AEGAEUM JOURNAL ISSN NO: 0776-3808

Dualism of Peroxisome Proliferator-Activated Receptor α/γ: A Potent Clincher in Insulin Resistance

Mr. Ravikumar R. Thakar1 and Dr. Nilesh J. Patel1*

1Faculty of Pharmacy, Shree S. K. Patel College of Pharmaceutical Education & Research, Ganpat University, Gujarat, India.

[email protected]

Abstract: Diabetes mellitus is clinical syndrome which is signalised by augmenting level of sugar in blood stream, which produced through lacking of insulin level and defective insulin activity or both. As per worldwide epidemiology data suggested that the numbers of people with T2DM living in developing countries is increasing with 80% of people with T2DM. Peroxisome proliferator-activated receptors are a family of ligand-activated transcription factors; modulate the expression of many genes. PPARs have three isoforms namely PPARα, PPARβ/δ and PPARγ that play a central role in regulating glucose, lipid and cholesterol metabolism where imbalance can lead to obesity, T2DM and CV ailments. It have pathogenic role in diabetes. PPARα is regulates the metabolism of lipids, carbohydrates, and amino acids, activated by ligands such as polyunsaturated fatty acids, and drugs used as Lipid lowering agents. PPAR β/δ could envision as a therapeutic option for the correction of diabetes and a variety of inflammatory conditions. PPARγ is well categorized, an element of the PPARs, also pharmacological effective as an insulin resistance lowering agents, are used as a remedy for insulin resistance integrated with type- 2 diabetes mellitus. There are mechanistic role of PPARα, PPARβ/δ and PPARγ in diabetes mellitus and insulin resistance. From mechanistic way, it revealed that dual PPAR-α/γ agonist play important role in regulating both lipids as well as glycemic levels with essential safety issues. Certain clinical and epidemiological data showed beneficial effects and limitation of dual PPAR-α/γ agonists in insulin resistance lowering through regulation of diabetes mellitus with some safety precaution.

Keywords: PPAR agonist, Dual PPAR α/γ, Type 2 Diabetes Mellitus, Insulin Resistance

Introduction: Diabetes Mellitus is a chronic clinical complex, affiliated with hyperglycemia, T2DM initiated by either insufficiency in insulin release, insulin unable to generate its activity and/or both at cell level. Uninterrupted hyperglycemia damaged the diverse vital body organs specifically nerves, kidneys, heart, eyes and blood vessels that lead to complications namely stroke, neuropathy, renal failure, retinopathy, blindness, amputations,

1 Dr. Nilesh J. Patel Associate Professor, Head of Pharmacology, Faculty of Pharmacy, Shree S. K. Patel College of Pharmaceutical Education & Research, Ganpat University – 384012 Email Id:- [email protected]

Page 1 of 27

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 965 AEGAEUM JOURNAL ISSN NO: 0776-3808

peripheral vascular diseases, cardiovascular diseases, etc. T2DM are categories into three types, IDDM (type 1), NIDDM (type 2) and Gestational diabetes. IDDM resulted by autoimmune destruction of the β cell of pancreas. NIDDM caused by insufficiency of insulin release and resistance towards the activity of insulin. [1,2] Worldwide current epidemiological data exhibits that approximately 366 million people had T2DM and 4.6 million deaths in 2011; it would have enhanced and reaches to 552 million in 2030. The numbers of people with T2DM living in low and middle-income countries is enhancing with 80% of people with T2DM.[3] The occurrence of T2DM diversifies from one geographical territory to the other through ecosystem as well as lifestyle predisposing factors.[4] India is the leader of the world with enormous number of diabetic patients earning the unreliable segregation of being designated the “World diabetes stock”. Honouring to the Diabetes Atlas 2006 circulated by the IDF, the number of population with diabetes in India currently around 40.9 million is predicted to uplift to 69.9 million by 2025 unless crucial preventive steps are taken. The “Asian Indian Phenotype” mentions that Indian has certain idiosyncratic clinical and biochemical deviations which encompass reduced insulin sensitivity, significant abdominal adiposity regardless of poor body mass index, lessen adiponectin and elevated high sensitive C-reactive protein levels. Elevated frequency of diabetes mellitus often outcome from in revises in food compositions and lack of physical functions in the urban population.[5] T2DM is fast capturing the status of a capable pandemic in India with greater than 62 million patients currently diagnosed with diabetic.[6,7]In the year of 2000, India exceeded the world with higher patients who have T2DM followed by China and the United States in second and third place respectively. Honouring to Wild et al. 2004, the universality of T2DM is expected to double ubiquitously from 171 to 366 million since 2006 to 2030 with a maximum rate in India. [8,9] IDDM is chiefly provoked by environmental factors. The important factors that play significant role in the development of T2DM comprise obesity[10],less physical activity and smoking. Obesity and poor socioeconomic level can convoyed enhancement of endemic of diabetes because of urbanisation, westernization and their affiliated lack of healthy food intake, lack of physical activity, unnutritional habits.[11,12]Weight of body is one of the most salient alterable etiologies in T2DM. Obesity is an unconventional etiology for dyslipidemia, elevated blood pressure, enhances the peril of CVDs and mortality in T2DM patients. [13] The pancreas of an elder’s individual doesn’t eject insulin as systematic as eject by adolescent. Higher blood pressure and inflated cholesterol level also contribute in T2DM.[14]

INSULIN RESISTANCE: Insulin resistance is one of major factor for initialization of T2DM.It is referred as a clinical circumstances of diminished sensibility of tissues towards insulin, notwithstanding its balance or uplifted level into blood stream; the ailment principally materialize in adipose tissue, skeletal muscle cells, and liver.[15,16]After the induction of insulin resistance in body as a results of this diminished glucose uptake, elevated efficiency of gluconeogenesis, and enhanced lipolysis by tissues.[17] There are various factors have been recommended for the elucidation of insulin resistance mechanism, which incorporate obesity, inflammation, mitochondrial dysfunction, hyperinsulinemia, hyperlipidemia, genetic background, stress of endoplasmic reticulum, aging, oxidative stress, fatty liver, hypoxia, lipodystrophy and pregnancy. These factors are affiliated with obesity

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 966 AEGAEUM JOURNAL ISSN NO: 0776-3808

that are crucial etiology for insulin resistance, have possible roles in the pathogenesis of insulin resistance.[18–20] Mechanism of insulin resistance at cellular level carried out by inadequate signaling is caused through diverse changes, which includes mutations and/or post-translational transformation in the receptors of insulin, IRS or in downregulating situated effect or molecules. Most common insulin resistance changes inclusive of a alleviate in insulin receptor numbers and their catalytic actions, an enhanced Ser/Thr phosphorylation phase in insulin receptor and IRS, an enhance tyrosine phosphatase action, mainly PTP-1B that take part in receptor and insulin receptor substrate dephosphorylation, a reduced in PI3K and Akt kinases effect, and defects in GLUT-4 expression and physiology.[21]Theses changes alleviate glucose uptake in adipose tissues, muscles and foster the changes at the metabolism level. An important factor play a central role for insulin resistance is Ser/Thr hyperphosphorylation of insulin receptor substrate and alleviates its phosphorylation in Tyrosine and lessen its interaction with PI3K, however changing Akt kinase phosphorylation and stimulation and IRS phosphorylation escalate its deterioration.Various agents likewise cytokines, saturated FAs, endothelin 1, angiotensin II, amino acids and states if elevated insulin levels in plasma.[22–24],It also enhance actions of kinases namely JNK stress kinase, mTOR, 70-kDa S6 ribosomal protein kinase, MAPK, diverse isoforms of PKC and PKA that phosphorylate insulin receptor substrate.[25] In addition, the development of ceramides because of saturated FAs metabolism enhanced likewise palmitate can control Akt action through modifying phosphor protein phosphatase 2A effect that dephosphorylate and immobilize it [26,27]and PKC effects that also phosphorylates it in Ser[28]and retards its translocation to the membrane in order to stimulated that mechanism control by at Akt level have been recognized.[29–31]

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS: In the journey of venturing, to particularize the methods via which few chemicals persuade peroxisome proliferation in experimental animals (rodents), as a receptor, peroxisome proliferator- activated receptor (PPAR) brought into light[32] and subsequently in short of time two others subtypes were identified that PPARβ/δ, PPARγ too. They diverse in expression, tissue allotment as well as ligand specificness.[33] PPARs synchronize a various biological actions in specific tissues that track down by specialism experimentation,[34] triggered by structurally numerous chemicals depends on as enlargement of size and/or quantity of peroxisome in the rodent liver acknowledged as peroxisome proliferators [35] The cloned receptor found that have structural similitude to a steroid hormone receptors. From the inception of the receptor, hope that delivers peroxisome proliferative action to the peroxisome proliferating chemicals, the receptor was entitled as PPAR. Succeeding pioneer of the mouse PPAR, the receptor recognized in other strain, inclusive of rat[36]also human. [37] Furthermore, three linked Xenopus receptors were cloned, PPAR, PPAR and PPAR.[38] PPAR recognized later in human also found that closely linked to the PPAR elucidated before time in Xenopus.[39–41]PPARs harmonize the expression of divers genes concerned with a small group of ailments; likewise diabetes, dyslipidemia, obesity and metabolic syndrome. From their discovery, PPARs have been studious for their fundamental role in glucose and lipid metabolism and vitality stability.[42]PPARs have powerful signaling molecule for improvisation in insulin resistance. PPARs are implying in the long-term

Page 3 of 27

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 967 AEGAEUM JOURNAL ISSN NO: 0776-3808

directive for breakdown of lipid, and their action is modified through endogenous lipid- acquired molecules. PPAR-α is controlling fasting fat oxidation, glucose sparing via enhancing fatty acid oxidation, ketone body generation also. PPAR-γ is controller for fat storing sugar utilizing via enhancing triglyceride depot and alleviating insulin resistance. The stimulation of PPARs as results ameliorating metabolic syndromes namely T2DM that are indicated through elevated levels of lipids in plasma and lower sensitivity towards insulin. PPARα and PPARγ is operative most likely via its action on oxidation of fat and elevation circulated fat into depot, persuading release of fruitful hormone respectively. Dual agonist of PPARα/γ were examined and shown to joint benefits action on lowering insulin resistance as well as fat variables.[43] PPARs associated with the steroid receptor superfamily; once they contact with their agonists, PPARs translocate to the nucleus, where they heterodimerize with the retinoid acid receptor. Furthermore, it binds with peroxisome proliferator response elements and commences the transcription of abundant genes involved in plenty of important processes. [33]The task of PPARs remake by a number of coactivators and co repressors, the existence of which can either activate or suppress receptor task, respectively. [44] The mechanism of PPARs (figure no. 1) when bind with agonists that trigger off PPAR-RXR cause an exchange of co-repressors for co-activators.[45,46] Human cells are signalized by a diverse availability of cofactors that rely on the type of cell and the alliance of specific cofactors to other genes.[45,47,48]

FIGURE NO. 1: MECHANISM OF PPARs

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS α:Element α of PPAR was introduced as a receptor that is elicited by peroxisome proliferators.[32,38,49,50]It is widely distributed in tissues identified by an increase the momentum of FAO reactions such as liver, skeletal muscles, the heart, where plays a key role in fatty acid homeostasis.[46,51]The notable distribution of PPAR α is observed also in kidneys, adrenal and BAT and macrophages, endothelial cells and smooth muscle cells are available in the blood.[46,52–59]

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 968 AEGAEUM JOURNAL ISSN NO: 0776-3808

PPARα governs the expression of overall of liver genes that involved in FA as well as lipoprotein metabolism too. Stimulation of PPARα via agonists is seen that elevate metabolic process of fatty acid, therefore, upregulates the transcriptional expression of genes that incorporated in the transportation of lipid, fatty acid β-oxidation, ω-oxidation also in a production of ketone bodies.[46,51,52] PPARα excitations harmonize the dominant gene expressions draw in VLDL-TG turnover, besides apo I & II which related with HDL.[53]Conclusive confirmation concerning the decisive contribution of α component of PPAR in liver FAO also lipoprotein breakdown has given through research comprising the utilization of PPARα compounds.[60–62] Lacking PPARα and transgenic mice (PPARαTG) from research in personage subjects possess natural mutations and polymorphisms in the receptor.[60,63]PPARα serves as a universal sensor of FA load. Furthermore, it is transcriptionally animate because of a bit of augment in the flowing amounts of free fatty acids, their metabolic substances or transitional. In mitochondria, upraise of important catabolic enzymes such as peroxisomal β-oxidation as well as microsomal ω-oxidation via PPAR stimulation because of, increased FA catabolism and secondly obstruct the pathological lipid aggregations in the liver.[46,51,52] Critically, alleviation in propagating quantity of TGs, sequentially the approachability of FAs for the VLDL-TG assembly obstructed augmented FA channelling for oxidation through PPARα related. Besides, initiated PPARα impairs hypertriglyceridemia by a direct route changing the expression of certain apolipoproteins also the crucial steps associated with VLDL-TG assembly and secretion.[53,60] Metabolic pathways are well accepted for becoming one of the important donors to unacceptable lipid accumulations in the liver as well as in skeletal muscles, elevated VLDL generation in the liver and later evolution of IR, Insulin resistance syndrome also T2DM because of various fairly dysregulated of it.[64]

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS β / δ:PPARβ/δ is wide- ranging conveyed comparatively outrageous extents as found in cardiac and skeletal muscle, liver, kidneys, brain, adipose tissue, colon and the blood.[59,61,65–67] PPAR β is well known as PPAR δ, NUCI, and FAAR. Go against PPARα and PPARγ, PPAR δ targeted molecules are integrated with its wide-ranging expression; the biological function of PPAR δ is much less researched and recognized, owing to that PPAR agonists not materialize as a target of some of the presently accessible molecules.[68] It is the majority copious elements among the three peroxisome proliferator activated receptors in skeletal muscle. Almost, 50% of body mass and greater than that metabolism happens in the skeletal muscle. Hence, actions bring in contraction may notably augment spending stamina plus depletion of glucose or metabolism of fat. Peroxisome proliferator activated receptor uplifts burning to skeletal muscle for deposited fatty components as fuel. That process becomes significantly worthwhile by cause of reduces TGs, LDL-C levels; decline IR, HDL - C levels too. Peroxisome proliferator activated receptor δ has been recognized to be an attainable answer because it burns the body’s fat. Lipids are the main birthplace for nourishment to tolerance efforts; hence, peroxisome proliferator activated receptor β is induced for augmenting metabolism of lipids of the body to produce stamina. Undeniably, augmentation of peroxisome proliferator activated receptor δ ameliorates dropping off the fat and work prolonged seeing that it accelerates utilization of lipids.[69–73]

Page 5 of 27

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 969 AEGAEUM JOURNAL ISSN NO: 0776-3808

The capacity of PPARβ/δ in the monitoring equilibrium of glucose come up with the results that agonists of PPARβ/δ alleviate obesity and enhance the resistance of glucose as well as IS in distinct mouse models of obesity. [74] Moreover, when a chow diet given to PPARβ/δ null mice that dispose of glucose intolerance. In obese insulin-resistant monkeys alleviated levels of insulin through endurobol treatment.[75] Utilization of PPARβ/δ tissues specified transgenic mice, in skeletal muscle or adipose tissue, appeared that animated PPARβ/δ persuades the gene expressions associated with FAO also in energy outlay via the initiation of uncoupling polypeptides in the BAT; skeletal muscle too.[76–78] For that reason, substrate proffer for storage of fat in WAT is minimized, as a result depletion of obesity. It is also considered truthful PPAR δ/β persuades burning lipid in muscle that conjunction with a chiefly enhancement in systemic fat metabolism is answerable for dropping lipid burden in IS tissues, as a result decline the IR.[79]

PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS γ:Itis well categorized, an element of the PPARs, also pharmacological effective as an insulin resistance lowering agents, which are used as a remedy for insulin resistance integrated with T2DM.[53] PPARγ prevails as two isoforms, PPARγ1 and PPARγ2, via replacement splicing and differential promoter consumption. PPARγ2 retains a thirty amino acid extension at its N-terminus. PPARγ1 and PPAR γ2 are distributed in lower intestines, macrophages, and adipose tissue and modest only in adipose tissue respectively. PPARγ is primarily augmented insulin sensitivity via glucose/fat uptake and store in peripheral tissues namely skeletal muscle, liver, and adipose tissue and key controller of metabolic genes.[54] Particularly, it is adequate along with requisite to differentiation of lipid cell. Mandatory PPARγ expression changed into adipocytes from fibroblasts, while preadipocytes cultured in controlling negative PPARγ mutants retard generation of adipocytes.[80–82] Moreover, adipose tissue is unsuccessful to grow in PPARγ knockout mice.[83–85] Therefore, PPARγ show signs of the controller for the biology of lipid cell also adipose tissue allied equilibrium of energy. In adult adipocytes, deactivation of PPARγ decline insulin sensitivity via impairment in genes allied escorted by insulin signalling, FFA uptake, and breakdown of fats.[86,87] Chiefly, amplified mice escorted activity of PPARγ are improved insulin sensitivity inspired by obesity,[88] whereas, PPARγ missing mice, particularly in lipid, muscle, or liver originate hyperlipidemia, hyperglycemia, or hyperinsulinemia.[89–92]Steady with findings, humans with assertive negative mutations in a solitary allele of PPARγ (the gene encoding PPARγ) have limited lipodystrophy and insulin resistance. [93–95]

What makes PPAR γ synthetic ligands controls IS? Two sensible biochemical mechanisms have been projected. Firstly, stimulation of PPARγ is lipid repartitioning. IR allied upgraded with free fatty acids plasma levels, also an aggregation of fats in the liver and skeletal muscle and other than adipose tissue. Owing to PPARγ have a central duty in fat metabolism, regulating genes expression that associated in metabolic conversions of fats, inclusive of aP2, CD36 LPL, FATP-1, glycerol kinase, SREBP-1, and SCD-1[96], deposition of lipids in adipose tissues is enhanced by stimulation of PPARγ by TZDs. Therefore, TG quantity ameliorated. There are dropping of FFAs in the propagation, liver, and muscle. Hence, lipotoxicity diminished by thiazolidinediones in the liver as well as in

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 970 AEGAEUM JOURNAL ISSN NO: 0776-3808

muscle. It also ameliorates insulin sensitivity.[97,98] Another developed biochemical mechanism is controlling the generation and release of adipokines, intervene by thiazolidinediones produced stimulation of PPARγ in adipose tissue. These adipokines, namely resistin, leptin, adiponectin and TNF-α, maybe influence the whole body insulin sensitivity via signalling pathways of endocrinal. In peripheral tissues, thiazolidinediones lower TNF-α, IL-6, and resistin genes expression in adipose tissue that raises insulin resistance. Nevertheless, results of PPARγ stimulation raising development of adiponectin, which reinforces FAO as well as insulin sensitivity, evoke alleviating glucose development and enhanced glucose utilization in liver and muscle, respectively.[98–104]PPAR γ controls lipid, glucose, and insulin uptake into adipocytes, as it is liable for controlling the expression of two markers of terminal adipocyte differentiation, adipocyte protein type 2 (aP-2) as well as phosphoenolpyruvate carboxykinase (PEPC). In addition, PPAR is in charge of controlling the expression of the genes which code for lipoprotein lipase (LPL), enhancing TGs lipolysis in very little density lipoproteins (VLDLs). PPAR is also enhancing high-density lipoproteins (HDLs)[105], the FATP, which monitors uptake of FA, and fatty acid translocase, which enhances uptake of FA in adipocytes, as the suppression expression of the ob gene for leptin, which enhances the hungriness, and this is consistent with the biological effects of TZDs, namely reducing blood glucose levels and correcting insulin sensitivity.[106–111] On the other hand, adipogenesis caused in response to remedy with TZDs has been related chiefly to the recognition of two PPAR-responsive members of the FGF family, FGF1 and FGF21, which act locally in visceral adipose tissue, raise insulin sensitization, for that reason the stimulation of the receptor in the brain, rather than in adipose tissue, has an utmost role in TZD-induced weight gain. [108] Obesity rates and westernization of lifestyle as a result augment of dysfunctional adipose tissue, which persistently stimulates NF-B and conveys inflammatory cytokines namely TNF, resistin, IL-6, and IL-1, which, along with the disrupted of reactive oxygen species (ROS) and water retention, are largely available in a broad range of ailments like insulin resistance, T2DM, hypertension, hyperlipidemia, and cardiovascular ailments (CVD), thus conserving a chronic inflammatory surroundings. [113- 125] Insulin resistance has been recognized as a crucial contributor to the initiation of T2DM and metabolic syndrome since it grows the transporting FAs into the propagation, which harmonize the potential of the heart to utilize glucose as an energy source [118, 120-124] leading to a cellular stress represented by an unrestricted ROS production, disrupted state of nitric oxide (NO) vasorelaxation, generation of inflammatory cytokines, mitochondrial dysfunction, enhanced AGEs, also dysfunction of endothelial progenitor cells, as the suppression of the anti-atherogenic adipokine adiponectin. [116, 118, 120-126] PPAR is broadly expressed in the vascular system, where it is allied in the restriction or expression of certain genes namely angiotensin type 1 receptor (AT1R), which can block or enhance endothelial dysfunction and atherosclerosis. [106, 119, 125, 127-130] According to this, it has been seen that, in animal models, restriction of the expression of PPAR raises cardiomyopathy, lipid deposition, arrhythmias, hypertrophy, and enhanced expression of cardiac inflammatory markers. [118, 123, 124, 131] It has also been seen that adiponectin enhances by PPRE in the contributor of adipocytes, playing an important role for the vascular protective actions of PPAR agonists, as the case where diabetic db/db mice treated with rosiglitazone activated the liberate adiponectin, which triggered AMPK/eNOS and

Page 7 of 27

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 971 AEGAEUM JOURNAL ISSN NO: 0776-3808

cAMP/PKA pathways in the aorta, However leading to the depletion of oxidative stress and the amplification of NO bioavailability, correcting endothelial function. [115, 125, 132] It has also been shown either in clinical practice or in animal models that the uninterrupted treatment with TZDs tends to impaired the advancement of carotid artery intima/media thickness, lowering the onset of restenosis, predominantly owing to the suppression of smooth cell migration, the enhanced apoptosis in vascular smooth cells, and the prevention of insulin carried atherosclerosis via shifting myocardial substrate metabolism toward glucose. [114, 123, 129, 130, 133]

PPARs AGONISTS HERBAL AND SYNTHETIC DRUGS USED IN DIABETES MELLITUS: Peroxisome proliferator activated receptor α is for a structurally manifold class of molecules, inclusive of organic and synthetic molecules. Inside the peroxisome proliferator activated receptor α LBD, there is an extensive area ~1400 µm3 where molecules are attached. The molecule acquires conformation inside the receptor that authorizes the generation of hydrogen bond interactions; these interactions strengthen the receptor in a configuration that brings to transcriptional excitation of PPAR-α by induction of coactivators. [134] Numbers of naturally occurring PPAR-α molecules, the bit of cells are capable to produce a domestic molecule, the phospholipid 1-palmitoyl- 2-oleoyl-sn-glycerol-3- phosphocholine, which is synthesized via fatty acid synthase enzyme. [135] Furthermore, other natural compounds such as polyunsaturated FAs are given through the foodstuffs such as α-linolenic, γ-linolenic, arachidonic acids and linoleic, which attached to α element of peroxisome proliferator activated receptor at physiologic concentrations. [40] The establishment of phytanic acid that is obtained from phytol, which presents in dairy goods and herbal agonist of PPAR-α. [136, 137] Conventionally, nutritional polyunsaturated FAs have authenticity on divergent biologic activity likewise insulinotropic effect, physiology of cardiovascular, improvement at a neural level, and physiology of immune, few of them revealed via α element of peroxisome proliferator activated receptor. Moreover, nutritional polyunsaturated FAs animate both, directly or indirectly, additional transcription factors likewise LXR, HNF – 4, also SREBP that reveal to a bit length additional biologic activity influence the specific gene expressions. [138,139]Chemically synthesized PPARα ligands known as fibrates decline the TG-lavish lipoproteins in serum via elevate expressions of genes associated in FAO and diminish in apo C-III expression of genes. Fibrates have been clinically utilized in the high blood levels of TGs very wide manner. Later on, initiation by agonist, PPAR receptors couple escorted to the RXR and then attach to PPRE. Class of fenofibrate not only exhibits a TG reducing action, augment HDL-C too. Their movements result in declining general accessibility of FAs and muffling of FA uptake in muscles. Fibrates dvts augment IS as well as minimize glucose strength in plasma. [58,140,141] The selective modulators of PPARγ are known as SPARMs via similitude to selective modulators of the estrogen receptor. The well-defined activities of SPARMs controlled on the cellular context as well as divergent conformation in receptors, as a result manifold gene interactions. [142] Handpicked FAs believed as natural PPARγ modulators; therefore, their attachment accompanied by the receptor does not all the time escort to PPAR initiation and target gene transcription. PPARγ is initiating through herbal compounds namely polyunsaturated FAs predominantly DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid) brings about a

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 972 AEGAEUM JOURNAL ISSN NO: 0776-3808

functional response against malignant cells. Numerous researchers have been proffered confirmation; stimulation of PPARγ via DHA that blocks the tumor production. [143] The growth of breast cancer cells prevented also encourages apoptosis; if DHA distributed into those cells via albumin or via abundant LDL with omega – 3 polyunsaturated FAs. [144-146] In this process, Syndecan-1 is the stimulating factor of apoptosis that takes parts. Later on, the transcriptional upregulation of the syndecan-1 target gene is existent when the activation of PPARγ through DHA. Into the preclinical researchers long chain monounsaturated FAs accompanied by chain spans prolonged than eighteen (i.e., amalgamated isomers C20:1 and C22:1) may improve metabolic dysfunction allied to obesity via enhanced PPARγ expression and in WAT, expression of inflammatory markers. [147] Into the in vitro researches, stimulation of PPARβ/δ also PPARα in human breast cancer’s cell lines triggered expansion of cell [148,149], whereas compounds for PPARγ suppressed this action. Aside phytanic acid is from polyunsaturated FAs and a natural PPARγ agonist in the human food, which exhibits a homogeneous action to n – 3 polyunsaturated FA also, augments uptake of glucose and lowers insulin resistance; so, accompanied by fewer potential for adipocytes differentiation. [150] PPARγ is a controller for the metabolic process of fat as well as glucose. Hence, its chemically synthesized compounds namely glitazones the by-products of TZDs (e.g., troglitazone, rosiglitazone and pioglitazone), which raise the parameters of glucose and insulin; it also ameliorates insulin sensitivity in whole body. So, glitazones are known as insulin sensitizing agents applicable for remedy in T2DM. [151] Glitazones incidentally ameliorate insulin-motivated uptake of glucose in skeletal muscle cells, adipocytes and hepatocytes. [152,153] Biological actions of γ isomer of PPAR stimulation through TZDs assigned, fewer in part, in adipose tissues to reduced FFA levels and ameliorated fat retention. As a result, accumulation of fats into the liver as well as muscles is decreased. Moreover, agonists of PPARγ have potential to redistribute lipid from interior to an exterior repository, enhance adiponectin also lowers TNF. [154,155] Additionally, pioglitazone and rosiglitazone are utilized as remedy for patients accompanied by T2DM for the reason that, pioglitazone and rosiglitazone lessen the development of glucose in liver also, they lengthen the functions of the pancreatic β-cells via blocking apoptosis. [152,153] In T2DM, long-term stimulation of PPARγ via TZDs lowers excessive amounts of glucose and insulin in the bloodstream as well as diminished dysfunctioning of the vascular system. The expression of PPARγ is in vessels, particularly in smooth muscle cells of vascular system also in endothelium. Modern investigations propound which PPARγ stimulation improves disturbances in metabolic processes as well as defend function of vascular system into T2DM. [155] In spite of the abundant advantageous quality of TZDs specifically in metabolic and anti-arteriosclerotic effects, TZDs also disclose unpalatable effects, namely weight gain, oedema, fractures of bone, congestive cardiac failure also enhanced the threat of myocardial infarction that have restricted exert of TZDs into T2DM sufferers accompanied by elevated fat levels. [156] Hopefully, newly discovered selective PPARγ ligands are presently under pipeline namely S26948 and INT131 also these agents would be provoke metabolic pathways of glucose as well as lessen the unpalatable effects of PPAR-γ full agonists. [157, 158]

Page 9 of 27

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 973 AEGAEUM JOURNAL ISSN NO: 0776-3808

DUALISM OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS α/γ:Dual agonists of PPAR- α/γ have been authorized for lipid and glycemic control. Countless dual PPAR agonists have been produced [159-162]; therefore, none of these drugs were marketed owing to collateral undesirable effect with the exclusive of saroglitazar. [160, 163] Owing to relates with their undesired actions of TZDs namely fluid restriction, weight gain and cardiac failure have resulted in new label caution for these molecules. Hence, there was a powerful need for a dual PPAR-α/γ agonist with advantageous activities in regulating both lipids as well as glycemic levels with essential safety issues.[164] Agents stimulating PPAR-α provokes significant refinements in unbalanced lipid profile and fall off atherosclerotic lesions, without any action on plasma sugar levels. PPAR-γ seems to ameliorate glycemic control by augmenting peripheral insulin sensitivity and lessening hepatic gluconeogenesis, as a result of that conserving the β-cell task. [165] Therefore, there is a recovery of interest in the production of newer antidiabetic agents, which amalgamate the insulin-sensitizing activities of PPAR-γ stimulation with the supplementary lipid improving an effect of the PPAR- α. Glitazars are a new inception of dual PPAR α / γ agonists. Dual stimulation of PPAR γ and PPAR α elevates the effort of adiponectin and augments its receptor expression in WAT. [166] Previously, various dual PPAR α/γ ligands namely glitazars, including of TZD and non- TZD compounds were produced, but every compound was profitless, as few have unpalatable effects namely an enhanced creatinine levels, dysfunctioning of the cardiovascular system or malignancy in bladder throughout the preclinical or clinical research. Therefore, former glitazars accompanied by a powerful agonist of PPAR α/γ was accepted for human studies; however, every compound was terminated owing to toxicity issues during a preclinical or clinical level. [171,172] Overall, according to their basic structure of molecules, glitazar produced dual effect accompanied by different levels into the involvement of PPAR α and PPAR γ. However, these evaluated compounds given off unpalatable effects, the effects molecules oriented also of various origins e.g. elevate into urothelial, renal, heart toxicity or adipose tissues with distinct PPAR α/γ agonists. On another hand, non-success of early PPAR α/γ agonists, there was an increasing ambition of a prospective molecule that could be free from those unpalatable events also but have an affirmative activity on insulin resistance for rectification of diabetic dyslipidaemia. [173]

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 974 AEGAEUM JOURNAL ISSN NO: 0776-3808

Increased reverse cholesterol Improved transport Increased insulin HDL sensitivityDUALIS expression Depots of Improves FAs via M lipoprotein adipocytes metabolism stimulation EFFECT S VIA Differentiatio FAO and n of pre- cellular FA adipocyte PPAR α/γ Increase Improve β glucose cell function homeostasis

TABLE NO.: 1 Major Effects of PPAR α and γ Activation [46, 52, 167-170]

The scientific study reported that when pioglitazone mixed with a half dose of fenofibrate, the amalgamation raised nonalcoholic steatohepatitis associated induced by fructose inconveniences. The inconvenience raised either same or better than, a full dose of fenofibrate given single may be owing to diminishing activities of pioglitazone on the expression of the gene sensible for insulin resistance, synthesis of fatty acid and fibrosis and rectifying the equilibrium between adiponectin and leptin expression of genes. Research supports to the hypothesis that stimulation of dual PPAR- α and PPAR- γ have phenomenal actions to improving nonalcoholic steatohepatitis. [174] Another study reports that Osthole, a coumarin substitute, is a vital molecule isolated from the medicinal plant Cnidium monnieri (L.) Cusson (Umbelliferae). It can enhance glucose as well as lipid breakdown and initiate a valuable therapeutic action on high fat and high sucrose produced fatty liver with insulin resistance in rats. Additionally, its mechanisms possibly related with synergic modulation of PPARα/γ-mediated target genes connected in glucose and lipid metabolism, inclusive of diminishing in SREBP-1c, FAS, and DGAT gene expression in liver and adipose tissues, and elevate in CPT-1A gene expression in hepatic and GLUT-4 gene expression in skeletal muscle. [175]

Sr. Name Clinical Status No. 1 Muraglitazar Discontinued - Phase-II for Type-2 diabetes mellitus

Page 11 of 27

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 975 AEGAEUM JOURNAL ISSN NO: 0776-3808

because of adverse effects on Cardiovascular system (heart failure) (2006) Discontinued - Phase-III for Metabolic syndrome and 2 Tesaglitazar Insulin resistance because of increased levels of creatinine affiliated with alleviated glomerular filtration (2006) Suspended - Phase-III for Type-2 diabetes mellitus in 3 Ragaglitazar Denmark because of Bladder tumors in rodents (2002) Chiglitazar is still in phase III trials for Type-2 diabetes 4 Chiglitazar mellitus in China (2016) Discontinued - Phase-II for Lipid metabolism disorders in 5 Cevoglitazar Switzerland because of lack of a sufficiently positive benefit/risk (2007) Discontinued for Type 2 Diabetes Mellitus because of 6 Naveglitazar adverse preclinical findings in rodents (2006) Discontinued - Phase-II for Diabetes mellitus in USA 7 Sipoglitazar because of serious safety concerns (2006) Discontinued - Phase-II for Type-2 diabetes mellitus due 8 Aleglitazar to GI bleeding, bone fractures, heart failure (2013) Development identified for preclinical development in 9 Lobeglitazar Type-2-diabetes-mellitus in USA (2017) 10 Saroglitazar Shown adverse effects like Gastritis, Asthenia, Pyrexia. Discontinued - Phase-II for Diabetes mellitus in Japan 11 MK-767/KRP-297 because of Preclinical toxicities (2004) 12 TZD-18 Preclinical Phase 13 PAR-5359 Preclinical Phase Discontinued - Phase-I for Diabetes mellitus in Japan 14 E3030 (2007) Discontinued - Phase-III for Type-2 diabetes mellitus in 15 Imiglitazar USA due to abnormalities in liver enzymes (2005) Discontinued - Phase-II for Type-2 diabetes mellitus in 16 AVE-0847 France because Development terminated due to glitazar: reprioritization of product portfolio (2008) Discontinued - Phase-I for Hyperlipidaemia in United 17 GW409544 Kingdom (2002) 18 LT175 Preclinical Phase 19 MHY908 Preclinical Phase Discontinued - Phase-I for Alzheimer's disease & Type-2 20 DSP-8658 diabetes mellitus in USA (2013) 21 CG301360 Preclinical Phase discontinued because of carcinogencity in rodent toxicity 22 MK0676 models and elevated serum creatinine & affiliated lessen in glomular filtration rate respectively 5-Substituted 2- 23 Preclinical Phase—type II diabetes benzoylamino-benzoic

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 976 AEGAEUM JOURNAL ISSN NO: 0776-3808

acid

derivatives: (BVT-142) O-arylmandelic acid 24 Preclinical Phase derivatives Azaindole--alkyloxy- 24 Preclinical Phase phenylpropionic acid Oxime substituted with

α-substituted-β- 25 phenylpropionic acid Preclinical Phase derivatives

with oxime Amide substituted with

26 α-substituted-β- Preclinical Phase phenylpropionic acid derivatives 2Alkoxydihydro 27 Preclinical Phase cinnamate derivatives 28 Farglitazar Discontinued-III for Type-2 diabetes mellitus Discontinued because of generation of tumour and mild 29 Compound3q hepatotoxocity 30 N15 Preclinical Phase 31 5-aminosalicylic acid Preclinical Phase (7E)-9-oxohexadec-7- 32 Preclinical Phas enoic acid (10E)-9-oxohexadec-10- 33 Preclinical Phase enoic acid

TABLE NO. 1: LIST OF GLITAZARS AND WITH CLINICAL STATUS [178-203]

FUTURE SCOPE OF DUALISM: PPARs are effective in treating diabetes by lowering the triglycerides and blood glucose levels. PPARα agonists are used for treating dyslipidemia especially low HDL cholesterol and increased triglyceride levels. It is also effective in reducing cardiovascular problems. PPAR γ agonists are used for treating type 2 diabetes. PPAR γ agonists regulate the fatty acid catabolism and energy uncoupling which in turn decreases the triglyceride stores and enhances the cardiac contractility. This dualism have great futuristic scope but controlling for the unwanted effects produced as like ancient molecules of dual PPAR α/γ agonists in beneficial against diabetes mellitus through regulating carbohydrate and lipid overload.

Page 13 of 27

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 977 AEGAEUM JOURNAL ISSN NO: 0776-3808

BIBILIGRAPHY:

1.Kahn CR, Weir GC, King GL, Jacobson AM, Moses AC, Smith RJ. Joslin’s diabetes mellitus. In: Bennett PH, Knowler WC. Definition, Diagnosis, and Classification of Diabetes Mellitus and Glucose Homeostasis. Philadelphia: Lippincott Williams & Wilkins, 2005: 331– 339. 2.Jothivel N, Ponnusamy SP, Appachi M, Singaravel S, Rasilingam D, Deivasigamani K, et al. Anti-diabetic Activity of Methanol Leaf Extract of Costuspictus D. DON in Alloxan- induced Diabetic Rats. Journal of Health Science [Internet]. 2007;53(6):655–63. 3.Olokoba AB, Obateru OA, Olokoba LB. Type 2 diabetes mellitus: a review of current trends. Oman medical journal. 2012;27(4):269–73. 4.Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature. 2001;414(6865):782–7. 5.Ramachandran A, Das AK, Joshi SR, Yajnik CS, Shah S, Kumar KMP. Current status of diabetes in India and need for novel therapeutic agents. Journal of Association of Physicians of India. 2010;58:7–9. 6.Joshi SR, Parikh RM. India - Diabetes Capital of the World. Journal of Association of Physicians of India. 2007;55:323–324. 7.Kumar A, Goel MK, Jain RB, Khanna P, Chaudhary V. India towards diabetes control: Key issues. Australasian Medical Journal.2013;6(10):524–31. 8.Whiting DR, Guariguata L, Weil C, Shaw J. IDF Diabetes Atlas: Global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Research and Clinical Practice. 2011;94(3):311–321. 9.Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes care. 2004;27(5):1047–53. 10. Kablan A, Saunders RA, Szkudlarek-Mikho M, Chin AJB, Bosio RM, Fujii K,Shapiro J, Chin KV. Prieurianin causes weight loss in diet-induced obese mice and inhibits adipogenesis in cultured preadipocytes. Journal of diabetes & metabolism. 2010;1(101). 11. Taloyan M, Saleh-Stattin N, Johansson S-E, Agréus L, Wändell P. Differences in cardiovascular risk factors in swedes and Assyrians/Syrians with type 2 diabetes: association with lifestyle-related factors. Journal of Diabetes & Metabolism. 2010;01(03):1–7. 12. Belmokhtar F, Belmokhtar R, Charef M, Dali-Sahi M. Risk factors associated with type 2 diabetes mellitus in west region of Algeria, Maghnia. Journal of Diabetes & Metabolism. 2011;02(05):1-6. 13. Mungrue K, Roper L-A, Chung T. Assessment of weight loss in the management of patients with type 2 diabetes mellitus in primary care in Trinidad. Journal of Diabetes & Metabolism. 2011;02(02):1–5. 14. Adapa D, Sarangi TK. A review on diabetes mellitus: complications, management and treatment modalities. Research & Reviews: Journal of Medical and Health Sciences. 2015;4(3):1–14. 15. Bhattacharya S, Dey D, Roy SS. Molecular mechanism of insulin resistance. Journal of biosciences. 2007;32(2):405–13. 16. Frank N, Tadros EM. Insulin dysregulation. Equine Veterinary Journal. 2014;46(1):103– 12.

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 978 AEGAEUM JOURNAL ISSN NO: 0776-3808

17. Treiber KH, Kronfeld DS, Geor RJ. Insulin resistance in equids: possible role in laminitis. The Journal of Nutrition. 2006;136(7):2094–2098. 18. Ye J. Role of insulin in the pathogenesis of free fatty acid-induced insulin resistance in skeletal muscle. Endocrine, Metabolic & Immune Disorders-Drug Targets. 2007 1;7(1):65– 74. 19. He Q, Gao Z, Yin J, Zhang J, Yun Z, Ye J. Regulation of HIF-1α activity in adipose tissue by obesity-associated factors: adipogenesis, insulin, and hypoxia. American Journal of Physiology-Endocrinology and Metabolism.2011;300(5):877–885. 20. Ye J, McGuinness OP. Inflammation during obesity is not all bad: evidence from animal and human studies. American Journal of Physiology-Endocrinology and Metabolism. 2013; 304(5):466–77. 21. Samuel VT, Shulman GI. The pathogenesis of insulin resistance: Integrating signaling pathways and substrate flux. Journal of Clinical Investigation. 2016;126(1):12–22. 22. Montagnani M, Ravichandran L V., Chen H, Esposito DL, Quon MJ. Insulin Receptor Substrate-1 and Phosphoinositide-Dependent Kinase-1 Are Required for Insulin-Stimulated Production of Nitric Oxide in Endothelial Cells. Molecular Endocrinology. 2002;16(8):1931–42. 23. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999;399(6736):601–5. 24. Lee JH, Ragolia L. AKT phosphorylation is essential for insulin-induced relaxation of rat vascular smooth muscle cells. American Journal of Physiology-Cell Physiology. 2006; 291(6):C1355–65. 25. Reyes, JAO, Plancarte AA. Bases moleculares de lasacciones de la insulina. Rev EduBioq. 2008;27(1):9–18. 26. Chavez JA, Knotts TA, Wang L-P, Li G, Dobrowsky RT, Florant GL, et al. A Role for Ceramide, but Not Diacylglycerol, in the Antagonism of Insulin Signal Transduction by Saturated Fatty Acids. Journal of Biological Chemistry. 2003 Mar 21;278(12):10297–303. 27. Salinas M, López-Valdaliso R, Martín D, Alvarez A, Cuadrado A. Inhibition of PKB/Akt1 by C2-ceramide involves activation of ceramide-activated protein phosphatase in PC12 cells. Molecular and cellular neurosciences. 2000;15(2):156–69. 28. Klaman LD, Boss O, Peroni OD, Kim JK, Martino JL, Zabolotny JM, et al. Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein- tyrosine phosphatase 1B-deficient mice. Molecular and cellular biology. 2000;20(15):5479– 89. 29. Chavez JA, Summers SA. A Ceramide-Centric View of Insulin Resistance. Cell Metabolism. 2012;15(5):585–94. 30. Stratford S, Hoehn KL, Liu F, Summers SA. Regulation of insulin action by ceramide dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. Journal of Biological Chemistry. 2004; 279(35):36608–15. 31. Bourbon NA, Sandirasegarane L, Kester M. Ceramide-induced Inhibition of Akt Is Mediated through Protein Kinase Cζ Implications for growth arrest. Journal of Biological Chemistry. 2002;277(5):3286–92.

Page 15 of 27

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 979 AEGAEUM JOURNAL ISSN NO: 0776-3808

32. Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990;347(6294):645–50. 33. Berger J, Moller DE. The Mechanisms of Action of PPARs. Annual Review of Medicine. 2002;53(1):409–35. 34. Kliewer SA, Xu HE, Lambert MH, Willson TM. Peroxisome proliferator-activated receptors: from genes to physiology. Recent ProgHorm Res. 2001;56:239–263. 35. Reddy J, Krishnakantha T. Hepatic peroxisome proliferation: induction by two novel compounds structurally unrelated to clofibrate. Science. 1975;190(4216):787–9. 36. Göttlicher M, Widmark E, Li Q, Gustafsson JA. Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor. Proceedings of the National Academy of Sciences of the United States of America. 1992;89(10):4653–7. 37. Schmidt A, Endo N, Rutledge SJ, Vogel R, Shinar D, Rodan GA. Identification of a new member of the steroid hormone receptor superfamily that is activated by α peroxisome proliferator and fatty acids. Molecular Endocrinology. 1992;6(10):1634–41. 38. Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W. Control of the peroxisomal β-oxidation pathway by a novel family of nuclear hormone receptors. Cell. 1992;68(5):879–87. 39. Kliewer SA, Sundseth SS, Jones SA, Brown PJ, Wisely GB, Koble CS, Devchand, P, Wahli, W, Willson, TM, Lenhard, JM, Lehmann, J M. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ. Proceedings of the National Academy of Sciences of the United States of America.1997;94(9):4318–23. 40. Forman BM, Chen J, Evans RM. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors α and δ. Proceedings of the National Academy of Sciences of the United States of America. 1997;94(9):4312–7. 41. Lalloyer F, Staels B. Fibrates, Glitazones, and Peroxisome Proliferator-Activated Receptors. Arteriosclerosis, Thrombosis, and Vascular Biology. 2010;30(5):894–9. 42. Polvani S, Tarocchi M, Tempesti S, Bencini L, Galli A. Peroxisome proliferator activated receptors at the crossroad of obesity, diabetes, and pancreatic cancer. World Journal of Gastroenterology. 2016;22(8):2441. 43. Ferré P. The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes. 2004; 53Suppl 1(Supplement 1):S43-50. 44. Viswakarma N, Jia Y, Bai L, Vluggens A, Borensztajn J, Xu J, Reddy, JK. Coactivators in PPAR-Regulated Gene Expression. PPAR Research. 2010;2010:1–21. 45. Heikkinen S, Auwerx J, Argmann C. PPARγ in human and mouse physiology. Biochimica et BiophysicaActa (BBA) - Molecular and Cell Biology of Lipids. 2007;1771(8):999–1013. 46. Feige JN, Gelman L, Michalik L, Desvergne B, Wahli W. From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Progress in lipid research. 2006;45(2):120–59. 47. Ren D, Collingwood TN, Rebar EJ, Wolffe AP, Camp HS. PPARγ knockdown by engineered transcription factors: Exogenous PPARγ2 but not PPARγ1 reactivates adipogenesis. Genes and Development. 2002;16(1):27–32. 48. Werman A, Hollenberg A, Solanes G, Bjørbæk C, Vidal-Puig AJ, Flier JS. Ligand- independent activation domain in the N terminus of peroxisome proliferator-activated

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 980 AEGAEUM JOURNAL ISSN NO: 0776-3808

receptor γ (PPARγ). Differential activity of PPARγ1 and -2 isoforms and influence of insulin. Journal of Biological Chemistry. 1997;272(32):20230–5. 49. Germain P, Staels B, Dacquet C, Spedding M, Laudet V. Overview of Nomenclature of Nuclear Receptors. Pharmacological Reviews. 2006;58(4):685–704. 50. Schoonjans K, Staels B, Auwerx J. Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. Journal of lipid research. 1996;37(5):907–25. 51. Azhar S, Kelley G. PPARα: its role in the human metabolic syndrome. Future Lipidology. 2007;2(1):31–53. 52. Lefebvre P, Chinetti G, Fruchart J-C, Staels B. Sorting out the roles of PPAR in energy metabolism and vascular homeostasis. Journal of Clinical Investigation. 2006;116(3):571– 80. 53. Duval C, Müller M, Kersten S. PPARα and dyslipidemia. Biochimica et BiophysicaActa - Molecular and Cell Biology of Lipids. 2007;1771(8):961–71. 54. Tontonoz P, Spiegelman BM. Fat and Beyond: The Diverse Biology of PPARγ. Annual Review of Biochemistry. 2008;77(1):289–312. 55. Wagner KD, Wagner N. Peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) acts as regulator of metabolism linked to multiple cellular functions. Pharmacology and Therapeutics. 2010;125(3):423–35. 56. Blaschke F, Takata Y, Caglayan E, Law RE, Hsueh WA. Obesity, peroxisome proliferator-activated receptor, and atherosclerosis in type 2 diabetes. Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26(1):28–40. 57. Bensinger SJ, Tontonoz P. Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature. 2008;454(7203):470–7. 58. Reilly SM, Lee CH. PPARδ as a therapeutic target in metabolic disease. FEBS Letters. 2008;582(1):26–31. 59. Robinson E, Grieve DJ. Significance of peroxisome proliferator-activated receptors in the cardiovascular system in health and disease. Pharmacology and Therapeutics. 2009;122(3):246–63. 60. Pyper SR, Viswakarma N, Yu S, Reddy JK. PPARα: energy combustion, hypolipidemia, inflammation and cancer. Nuclear Receptor Signaling. 2010;8:1-21. 61. Hamblin M, Chang L, Fan Y, Zhang J, Chen YE. PPARs and the Cardiovascular System. Antioxidants & Redox Signaling. 2009; 11(6):1415–52. 62. Gonzalez FJ, Shah YM. PPARα: Mechanism of species differences and hepatocarcinogenesis of peroxisome proliferators. Toxicology. 2008;246(1):2–8. 63. Fruchart JC. Peroxisome proliferator-activated receptor-alpha (PPARα): At the crossroads of obesity, diabetes and cardiovascular disease. Atherosclerosis. 2009;205(1):1– 8. 64. Muoio DM, Newgard CB. Obesity-Related Derangements in Metabolic Regulation. Annual Review of Biochemistry. 2006;75(1):367–401. 65. Neschen S, Morino K, Dong J, Wang-Fischer Y, Cline GW, Romanelli AJ, Rossbacher, JC, Moore, IK, Regittnig, W, Munoz, DS, Kim, JH, Shulman, GI. N-3 Fatty Acids Preserve Insulin Sensitivity in Vivo in a Peroxisome Proliferator-Activated Receptor-Α-Dependent Manner. Diabetes. 2007;56(4):1034–41.

Page 17 of 27

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 981 AEGAEUM JOURNAL ISSN NO: 0776-3808

66. Barish GD, Narkar VA, Evans RM. PPARδ: A dagger in the heart of the metabolic syndrome. Journal of Clinical Investigation. 2006;116(3):590–7. 67. Kilgore KS, Billin AN. PPARbeta/delta ligands as modulators of the inflammatory response. Current opinion in investigational drugs (London, England : 2000). 2008;9(5):463–9. 68. Bishop-Bailey D, Bystrom J. Emerging roles of peroxisome proliferator-activated receptor-β/δ in inflammation. Pharmacology & Therapeutics. 2009;124(2):141–50. 69. Berger J, Leibowitz MD, Doebber TW, Elbrecht A, Zhang B, Zhou G, Biswas, C, Cullinan, CA, Hayes, NS, Li, Y, Tanen, M, Ventre, J, Wu, MS, Berger, GD, Mosley, R, Marquis, R, Santini, C, Sahoo, SP, Tolman, RL, Smith, RG, Moller, DE. Novel peroxisome proliferator-activated receptor (PPAR) γ and PPARδ ligands produce distinct biological effects. Journal of Biological Chemistry. 1999;274(10):6718–25. 70. Lim H, Dey SK. PPARδ Functions as a Prostacyclin Receptor in Blastocyst Implantation. Trends in Endocrinology & Metabolism. 2000;11(4):137–42. 71. Martens FMAC, Visseren FLJ, Lemay J, de Koning EJP, Rabelink TJ. Metabolic and additional vascular effects of thiazolidinediones. Drugs. 2002;62(10):1463–80. 72. Duval C, Chinetti G, Trottein F, Fruchart JC, Staels B. The role of PPARs in atherosclerosis. Trends in Molecular Medicine. 2002 Sep;8(9):422–30. 73. Bishop-Bailey D, Wray J. Peroxisome proliferator-activated receptors: A critical review on endogenous pathways for ligand generation. Prostaglandins and Other Lipid Mediators. 2003;71(1–2):1–22. 74. Tanaka T, Yamamoto J, Iwasaki S, Asaba H, Hamura H, Ikeda Y, Watanabe, M, Magoori, K, Ioka, RX, Tachibana, K, Watanabe, Y, Uchiyama, Y, Sumi, K, Iguchi, H, Ito, S, Doi, T, Hamakubo, T, Naito, M, Auwerx, J, Yanagisawa, M, Kodama, T, Sakai, J. Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome. Proceedings of the National Academy of Sciences. 2003;100(26):15924–9. 75. Oliver WR, Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, Lewis, MC, Winegar, DA, Sznaidman, ML, Lambert, MH, Xu, HE, Sternbach, DD, Kliewer, SA, Hansen, BC, Willson, TM. A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport. Proceedings of the National Academy of Sciences. 2001;98(9):5306–11. 76. Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H, Evans, RM. Peroxisome-proliferator- activated receptor δ activates fat metabolism to prevent obesity. Cell. 2003;113(2):159–70. 77. Luquet S, Lopez-Soriano J, Holst D, Fredenrich A, Melki J, Rassoulzadegan M, Grimaldi, PA. Peroxisome proliferator-activated receptor δ controls muscle development and oxydative capability. The FASEB Journal. 2003;17(15):2299–301. 78. Wang YX, Zhang CL, Yu RT, Cho HK, Nelson MC, Bayuga-Ocampo CR, Ham, J, Kang, H, Evans, RM. Regulation of muscle fiber type and running endurance by PPARδ. PLoS Biology. 2004;2(10):1532–9. 79. Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ). Journal of Biological Chemistry. 1995;270(22):12953–6.

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 982 AEGAEUM JOURNAL ISSN NO: 0776-3808

80. Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell. 1994;79(7):1147–56. 81. Barroso I, Gurnell M, Crowley VE, Agostini M, Schwabe JW, Soos MA, Maslen, GL, Williams, TD, Lewis, H, Schafer, AJ, Chatterjee, VK, O'Rahilly, S. Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension. Nature. 1999; 402(6764):880–3. 82. Berger J, Patel H V., Woods J, Hayes NS, Parent SA, Clemas J, Leibowitz, MD, Elbrecht, A, Rachubinski, RA, Capone, JP, Moller, DE. A PPARγ mutant serves as a dominant negative inhibitor of PPAR signaling and is localized in the nucleus. Molecular and Cellular Endocrinology. 2000; 162(1–2):57–67. 83. Barak Y, Nelson MC, Ong ES, Jones YZ, Ruiz-Lozano P, Chien KR, Koder, A, Evans, RM. PPARγ is required for placental, cardiac, and adipose tissue development. Molecular Cell. 1999;4(4):585–95. 84. Rosen ED, Sarraf P, Troy AE, Bradwin G, Moore K, Milstone DS, Spiegelman, BM, Mortensen, RM. PPARγ is required for the differentiation of adipose tissue in vivo and in vitro. Molecular Cell. 1999;4(4):611–7. 85. Kubota N, Terauchi Y, Miki H, Tamemoto H, Yamauchi T, Komeda K, Satoh, S, Nakano, R, Ishii, C, Sugiyama, T, Kazuhiro, E, Tsubamoto, Y, Okuno, A, Murakami, K, Sekihara, H, Hasegawa, G, Naito, M, Toyoshima, Y, Tanaka, S, Shiota, K, Kitamura, T, Fujita, T, Ezaki, O, Aizawa, S, Nagai, R, Tobe, K, Kimura, S, Kadowaki, T. PPARγ mediates high-fat diet- induced adipocyte hypertrophy and insulin resistance. Molecular Cell. 1999;4(4):597–609. 86. Gray SL, Dalla Nora E, Grosse J, Manieri M, Stoeger T, Medina-Gomez G, Burling, K, Wattler, S, Russ, A, Yeo, GSH, Chatterjee, VK, O'Rahilly, S, Voshol, PJ, Cinti, S, Vidal-Puig, A. Leptin deficiency unmasks the deleterious effects of impaired peroxisome proliferator- activated receptor γ function (P465L PPARγ) in mice. Diabetes. 2006; 55(10):2669–77. 87. Tamori Y, Masugi J, Nishino N, Kasuga M. Role of peroxisome proliferator-activated receptor-γ in maintenance of the characteristics of mature 3T3-L1 adipocytes. Diabetes. 2002;51(7):2045–55. 88. Rangwala SM, Rhoades B, Shapiro JS, Rich AS, Kim JK, Shulman GI, Kaestner, KH, Lazar, MA. Genetic modulation of PPARγ phosphorylation regulates insulin sensitivity. Developmental Cell. 2003;5(4):657–63. 89. He W, Barak Y, Hevener A, Olson P, Liao D, Le J, Nelson, M, Ong, E, Olefsky, JM, Evans, RM. Adipose-specific peroxisome proliferator-activated receptor knockout causes insulin resistance in fat and liver but not in muscle. Proceedings of the National Academy of Sciences. 2003;100(26):15712–7. 90. Hevener AL, He W, Barak Y, Le J, Bandyopadhyay G, Olson P, Wilkes, J, Evans, RM, Olefsky, J. Muscle-specific Pparg deletion causes insulin resistance. Nature Medicine. 2003;9(12):1491–7. 91. Matsusue K, Haluzik M, Lambert G, Yim S-H, Gavrilova O, Ward JM, Brewer, B, Reitman, ML, Gonzalez, FJ. Liver-specific disruption of PPARγ in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. Journal of Clinical Investigation. 2003; 111(5):737–47. 92. Norris AW, Chen L, Fisher SJ, Szanto I, Ristow M, Jozsi AC, Hirshman, MF, Rosen, ED, Goodyear, LJ, Gonzalez, FJ, Spiegelman, BM, Kahn, CR.Muscle-specific PPARγ-deficient

Page 19 of 27

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 983 AEGAEUM JOURNAL ISSN NO: 0776-3808

mice develop increased adiposity and insulin resistance but respond to thiazolidinediones. Journal of Clinical Investigation. 2003;112(4):608–18. 93. Agarwal AK, Garg A. A Novel Heterozygous Mutation in Peroxisome Proliferator- Activated Receptor-γ Gene in a Patient with Familial Partial Lipodystrophy. The Journal of Clinical Endocrinology & Metabolism. 2002;87(1):408–408. 94. Hegele RA, Cao H, Frankowski C, Mathews ST, Leff T. PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy. Vol. 51, Diabetes. 2002. 95. Savage DB, Tan GD, Acerini CL, Jebb SA, Agostini M, Gurnell M, Williams, RL, Umpleby, AM, Thomas, EL, Bell, JD, Dixon, AK, Dunne, F, Boiani, R, Cinti, S, Vidal-Puig, A, Karpe, F, Chatterjee, VK, O'Rahilly, S. Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-γ. Diabetes. 2003;52(4):910–7. 96. Evans RM, Barish GD, Wang YX. PPARs and the complex journey to obesity. Nature Medicine. 2004;10(4):355–61. 97. Yamauchi T, Kamon J, Waki H, Murakami K, Motojima K, Komeda K, Ide, T, Kubota, N, Terauchi, Y, Tobe, K, Miki, H, Tsuchida, A, Akanuma, Y, Nagai, R, Kimura, S, Kadowaki, T. The Mechanisms by Which Both Heterozygous Peroxisome Proliferator-activated Receptor γ (PPARγ) Deficiency and PPARγ Agonist Improve Insulin Resistance. Journal of Biological Chemistry. 2001;276(44):41245–54. 98. Guan HP, Li Y, Jensen MV, Newgard CB, Steppan CM, Lazar MA. A futile metabolic cycle activated in adipocytes by antidiabetic agents. Nature Medicine. 2002;8(10):1122–8. 99. Peraldi P, Xu M, Spiegelman BM. Thiazolidinediones block tumor necrosis factor-α induced inhibition of insulin signaling. J Clin Invest. 1997;100(7):1863–9. 100. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel, HR, Ahima, RS, Lazar, MA. The hormone resistin links obesity to diabetes. Nature. 2001;409(6818):307– 12. 101. Rajala MW, Obici S, Scherer PE, Rossetti L. Adipose-derived resistin and gut-derived resistin-like molecule–β selectively impair insulin action on glucose production. J ClinInvest. 2003;111(2):225–30. 102. Combs TP, Berg AH, Obici S, Scherer PE, Rossetti L. Endogenous glucose production is inhibited by the adipose-derived protein Acrp30. J Clin Invest. 2001;108(12):1875–81. 103. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med. 2001;7(8):947–53. 104. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori, Y, Ide, T, Murakami, K, Tsuboyama-Kasaoka, N, Ezaki, O, Akanuma, Y, Gavrilova, O, Vinson, C, Reitman, ML, Kagechika, H, Shudo, K, Yoda, M, Nakano, Y, Tobe, K, Nagai, R, Kimura, S, Tomita, M, Froguel, P, Kadowaki, T. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7(8):941–6. 105. Scheen AJ, Esser N, Paquot N. Antidiabetic agents: Potential anti-inflammatory activity beyond glucose control. Diabetes Metab. 2015;41(3):183–94. 106. Grygiel-Górniak B. Peroxisome proliferator-activated receptors and their ligands: Nutritional and clinical implications - A review. Nutr J. 2014;13(1):17.

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 984 AEGAEUM JOURNAL ISSN NO: 0776-3808

107. Youssef JA, Badr MZ. Peroxisome Proliferator-Activated Receptors. In: Peroxisome Proliferator- Activated Receptors Discovery and Recent Advances. 1st ed. New York: Humana Press; 2013. p. 18–9. 108. Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, Evans, RM. PPARγ signaling and metabolism: The good, the bad and the future. Nat Med. 2013;19(5):557–66.] 109. Verma VA, Halu B, Kulkarni VR. Understanding the Antihyperglycemic Agents of Thiazolidinediones Analogues Using Quantitative Structure Activity Relationship (QSAR) Models. World J Pharm Pharm Sci. 2014;3(3):2212–21. 110. Cariou B, Hanf R, Lambert-Porcheron S, Zair Y, Sauvinet V, Noel B, Flet, L, Vidal, H, Staels, B, Laville, M. Dual Peroxisome Proliferator-Activated Receptor α/δ Agonist GFT505 Improves Hepatic and Peripheral Insulin Sensitivity in Abdominally Obese Subjects. Diabetes Care. 2013;36(10):2923–30. 111. Lodhi IJ, Yin L, Jensen-Urstad APL, Funai K, Coleman T, Baird JH, El Ramahi, MK, Razani, B, Song, H, Fu-Hsu, F, Turk, J, Semenkovich, CF. Inhibiting adipose tissue lipogenesis reprograms thermogenesis and PPARγ activation to decrease diet-induced obesity. Cell Metab. 2012;16(2):189–201.

112.Bozaykut P, Karademir B, Yazgan B, Sozen E, Siow RCM, Mann GE, et al. Effects of vitamin E on peroxisome proliferator-activated receptor and nuclear factor-erythroid 2- related factor 2 in hypercholesterolemia-induced atherosclerosis. Free RadicBiol Med 2014;70:174–81.

113.Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes: A patient-centered approach. Diabetes Care 2012;35:1364–79.

114.García-García HM, Garg S, Brugaletta S, Morocutti G, Ratner RE, Kolatkar NS, et al. Evaluation of in-stent restenosis in the APPROACH trial (assessment on the prevention of progression by Rosiglitazone on atherosclerosis in diabetes patients with cardiovascular history). Int J Cardiovasc Imaging 2012;28:455–65.

115.Kim T, Yang Q. Peroxisome-proliferator-activated receptors regulate redox signaling in the cardiovascular system. World J Cardiol 2013;5:164.

116.Fuentes E, Guzmán-Jofre L, Moore-Carrasco R, Palomo I. Role of PPARs in inflammatory processes associated with metabolic syndrome (Review). Mol Med Rep 2013;8:1611–6.

117. Bays HE. Adiposopathy: Is “sick fat” a cardiovascular disease? J Am Coll Cardiol 2011;57:2461–73. 118.Abel ED, O’Shea KM, Ramasamy R. Insulin resistance : metabolic mechanisms and consequences in the heart. Arter Thromb Vasc Biol 2013; 32:22895668. 119.Cheung BMY, Li C. Diabetes and hypertension: Is there a common metabolic pathway? CurrAtheroscler Rep 2012;14:160–6.

Page 21 of 27

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 985 AEGAEUM JOURNAL ISSN NO: 0776-3808

120.Ali KM, Wonnerth A, Huber K, Wojta J. Cardiovascular disease risk reduction by raising HDL cholesterol - Current therapies and future opportunities. Br J Pharmacol 2012;167:1177–94. 121.Jung U, Choi M-S. Obesity and Its Metabolic Complications: The Role of Adipokines and the Relationship between Obesity, Inflammation, Insulin Resistance, Dyslipidemia and Nonalcoholic Fatty Liver Disease. Int J MolSci 2014;15:6184–223. 122.Huang J V., Greyson CR, Schwartz GG. PPAR-γ as a therapeutic target in cardiovascular disease: evidence and uncertainty. J Lipid Res 2012;53:1738–54. 123.Huang TH-W, Roufogalis BD. Healing the diabetic heart: modulation of cardiometabolic syndrome through peroxisome proliferator activated receptors (PPARs). CurrMolPharmacol 2012;5:241–7. 124.Drosatos K, Khan RS, Trent CM, Jiang H, Son N-H, Blaner WS, et al. Peroxisome Proliferator–Activated Receptor-γ Activation Prevents Sepsis-Related Cardiac Dysfunction and Mortality In Mice. Circ Hear Fail 2013;6:550–62. 125.Balakumar P, Kathuria S. Submaximal PPARγ activation and endothelial dysfunction: New perspectives for the management of cardiovascular disorders. Br J Pharmacol 2012;166:1981–92. 126.Balakumar P, Mahadevan N. Interplay between statins and PPARs in improving cardiovascular outcomes: A double-edged sword? Br J Pharmacol 2012;165:373–9. 127.Atamer Y, Atamer A, Can AS, Hekimoglu A, Ilhan N, Yenice N, et al. Effects of rosiglitazone on serum paraoxonase activity and metabolic parameters in patients with type 2 diabetes mellitus. Brazilian J Med Biol Res 2013;46:528–32. 128.Auclair M, Vigouroux C, Boccara F, Capel E, Vigeral C, Guerci B, et al. Peroxisome proliferator-activated receptor-γ mutations responsible for lipodystrophy with severe hypertension activate the cellular renin-angiotensin system. ArteriosclerThrombVascBiol 2013;33:829–38. 129.Giaginis C, Klonaris C, Katsargyris A, Kouraklis G, Spiliopoulou C, Theocharis S. Correlation of Peroxisome Proliferator-Activated Receptor-gamma (PPAR-gamma) and Retinoid X Receptor-alpha (RXR-alpha) expression with clinical risk factors in patients with advanced carotid atherosclerosis. Med SciMonit 2011;17:381--91. 130.Jung U J, Torrejon C, Chang CL, Hamai H, Worgall TS, Deckelbaum RJ. Fatty acids regulate endothelial lipase and inflammatory markers in macrophages and in mouse aorta: a role for PPARγ. ArterThrombVascBiol 2012;32:2929–37. 131.He H, Tao H, Xiong H, Duan SZ, McGowan FX, Mortensen RM, et al. Rosiglitazone causes cardiotoxicity via peroxisome proliferator-activated receptor γ-independent mitochondrial oxidative stress in mouse hearts. ToxicolSci 2014;138:468–81. 132.Hulsmans M, Geeraert B, Arnould T, Tsatsanis C, Holvoet P. PPAR Agonist-Induced Reduction of Mcp1 in Atherosclerotic Plaques of Obese, Insulin-Resistant Mice Depends on Adiponectin-Induced Irak3 Expression. PLoS One 2013;8:1–12. 133.Huang Y, Lorenzo A Di, Jiang W, Cantalupo A, C. WS, Giordano FJ. HIF-1α in vascular smooth muscle regulates blood pressure homeostasis through a PPARγ-angiotensin II receptor type 1 (ATR1) axis. Hypertension 2013;62:1–16.

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 986 AEGAEUM JOURNAL ISSN NO: 0776-3808

134.Xu HE, Lambert MH, Montana VG, Plunket KD, Moore LB, Collins JL, et al. Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. Proc Natl Acad Sci U S A 2001;98:13919–24. 135.Chakravarthy M V, Lodhi IJ, Yin L, Malapaka RR V, Xu HE, Semenkovich CF. Identification of a Physiologically Relevant Endogenous Ligand for PPARα in Liver. Cell 2010;138:476–88. 136.Gloerich J, van den Brink DM, Ruiter JPN, van Vlies N, Vaz FM, Wanders RJ a, et al. Metabolism of phytol to phytanic acid in the mouse, and the role of PPARalpha in its regulation. J Lipid Res 2007;48:77–85. 137.Goto T, Takahashi N, Kato S, Egawa K, Ebisu S, Moriyama T, et al. Phytol directly activates peroxisome proliferator-activated receptor alpha (PPARα) and regulates gene expression involved in lipid metabolism in PPARalpha-expressing HepG2 hepatocytes. Biochem Biophys Res Commun 2005;337:440–5. 138.Martin PGP, Guillou H, Lasserre F, Déjean S, Lan A, Pascussi JM, et al. Novel aspects of PPARα-mediated regulation of lipid and xenobiotic metabolism revealed through a nutrigenomic study. Hepatology 2007;45:767–77. 139.Jump DB, Botolin D, Wang Y, Xu J, Christian B, Demeure O. Fatty Acid Regulation of Hepatic Gene Transcription. Recent AdvNutrSci Fat 2005;135:2503–6. 140.Taniguchi A, Fukushima M, Sakai M, Tokuyama K, Nagata I, Fukunaga A, et al. Effects of bezafibrate on insulin sensitivity and insulin secretion in non-obese Japanese type 2 diabetic patients. Metabolism 2001;50:477–80. 141.Fruchart JC, Staels B, Duriez P. The role of fibric acids in atherosclerosis. CurrAtheroscler Rep 2001;3:83–92. 142.Sporn MB, Suh N, Mangelsdorf DJ. Prospects for prevention and treatment of cancer with. Trends Mol Med 2001;7:395–400. 143.Trombetta A, Maggiora M, Martinasso G, Cotogni P, Canuto RA, Muzio G. Arachidonic and docosahexaenoic acids reduce the growth of A549 human lung-tumor cells increasing lipid peroxidation and PPARs. ChemBiol Interact 2007;165:239–50. 144.Edwards IJ, Berquin IM, Sun H, Flaherty JTO, Daniel LW, Thomas MJ, et al. Differential Effects of Delivery of Omega-3 Fatty Acids to Human Cancer Cells by Low- Density Lipoproteins versus Albumin Differential Effects of Delivery of Omega-3 Fatty Acids to Human Cancer Cells by Low-Density Lipoproteins versus Albumin. Clin Cancer Res 2004;10:8275–83. 145.Sun HG, Berquin IM, Edwards IJ. Omega-3 polyunsaturated fatty acids regulate syndecan-1 expression in human breast cancer cells. Cancer Res 2005;65:4442–7. 146.Sun H, Berquin IM, Owens RT, O’Flaherty JT, Edwards IJ. Peroxisome proliferator- activated receptor gamma-mediated up-regulation of syndecan-1 by n-3 fatty acids promotes apoptosis of human breast cancer cells. Cancer Res 2008;68:2912–9. 147.Yang Z-H, Miyahara H, Iwasaki Y, Takeo J, Katayama M. Dietary supplementation with long-chain monounsaturated fatty acids attenuates obesity-related metabolic dysfunction and increases expression of PPAR gamma in adipose tissue in type 2 diabetic KK-Ay mice. Nutr Metab (Lond) 2013;10:1–10. 148.Mishra A, Chaudhary A, Sethi S. Oxidized omega-3 fatty acids inhibit NF-κβ activation via a PPARα-dependent pathway. ArteriosclerThrombVascBiol 2004;24:1621–7.

Page 23 of 27

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 987 AEGAEUM JOURNAL ISSN NO: 0776-3808

149.Suchanek KM, May FJ, Robinson JA, Lee WJ, Holman NA, Monteith GR, et al. Peroxisome proliferator-activated receptor α in the human breast cancer cell lines MCF-7 and MDA-MB-231. MolCarcinog 2002;34:165–71. 150.Heim M, Johnson J, Boess F, Bendik I, Weber P, Hunziker W, et al. Phytanic acid, a natural peroxisome proliferator-activated receptor (PPAR) agonist, regulates glucose metabolism in rat primary hepatocytes. FASEB J 2002; 16:718–20. 151.Elstner E, Müller C, Koshizuka K, Williamson E a, Park D, Asou H, et al. Ligands for peroxisome proliferator-activated receptor γ and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc Natl Acad Sci U S A 1998;95:8806–11. 152.Tan MH. Current treatment of insulin resistance in type 2 diabetes mellitus. Int J Clin Pract Suppl 2000;113:54–62. 153.Deeg MA, Tan MH. Pioglitazone versus Rosiglitazone: Effects on Lipids, Lipoproteins, and Apolipoproteins in Head-to-Head Randomized Clinical Studies. PPAR Res 2008;2008:1 – 6. 154.Krishnaswami A, Ravi-Kumar S, Lewis JM. Thiazolidinediones : A 2010 Perspective. Perm J 2010;14:64–72. 155.Caballero AE, Saouaf R, Lim SC, Hamdy O, Abou-Elenin K, O’Connor C, et al. The effects of troglitazone, an insulin-sensitizing agent, on the endothelial function in early and late type 2 diabetes: A placebo-controlled radomized clinical trial. Metabolism 2003;52:173–80. 156.Rubenstrunk A, Hanf R, Hum DW, Fruchart JC, Staels B. Safety issues and prospects for future generations of PPAR modulators. BiochimBiophysActa - Mol Cell Biol Lipids 2007;1771:1065–81. 157.Carmona, MC., Louche, K., Lefebvre, B., Pilon, A., Hennuyer, N., Audinot-Bouchez V, Fievet, C., Torpier, G., Formstecher, P., Renard, P., Lefebvre, P., Dacquet, C., Staels, B., Casteilla, L., Pénicaud L. S26948: a new specific peroxisome proliferator activated receptor gamma modulator with potent antidiabetes and antiatherogenic effects. Diabetes 2007;56:2797–2808. 158.Dunn FL, Higgins LS, Fredrickson J, Depaoli AM. Selective modulation of PPARγ activity can lower plasma glucose without typical thiazolidinedione side effects in patients with Type 2 diabetes. J Diabetes Complications 2011;25:151–8. 159.Henry RR, Lincoff AM, Mudaliar S, Rabbia M, Chognot C, Herz M. Effect of the dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose- ranging study. Lancet 2009;374:126–35. 160.Vamecq J, Latruffe N. Medical significance of peroxisome proliferator-activated receptors. Lancet 1999;354:141–8. 161.Massaro M, Scoditti E, Pellegrino M, Carluccio MA, Calabriso N, Wabitsch M, et al. Therapeutic potential of the dual peroxisome proliferator activated receptor (PPAR)α/γ agonist aleglitazar in attenuating TNF-α-mediated inflammation and insulin resistance in human adipocytes. Pharmacol Res 2016;107:1-36.

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 988 AEGAEUM JOURNAL ISSN NO: 0776-3808

162.Mamnoor PK, Hegde P, Datla SR, Damarla RKB, Rajagopalan R, Chakrabarti R. Antihypertensive effect of ragaglitazar: A novel PPARα and γ dual activator. Pharmacol Res 2006;54:129–35. 163.Tenenbaum A, Motro M, Fisman EZ. Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons. CardiovascDiabetol 2005;4:1–5. 164.Bhadania M, Majmudar F. PPAR- α/γ Agonists: A Newer Approach to Diabetic Dyslipidemia. World J Pharm Res 2016;5:1147–63. 165.Balakumar P, Rose M, Ganti SS, Krishan P, Singh M. PPAR dual agonists: Are they opening Pandora’s Box? Pharmacol Res 2007;56:91–8. 166.Gross B, Staels B. PPAR agonists: multimodal drugs for the treatment of type-2 diabetes. Best Pract Res ClinEndocrinol Metab 2007;21:687–710. 167.Lalloyer F, Vandewalle B, Percevault F, Torpier G, Kerr-Conte J, Oosterveer M, et al. Peroxisome proliferator-activated receptor α improves pancreatic adaptation to insulin resistance in obese mice and reduces lipotoxicity in human islets. Diabetes 2006;55:1605– 13. 168.Ravnskjaer K, Boergesen M, Rubi B, Larsen JK, Nielsen T, Fridriksson J, et al. Peroxisome proliferator-activated receptor α (PPARα) potentiates, whereas PPARγ attenuates, glucose-stimulated insulin secretion in pancreatic β cells. Endocrinology 2005;146:3266–76. 169.Staels B, Fruchart JC. Therapeutic roles of peroxisome proliferator-activated receptor agonists. Diabetes 2005;54:2460–70. 170.Lee C-H, Olson P, Evans RM. Mini review: Lipid Metabolism, Metabolic Diseases, and Peroxisome Proliferator-Activated Receptors. Endocrinology 2003;144:2201–7. 171.Aggarwal A. Saroglitazar: India’s answer to diabetic dyslipidemia. Int J Pharmacol ClinSci 2014;3:7–14. 172.Bailey CJ. New drugs for the treatment of diabetes mellitus. In: 3rdedtn International Textbook of Diabetes Mellitus, Wiley: Chichester; 2004, p. 951-79. 173.Vaishnav RA, Mistry CB, Shah MH. PPAR α/γ Agonist in Management of Diabetic Dyslipidemia: A Review. Int J ClinPharmacolToxicol 2015;4:143–9. 174.Abd El-Haleim EA, Bahgat AK, Saleh S. Effects of combined PPAR-γ and PPAR-α agonist therapy on fructose induced NASH in rats: Modulation of gene expression. Eur J Pharmacol 2016;773:59–70. 175.Qi Z-G, Zhao X, Zhong W, Xie M-L. Osthole improves glucose and lipid metabolism via modulation of PPARα/γ-mediated target gene expression in liver, adipose tissue, and skeletal muscle in fatty liver rats. Pharm Biol 2016;54:882–8. 176.Berger JP, Akiyama TE, Meinke PT. PPARs: Therapeutic targets for metabolic disease. Trends PharmacolSci 2005;26:244–51. 177.JiříEhrmann Jr., Vavrušováa N, Collanb Y, Kolářa Z. Peroxisome proliferator-activated receptors (PPARs) in health and disease. Biomed. Papers 2002;146:11–4. 178.Hill C, Carolina N, Hospital ZC, Gables C, Physicians S. Muraglitazar , a Dual ( α / γ ) PPAR Activator : A Randomized , Trial in Adult Patients with Type 2 Diabetes. Cinical Therapeutics 2005;27:1181–95. 179.Goldstein BJ, Rosenstock J, Anzalone D, Tou C, Peter Öhman K. Effect of tesaglitazar, a dual PPARα/γ agonist, on glucose and lipid abnormalities in patients with type 2 diabetes: a

Page 25 of 27

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 989 AEGAEUM JOURNAL ISSN NO: 0776-3808

12‐week dose-ranging trial. Current Medical Research and Opinion 2006;22:2575–90. 180.Skrumsager BK, Nielsen KK, Müller M, Pabst G, Drake PG, Edsberg B. Ragaglitazar: the pharmacokinetics, pharmacodynamics, and tolerability of a novel dual PPAR alpha and gamma agonist in healthy subjects and patients with type 2 diabetes. Journal of Clinical Pharmacology 2003;43:1244–56. 181.Li PP, Shan S, Chen YT, Ning ZQ, Sun SJ, Liu Q, et al. The PPARα/γ dual agonist chiglitazar improves insulin resistance and dyslipidemia in MSG obese rats. British Journal of Pharmacology 2006;148:610–8. 182.Chen H, Dardik B, Qiu L, Ren X, Caplan SL, Burkey B, et al. Cevoglitazar, a novel peroxisome proliferator-activated receptor-alpha/gamma dual agonist, potently reduces food intake and body weight in obese mice and cynomolgus monkeys. Endocrinology 2010;151:3115–24. 183.Younk LM, Uhl L, Davis SN. Pharmacokinetics, efficacy and safety of aleglitazar for the treatment of type 2 diabetes with high cardiovascular risk. Expert Opinion on Drug Metabolism & Toxicology 2011;7:753–63. 184.Sakamoto J, Kimura H, Moriyama S, Imoto H, Momose Y, Odaka H, et al. A novel oxyiminoalkanoic acid derivative, TAK-559, activates human peroxisome proliferator- activated receptor subtypes. European Journal of Pharmacology 2004;495:17–26. 185.Yi P, Hadden CE, Annes WF, Jackson D a, Peterson BC, Gillespie T a, et al. The disposition and metabolism of naveglitazar, a peroxisome proliferator-activated receptor α-γ dual, γ-dominant agonist in mice, rats, and monkeys. Drug Metabolism and Disposition: The Biological Fate of Chemicals 2007;35:51–61. 186.Nishihara M, Sudo M, Kamiguchi H, Kawaguchi N, Maeshiba Y, Kiyota Y, et al. Metabolic Fate of Sipoglitazar a Novel Oral PPAR Agonist with Activities for PPAR-γ, -α and -δ, in Rats and Monkeys and Comparison with Humans In Vitro. Drug Metabolism and Pharmacokinetics 2012;27:223–31. 187.Lee Y, Kim JH, Kim SR, Jin HY, Rhee EJ, Cho YM, et al. Lobeglitazone , a Novel Thiazolidinedione , Improves Non-Alcoholic Fatty Liver Disease in Type 2 Diabetes: Its Efficacy and Predictive Factors Related to Responsiveness Study patients. Endocrinology, Nutrition & Metabolism 2017;32:60–9. 188.Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012;55:2005–23. 189.Fiévet C, Fruchart JC, Staels B. PPARα and PPARγ dual agonists for the treatment of type 2 diabetes and the metabolic syndrome. Current Opinion in Pharmacology 2006;6:606– 14. 190.Balakumar P, Rose M, Ganti SS, Krishan P, Singh M. PPAR dual agonists: Are they opening Pandora’s Box? Pharmacological Research 2007;56:91–8. 191.Lamers C, Schubert-Zsilavecz M, Merk D. Therapeutic modulators of peroxisome proliferator-activated receptors (PPAR): a patent review (2008–present). Expert Opinion on Therapeutic Patents 2012;22:803–41. 192.Heald M, Cawthorne MA. Dual Acting and Pan-PPAR Activators as Potential Anti- diabetic Therapies. Handbook of Experimental Pharmacology, vol. 203, 2011, p. 35–51.

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 990 AEGAEUM JOURNAL ISSN NO: 0776-3808

193.Takeuchi Y, Nishioka Y, Kitahara Y, Hasegawa S, Ohnishi A. Safety , Tolerability , and Pharmacokinetics of E3030 , a Novel Peroxisome Proliferator-Activated Receptor α / γ Dual Agonist , in Healthy Japanese Male Subjects. Pharmacology & Pharmacy 2014;5:139–48. 194.Ma Y, Wang SQ, Xu WR, Wang RL, Chou KC. Design novel dual agonists for treating type-2 diabetes by targeting peroxisome proliferator-activated receptors with core hopping approach. PLoS ONE 2012;7:1–9. 195.Gilardi F, Giudici M, Mitro N, Maschi O, Guerrini U, Rando G, et al. LT175 is a novel PPARα/γ ligand with potent insulin-sensitizing effects and reduced adipogenic properties. Journal of Biological Chemistry 2014;289:6908–20. 196.Park MH, Park JY, Lee HJ, Kim DH, Park D, Jeong HO, et al. Potent anti-diabetic effects of MHY908, a newly synthesized PPAR α/γ dual agonist in db/db mice.PLoS ONE 2013;8:e78815–e78815. 197.Goto T, Nakayama R, Yamanaka M, Takata M, Takazawa T, Watanabe K, et al. Effects of DSP-8658, a Novel Selective Peroxisome Proliferator-activated Receptors α/γ Modulator, on Adipogenesis and Glucose Metabolism in Diabetic Obese Mice. Experimental and Clinical Endocrinology and Diabetes 2015;123:492–9. 198.Jeong HW, Lee J, Kim WS, Choe SS, Shin HJ, Lee GY, et al. A Non-TZD PPARα/γ Dual Agonist CG301360 Alleviates Insulin Resistance and Lipid Dysregulation in db/db Mice. Molecular Pharmacology 2010:1–45. 199.Dagdelen S. From Dual Peroxisome Proliferator Activated Receptor Agonists to Selective Peroxisome Proliferator Activated Receptor Modulators. Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2008;2:24–8. 200.McHutchison J, Goodman Z, Patel K, Makhlouf H, Rodriguez-Torres M, Shiffman M, et al. Farglitazar Lacks Antifibrotic Activity in Patients With Chronic Hepatitis C Infection. Gastroenterology 2010;138:1365–1373.

201. Ren T, Yang WS, Lin Y, Liu JF, Li Y, Yang LC, Zeng KY, Peng L, Liu YJ, Ye ZH, Luo XM, Ke YJ, Diao Y, Jin X. A novel PPARα/γ agonist, propane-2-sulfonic acid octadec-9-enyl- amide, ameliorates insulin resistance and gluconeogenesis in vivo and in vitro. European Journal of Pharmacology 2018;18:1-33.

202. Wang Z, Koonen D, Hofker M, Bao Z. 5-aminosalicylic acid improves lipid profile in mice fed a high-fat cholesterol diet through its dual effects on intestinal PPARγ and PPARα. PLoS ONE 2018;13(1): 1-15

203. Saether T, Paulsen SM, Tungen JE, Vik A, Aursnes M, Holen T, Hansen TV, Nebb HI. Synthesis and biological evaluations of marine oxohexadecenoic acids: PPARα/γ dual agonism and anti-diabetic target gene effects. European Journal of Medicinal Chemistry 2018; 155:736-753.

Page 27 of 27

Volume 8, Issue 3, 2020 http://aegaeum.com/ Page No: 991