

Sesamin

Sesamin is a naturally occurring lignan found in sesame seeds and oil. A lignan is a molecule that combines with a receptor or another entity acting as an "activator." Sesamin has been shown to be a potent PPAR-alpha agonist. The majority of sesamin research has been done on rats, but the results are very promising for use of sesamin to treat type-2 diabetes and obesity. Fat can be oxidized in the mitochondria and the peroxisomes of cells, the majority of this oxidation occurring in skeletal muscle cells and the liver.

PPAR alpha activation by sesamin increases fat oxidation in mitochondria and peroxisomes by increasing the expression of enzymes involved in beta-oxidation of fatty acids. Of vital important, sesamin increases the expression of the mitochondrial enzyme carnitine palmitoyl transferase (CPT). CPT, the rate-limiting enzyme in beta-oxidation of fatty acids in skeletal muscle and liver cell mitochondria, is found on the outer membrane of mitochondria and carries fatty acids across the membrane into the mitochondria by binding to them. Increasing the expression of CPT will allow more fatty acids to be transported into the mitochondria where they can be oxidized. In addition to increasing the oxidation of fat, sesamin supplementation has also been shown to decrease lipogenesis by decreasing lipogenic enzymes in the liver.

Tetradecyl Thioacetic Acid (TTA)

TetradecylThioacetic Acid (TTA), a non beta-oxidizable fatty acid analog, has been shown to activate all three of the PPAR receptors in rats, in the ranking order of Alpha > Beta/Delta > Gamma. TTA has been shown to increase insulin sensitivity by increasing hepatic fat oxidation and ketogenesis while draining fatty acids from the blood and extrahepatic tissues. This drainage of fatty acids by the liver increases the ability of adipocytes and skeletal muscle in uptake glucose.

TTA has been shown to cause mitochondrial and peroxisomal proliferation in rats, leading to increased beta-oxidation of fatty acids in the liver, along with increasing uncoupling protein-2 (UCP-2) expression. UCP-2, and UCP-3, is involved in preventing the accumulation of oxygen-specific free radicals and in regulating lipogenesis and ketogenesis. UCP-2 is found throughout the body. These three adaptations, increased mitochondria, peroxisomes, and UCP-2 concentrations, all aid in increasing insulin sensitivity and reducing adiposity.

Conjugated Linoleic Acid (CLA)

Conjugated Linoleic Acid (CLA) is a mix of isomers of linoleic acid (commercially sold as a 50:50 mix of cis-9, trans-11 and trans-10, cis-12 isomers). Studies done on humans have shown decreased body fat and/or increased lean mass (though results are mixed). CLA is believed to influence body composition through regulation of lipid metabolism. Studies have shown CLA to inhibit transcription of enzymes involved in de novo fatty acid synthesis/lipogenesis, desaturation of fatty acids, and triglyceride synthesis. It is believed that CLA is a PPARgamma antagonist, resulting in the attenuation of fat cell differentiation.

Oleoylethanolamide (OEA)

Oleoylethanolamide (OEA) is an endogenous lipid being investigated as a potential anti-obesity drug. OEA is synthesized in the intestines. Its synthesis is increased with food intake and decreased with fasting. OEA has been shown to have anorexic properties, meaning it decreases food intake. A study done on rats showed that OEA's ability to decrease appetite did not change plasma levels of various intestinal hormones involved in satiety, such as ghrelin and cholecystokinin, showing OEA works independently of these hormones. OEA is also an activator of the PPAR receptor. Activation of PPARα by OEA will cause an increase in fat oxidation along with a decrease in fat storage, as described in the above sections. OEA's ability to decrease appetite and regulate body weight is accomplished by the activation of PPARα

Stearoylethanolamide (SEA)

Stearoylethanolamide (SEA) has been shown to decrease food intake independent of PPAR and without changing hematochemical parameters such as glucose and triglyceride levels or leptin (a hormone involved with satiety) expression. sThe appetite decreasing effect of SEA was associated with a reduction in liver stearoyl-CoA desaturase-1 (SCD-1) mRNA expression. SCD-1 is the rate-limiting enzyme in the biosynthesis of monounsaturated fats and its reduction is believed to lead to increased fatty acid oxidation and decreased lipogenesis in skeletal muscle and the liver.

CONCLUSION:

PPARs play key roles in the regulation of energy homeostasis and inflammation, and agonists of PPARα and are currently used therapeutically. Fibrates, first used in the 1970s for their lipid-modifying properties, were later shown to activate PPARα. These agents lower plasma triglycerides and VLDL particles and increase HDL cholesterol, effects that are associated with cardiovascular benefit. Thiazolidinediones, acting via PPAR, influence free fatty acid flux and thus reduce insulin resistance and blood glucose levels. PPARgamma agonists are therefore used to treat type 2 diabetes. PPARα and agonists also affect inflammation, vascular function, and vascular remodeling. As knowledge of the pleiotropic effects of these agents’ advances, further potential indications are being revealed, including roles in the management of cardiovascular disease (CVD) and the metabolic syndrome. Dual PPARα/ agonists which are currently in development look set to combine the properties of thiazolidinediones and fibrates, and they hold considerable promise for improving the management of type 2 diabetes and providing an effective therapeutic option for treating the multifactorial components of CVD and the metabolic syndrome. The functions of a third PPAR isoform, PPAR, and its potential as a therapeutic target are currently under investigation. PPARs are promising targets for therapeutic intervention, through the development of agonists but also antagonists, in disorders such as obesity and diabetes, atherosclerosis, chronic inflammatory diseases, and tumorigenesis.

ACKNOWLEDGEMENT:

The authors thank Shri. T.G. Hari Kumar, General Secretary, Ezhuthachan College of Pharmaceutical Sciences, Marayamuttom for providing the necessary facilities.

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Received on 25.02.2014 Accepted on 10.03.2014

Asian J. Res. Pharm. Sci. 4(1): Jan.-Mar. 2014; Page 32-37