Abstract
Peroxisome proliferator-activated receptors (PPARs) are members of the ligand-dependent nuclear receptor family. PPARs have attracted wide attention as pharmacologic mediators to manage multiple diseases and their underlying signaling targets. They mediate a broad range of specific biological activities and multiple organ toxicity, including cellular differentiation, metabolic syndrome, cancer, atherosclerosis, neurodegeneration, cardiovascular diseases, and inflammation related to their up/downstream signaling pathways. Consequently, several types of selective PPAR ligands, such as fibrates and thiazolidinediones (TZDs), have been approved as their pharmacological agonists. Despite these advances, the use of PPAR agonists is known to cause adverse effects in various systems. Conversely, some naturally occurring PPAR agonists, including polyunsaturated fatty acids and natural endogenous PPAR agonists curcumin and resveratrol, have been introduced as safe agonists as a result of their clinical evidence or preclinical experiments. This review focuses on research on plant-derived active ingredients (natural phytochemicals) as potential safe and promising PPAR agonists. Moreover, it provides a comprehensive review and critique of the role of phytochemicals in PPARs-related diseases and provides an understanding of phytochemical-mediated PPAR-dependent and -independent cascades. The findings of this research will help to define the functions of phytochemicals as potent PPAR pharmacological agonists in underlying disease mechanisms and their related complications.
1. Introduction
Peroxisome proliferator-activated receptors (PPARs) are a subfamily of the ligand-dependent nuclear receptor family. PPARs consist of three distinct subtypes, namely, peroxisome proliferator-activated receptor alpha (PPARα), peroxisome proliferator-activated receptor gamma (PPARγ), and peroxisome proliferator-activated receptor beta or delta (PPARβ or PPARδ), each exerting specific biological activities depending on the particular targeting ligands and tissue localization [1–3]. They regulate a wide range of biological processes, including fatty acid metabolism, metabolic pathways, cellular differentiation, insulin sensitivity, cell migration, and inflammation. Therefore, PPARs can provide unique beneficial effects on cancer, atherosclerosis, metabolic diseases, cardiovascular diseases, neurodegeneration, reproduction, and inflammation via activation or inhibition of various up/downstream signaling pathways, including AMP-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Sirtuins, and oxidative and inflammatory responses [1, 2, 4].
PPARα is mainly known as a metabolic regulator which is expressed in liver and brown adipose tissue. It is associated with energy storage, lipogenesis, fatty acid up-regulation and β-oxidation, ketogenesis, gluconeogenesis, and inflammation in these tissues [1]. PPARβ/δ is involved in energy expenditure in fatty acid (FA) uptake, β-oxidation, placenta and gut development, inflammation reduction, cell proliferation, differentiation, cell survival, tissue repair, and energy homeostasis in muscle and white adipose tissue. It is ubiquitously observed in renal, gut, gastrointestinal tract, liver, and the central nervous systems [1, 2]. PPARγ mediates energy storage-lipogenesis, glucose metabolism, and inflammation in white adipose tissue (WAT) and macrophages [1, 5]. Additionally, PPARγ is an important target to treat several types of cancer, neurodegenerative diseases, long-chain fatty acid processing in the intestinal epithelium, body adiposity, mucosal defenses, and hypotensive and anticoagulant effects [1, 2, 4, 5]. Moreover, the PPARγ isotype is expressed as two isoforms, PPARγ1 and PPARγ2. PPARγ2 is expressed in adipose tissue, whereas PPARγ1 occurs in adipose tissue, gut, vascular cells, brain, and special immune and inflammatory cells [1].
As a result of the broad and specific biological activities of PPARs, researchers have actively pursued the development of PPAR-targeting drugs. Some synthetic PPAR agonists, including thiazolidinediones (TZDs), pioglitazone, troglitazone, fibrates, glitazars, rosiglitazone, and gemfibrozil, were approved following several experimental and clinical studies [1, 2, 5]. Despite these advances, various studies have reported significant side effects of these PPAR agonists, such as heart failure, hepatotoxicity, fluid retention, edema, tumorigenesis, weight gain, and cardiotoxicity [2]. On the other hand, natural phytochemicals have shown promising potential as PPAR agonists, including endogenous unsaturated fatty acids, polyacetylenes, terpenoids, and polyphenols [3–6]. Hence, this review examines the impact of phytochemicals on PPAR receptors, with particular emphasis on the signaling pathways which PPARs enhance or inhibit in the management of various diseases. The mechanisms responsible for their toxicity are also discussed.
2. PPAR Mechanism of Action and Therapeutic Targets of Diseases
PPARs are involved in regulation of a wide spectrum of adverse reactions, including oxidative stress, inflammation, neuron degeneration, cardiovascular disease (CVD), multiple sclerosis (MS), Alzheimer’s disease, diabetes, dyslipidemia, kidney dysfunction, gastrointestinal toxicity, cancer, autophagy, and immunity. This is associated with particular signaling pathways as well as the presence of specific coactivators/corepressors in each organ, such as inflammatory and antioxidant elements [1, 2, 6]. It is known that B-cell lymphoma 6 (BCL-6), the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT), and the nuclear corepressor 1 (NCoR1) act as PPAR corepressors. Additionally, enzymatic coactivators modulate PPAR activity, including histone acetylase activity (steroid receptor coactivator 1 (SRC-1), cAMP response element-binding protein/p300), helicases (PPAR A–interacting complex (Pric)285), and an ATPase (SWItch/sucrose non-fermentable (SWI/SNF)). Additionally, nonenzymatic coactivators that bind to PPAR complex, such as PGC-1α (PPAR coactivator- (PGC-) 1α) and SMARCD1 (SWI/SNF related, matrix associated, actin-dependent regulator of chromatin subfamily d, member 1), have been reported [1, 6].
Mechanistically, PPARs heterodimerize with retinoid X receptors (RXRs) for binding to the peroxisome proliferator response elements (PPREs) as their upstream DNA binding site [1, 2, 6]. After a ligand binds to PPARs, and then making a heterodimer and binding to PPRE, PPARs regulate gene transcription by recruiting coactivators in transactivation, while they recruit corepressors in the transrepression of certain genes by activation of the heterodimer in the presence of RXR ligand. PPARs regulate gene transcription by recruiting coactivators in transactivation and coactivators/corepressors in the transrepression of certain genes. In transrepression function, PPARs recruit coactivators/corepressors and exert their negative regulation on certain genes by preserving or releasing corepressors, mitogen-activated protein kinase (MAPK) pathways, and physical interaction with transcription proteins (nuclear factor kappa B (NF-kB), Smad-3, activator protein 1 (AP-1), and signal transducer and activator of transcription (STAT)) and competing with target genes for binding their co-regulators [6]. Furthermore, PPARs show distinct functions in various pathways such as energy storage, modulating mTOR activity, flexible interaction with AMPK, regulation of insulin signaling and insulin sensitivity, tissue repair and remodeling, lipid metabolism, cell survival, and inflammatory cascades [1, 2, 6].
Although PPARs show mainly transcriptional activities (genomic action), they may also operate via the stimulation of nongenomic pathways (such as insulin-like growth factor- (IGF-) insulin receptor (IR), stress response, calcium influx, and MAPK). In light of these considerations, PPARγ downregulates MAPK pathway as a main insulin/IGF axis cascade and reduces circulating insulin to prevent cell migration and proliferation [6]. In addition, PPARγ can inhibit production of inflammatory cytokines by MAPK suppression in colon mucosal [1]. It can also decrease angiotensin II-induced proliferation in vascular smooth muscle cells (VSMCs) through diminishing c-fos and via blocking MAPK signaling pathways. Moreover, activation of PPARγ suppresses MAPK pathway and its downstream signaling (Ets-1, matrix metalloproteinase (MMP)2, and MMP9) for inhibiting platelet-derived growth factor (PDGF) and thrombin-triggered VSMC migration [6].
It is therefore clear that PPARs play a critical role in management of diseases by genomic/nongenomic actions plus cross talk between PPARs and other key survival pathways and through their multiple functions with up-and downstream coactivators and co-regulators (Figure 1). To utilize these properties, multitask and safe PPAR agonists or antagonists are needed.
3. Methods
A systematic search strategy was developed to identify the impact of phytochemicals on PPAR receptors and the implications for the treatment of diseases. Searches were undertaken in PubMed, Scopus, and Google Scholar (January 2010 to March 2021). The terms “diseases,” “phytochemicals,” “herbal medicine,” and “PPARs receptor” were incorporated into an electronic search strategy. For each selected nutraceutical, the plausible mechanism of action was identified from the in vitro and in vivo evidence, and their clinically observed effects and relevant tolerability information were reported.
4. Phytochemicals with PPAR Modulation Activities
Plant-derived phytochemicals are well-known as modulators of the PPAR family, and their mechanisms in the prevention and treatment of human diseases have been ascribed to their physiological effects on carbohydrate and lipid metabolism. The versatile activities of phytochemicals are illustrated in Table 1 in terms of their PPAR activating abilities. The critical role of natural phytochemicals to human health in relation to their PPAR activating properties is discussed in the following section.
4.1. Curcumin
Curcumin is a natural lipophilic polyphenol from the rhizome of turmeric, Curcuma longa L. (Zingiberaceae), which can modulate a number of signaling pathways in its biological activities, including inflammation, atherosclerosis, and cardiovascular disease [7, 8]. Curcumin has been found to remarkably enhance peroxisome proliferator-activated receptor-α and γ (PPARα and PPARγ) in its anti-inflammatory, antioxidant, antihyperglycemic, and insulin sensitizer effects (Table 1) [8–10]. In this regard, it can initiate the PPARγ/liver X receptor (LXR)/ATP-binding cassette transporter A1 (ABCA1) pathway by up-regulation of ABCA1, ATP-binding cassette transporters G1 (ABCG1), LXRα, scavenger receptor (class B) (CD36), and cytochrome P450 oxidase or sterol 27-hydroxylase (Cyp27); this then leads to reverse cholesterol transport and cellular cholesterol efflux in the prevention of hyperlipidaemia and atherosclerosis. In fact, curcumin can bind directly to PPARγ or indirectly induce the production of intracellular ligands of PPARγ [11]. Therefore, the induction of PPARγ by curcumin could regulate glucose homeostasis and insulin resistance and also suppress inflammatory cytokines (including nuclear factor-κB (NF-κB) and matrix metalloproteinases (MMPs)) in macrophages and oxidative stress [9, 11]. Furthermore, curcumin drives PPARα activation by regulating mitochondrial fatty acid β-oxidation, down-regulating sterol regulatory element-binding protein-1c (SREBP-1c) through suppression of LXR/RXR formation, inhibiting acyl-CoA:cholesterol acyltransferase (ACAT), interfering with NF-κB and AP-1, and upregulating apolipoprotein A-I (Apo-AI), apolipoprotein A-II (Apo-AII), and mitochondrial 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, thereby protecting against hypercholesterolemia and subsequent atherosclerosis [11, 12].
In addition, curcumin exerts an influence on metabolism through the activation of PPARγ to ameliorate obesity/insulin resistance related disorders and certain inflammatory diseases. Some in vitro or in vivo studies indicated activity of curcumin on PPAR in the PPARγ gene regulatory region is able to attenuate inflammation by inhibiting NF-κB, tumor necrosis factor alpha (TNF-α), c-Jun N-terminal kinase (JNK), interferon gamma (IFN-γ), nitric oxide (NO), inducible nitric oxide synthase (iNOS), and AP-1. As well, antidiabetic properties of curcumin revealed through its antioxidant, anti-inflammatory, and antiapoptotic activities via mediation of PPARα/γ lead to regulation of insulin signaling and phosphodiesterase/cyclic adenosine monophosphate (PDE/cAMP) in metabolism [13, 14]. Likewise, promoting PPARγ ligand-binding activity by curcumin can stimulate free fatty acid catabolism, which can modulate glucose homeostasis, insulin resistance, and hemoglobin A1c (HbA1c) levels in related disorders such as diabetes and obesity [15]. Curcumin can also inhibit several inflammatory pathways and modulate obesity-related metabolic diseases by inhibiting low-density lipoprotein (LDL) and the level of intracellular cholesterol by activation of PPARγ, leading to the suppression of α1 collagen, alpha smooth muscle actin (α-SMA), connective tissue growth factor (CTGF), transforming growth factor (TGF-β) receptors, platelet-derived growth factor subunit B (PDGF-β), interleukin-1 (IL-1), interleukin-13 (IL-13), and epidermal growth factor (EGF) [16]. Furthermore, molecular docking studies showed that curcumin as a PPARγ agonist binds with Ile(341), Arg(288), Ser(289), Ala(292), Leu(333), Ile(326), Leu(330), and Met(329) amino acids in the active site of PPARγ [8].
Curcumin has also demonstrated anticancer and apoptosis properties on many tumor cells. For instance, curcumin down-regulated the β-catenin/T-cell factors (Tcf) signaling pathway in the human colon cancer cell line HT-29, which leads to suppression of the expression of PPARδ, 14-3-3ε, and vascular endothelial growth factor (VEGF) and subsequent induction of apoptosisin HT-29 cells [17]. In MCF-7 breast cancer cells, curcumin activated AMPK as an upstream signal of PPARγ in 3T3-L1 adipocytes, resulting in the down-regulation of PPARγ and a decrease in differentiation of adipocytes [18]. Furthermore, curcumin as a cancer therapy candidate is shown to exert its anticancer effect through PPARγ activation and down-regulation of the aberrant WNT/β-catenin pathway leads to activation of glycogen synthase kinase-3β (GSK-3β), leading to the control of inflammation, proliferation, and angiogenesis in cancers [19]. Curcumin mediates its antifibrotic effects by the PPARγ upregulation of matrix-degrading proteases, cathepsin B/L (CatB and CatL) [20]. Recently, it has been reported that curcumin mediates organic cation transporter 2 (OCTN2) expression through activation of the PPARγ/RXRα pathway by binding to the peroxisome proliferator response elements (PPRE) in colorectal cancer SW480 cells [21].
Curcumin can suppress hepatic stellate cell (HSC) activation and modulate liver inflammatory injury by upregulation of PPARγ, which can increase apoptosis or decrease cyclin D1 and proliferation to inhibit angiogenesis/cell growth, and also can cause a reduction in TGF-β signaling and extracellular matrix in regard to inhibition of HSC activation and liver fibrosis [22]. Much research shows that curcumin alleviates cholangiopathy and biliary fibrosis in multidrug resistance-2 gene (Mdr2−/−) mice via PPARγ activation, TNF-α inhibition, and the stimulation of vascular cell adhesion molecule-1 (VCAM-1) expression in cholangiocytes [23]. Likewise, it can attenuate liver injuries by PPARγ activation, the elevation of cellular glutathione (GSH) content, extracellular-signal regulated kinase (ERK) inhibition, and prevention of toll-like receptor 4 (TLR-4) expression leading to down-regulation of NF-kB in hepatic stellate cells [24]. Curcumin-low-molecular-weight PEGs (mPEG454) showed a therapeutic effect on dyslipidemia and nonalcoholic fatty liver disease via cAMP response element binding (CREB)/PPARγ/CD36 pathway, by which the activation of CREB triggered inhibition of PPARγ and CD36 expression in mediation of lipid homeostasis [25]. Meanwhile, curcumin improved lipid accumulation in nonalcoholic fatty liver disease via increasing PPARα mRNA and protein levels in the liver and inhibition of DNA methylation at the PPARα gene [26]. Thus, curcumin may prevent nonalcoholic steatohepatitis (NASH)/cirrhosis and nonalcoholic fatty liver disease through direct/indirect induction of PPARγ expression [27].
In lung inflammation, curcumin acts as a mediator of inflammation and oxidative stress by the upregulation of PPARγ, leading to the inhibition of TNF-α in acute lung injury and pulmonary diseases such as idiopathic pulmonary arterial hypertension [28]. PPARγ activation by curcumin causes the upregulation of heme oxygenase-1 (HO-1) and blocks pulmonary cell proliferation, remodeling, differentiation, and apoptosis by mediating the protein kinase C (PKC)/AMPK/p38MAPK/NAD-dependent protein deacetylase (SIRT1)/PPARγ pathway, and then, through attenuation of NF-κB, signal transducer and activator of transcription-1 (STAT-1) and AP-1, protecting against lung inflammation [29].
In addition, curcumin can ameliorate renal fibrosis, a common pathology in chronic kidney disease, and arrest the cell cycle in the G1 phase. It seems that curcumin reduces fibroblast proliferation and extracellular matrix (ECM) accumulation through up-regulation of PPARγ and down-regulation of Smad2/3-dependent TGF-β1 signaling [30]. Other studies indicated that curcumin inhibited TGF-β1-induced epithelial mesenchymal transition (EMT) via the ERK/PPARγ signaling pathway in a Smad2/3-independent manner in renal tubular epithelial cells [25]. However, curcumin reveals its antifibrotic effect at the activation stage of renal fibrosis by reducing TGF/Smad, MAPK/ERK, and sphingosine kinase 1 (Sphk1)/sphingosine-1-phosphate (S1P), as well as increasing PPARγ pathways to block fibrosis.
Growing evidence showed that curcumin exhibited a therapeutic effect in cardiometabolic syndrome treatment by an increase/activation of PPARγ and suppressing the levels of inflammatory markers including NF-κB, TNF-α, IL-6, and high-sensitivity C-reactive protein (hs-CRP) in both animal model and molecular docking [31]. Curcumin also inhibited myocardial cell necrosis and apoptosis by abrogating NF-κB expression and stimulating expression of PPARγ and B-cell lymphoma 2 (Bcl-2) in myocardial cells in a rat myocardial infarction model [32]. In vascular smooth muscle cells, curcumin diminished AngII-induced inflammatory factors and oxidative stress by enhancing PPAR-γ activity, leading to down-regulation of TNF-α, IL-6, NO, cell proliferation, p47phox, reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, and reactive oxygen species (ROS) production. These beneficial effects of curcumin enabled an explanation of its molecular mechanisms on atherosclerosis [33].
Previous studies have demonstrated the protective potential of curcumin on neurological diseases such as Alzheimer’s disease, ischemic stroke, central nervous system (CNS) injury, chronic pain, trauma, multiple sclerosis, and Parkinson’s disease. Curcumin alleviates neuroinflammation and the production of microglia, astrocytes, and inflammatory cytokines due to PPARγ activation, leading to inhibition of amyloid-β accumulation as well as inflammatory signaling cascades such as Janus kinase (JAC)/signal transducer and activator of transcription (STAT), NF-κB, and IL-12/IFNγ [34–37].
In addition, curcumin has immune-modulatory properties in various pathological or age-related diseases such as cancer, Alzheimer’s disease, atherosclerosis, and metabolic disorders. It can enhance the immune system by the activation of PPARγ, thereby decreasing the levels of proinflammatory cytokines (IL-1α, IL-1β, IL-12, IL-6, TNF-α, NF-κB) and up-regulation of CD36, HO-1, and NADPH quinine oxidoreductase-1 (NQ-1) can occur, revealing an immunomodulatory effect of curcumin [35, 38, 39].
4.2. Resveratrol
Resveratrol, a natural polyphenol (stilbene) found in several plants such as grapes, peanuts, and other berries, has been reported to have antioxidant, anticancer, anti-inflammatory, cardioprotective, hypolipidemic, and metabolic regulation properties [40, 41], though therapeutic effects have been questioned in some clinical studies [41–43]. Previous studies indicated that resveratrol acts as a natural PPAR agonist onisotypes of PPARs and regulates metabolism [40, 41]. Resveratrol ameliorates atherosclerosis, platelet aggregation, lipid homeostasis, and total cholesterol accumulation through its antioxidant, anti-inflammatory, antiapoptotic, and lipid overload inhibition, and in addition improves endothelial function [42]. Interestingly, these effects have been shown to occur through activation of the PPARγ/LXRα cascade, SIRT1, endothelial nitric oxide synthase (eNOS), AMPK, ABCA1, and G1, ERK1/2, inhibiting TNFα, IFNγ and NF-κB, and promoting cholesterol efflux [40–42].
Resveratrol also ameliorates carboxymethyllysine- (CML-) induced pancreas damage and hyperglycemia through increasing insulin synthesis and upregulating pancreatic PPARγ and pancreatic and duodenal homeobox-1 (PDX-1), as well as activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway [43]. Resveratrol suppresses oxidative stress by activation of Nrf2 and PPARγ signaling pathways and their crosstalk.
In diabetic cardiomyopathy, resveratrol inhibits myocardial fibrosis during hyperglycemic conditions by suppressing the ROS/ERK/TGF-β/periostin and TGF-β1/Smad3 pathways, along with modulating the SIRT1/CDK2-associated cullin 1 (CACUL1)/PPARγ axis [42]. It seems that anti-inflammatory, antioxidant, antiapoptotic, and antifibrotic properties of resveratrol play a pivotal role in the up/down-regulations of the signaling cascades involved.
In further actions, resveratrol protects retinal pigment epithelium (RPE) cells from sodium iodate injury via its antioxidant and anti-inflammatory effects, leading to regulation of PPARα and PPARδ conformation and suppression of ROS and IL-8 production, as well as GSH up-regulation to attenuate oxidative stress and progression of age-related macular degeneration [44]. Furthermore, resveratrol in dyslipidemia or metabolic syndrome decreases body weight, regulates lipid deposition, modulates adipocyte gene expression, and stimulates white adipose browning, via phosphatidylinositol-3kinase (PI3K)/SIRT1, Nrf2, PPARγ, TNF-α, and protein kinase A (PKA)/LKB1/AMPK signaling pathways [45]. Resveratrol exerts immunomodulatory effects through regulating PPARα/RXRα activation, IL-10 signaling, natural killer cell signaling, leucocyte extravasation signaling, and IL-6 signaling, immune response pathways involved in disease [45]. Recently, a novel hybrid compound (PTER-ITC) was synthetized from trans-3,5-dimethoxy-49-hydroxystilbene (PTER), a natural dimethylated analog of resveratrol, and an isothiocyanate (ITC) conjugate. PTER-ITC revealed anticancer potential on breast cancer cell lines (MCF-7 and MDA-MB-231) through activation of PPARγ, PPARβ,p38 MAPK, JNK, caspase 9, caspase 7, and caspase 3 pathways and downregulation of Bcl-2 and survivin [46]. Thus, resveratrol may be considered a natural PPAR agonist which qualifies as an effective candidate to prevent and treat a number of chronic diseases (Table 1).
4.3. Polydatin
Polydatin, also known as piceid, is a glycoside compound of resveratrol which exists in grape, Polygonum cuspidatum, Fallopia japonica, peanut, berries, and other sources [47–49]. Polydatin has shown biological activities, such as antagonist of platelet aggregation, cardioprotective, neuroprotective, hepatoprotective, antithrombotic, antiatherosclerotic, antitumor, antibacterial, protection of lungs, anti-inflammatory, antioxidant, nephroprotective, melanogenesis inhibitor, and immunostimulant [47, 48, 50–52]. Moreover, polydatin restored vascular endothelial cells (VECs) functions in high glucose conditions by PPARβ-NO signaling pathways which ameliorate diabetes-related cardiovascular diseases [52]. Polydatinin addition exerted antiatherosclerotic effects by Pre-B cell colony enhancing factor (PBEF) downregulation and activation of PPARγ and SREBP-1, thereby regulating intracellular lipid metabolism in peritoneal macrophage, as well as decreasing cholesterol deposition and prevention of development of atherosclerosis [49, 50]. In diabetes mellitus- (DM-) associated liver disease, polydatin acts as PPARα/β signaling pathway activator through its anti-inflammatory and antioxidant effects (Table 1) [53, 54]. To sum up, polydatin exerts a pronounced effect on oxidative stress and inflammatory-induced diseases through activation of PPAR subunits and associated signaling pathways.
4.4. Phlorotannins
Phlorotannins, polymers of phloroglucinol, are a group of polyphenolic bioactive compounds which were found in brown alga [55, 56]. They possess several biological activities including antimicrobial, antiviral, hepatoprotective, cardioprotective, anti-inflammatory, neuroprotective, anticarcinogenic, immunomodulatory, hypolipidemic, antidiabetic, and antioxidant properties [55–57]. Ecklonia, a genus of kelp and brown alga which has abundance of phlorotannins, especially of the eckol-type, has hepatoprotective activity by increasing PPARα and carnitine palmitoyl-transferase 1 (CPT-1) along with decreasing SREBP-1 and triglyceride (TG) to prevent fatty acid oxidation and reducing lipogenesis in ethanol-induced fatty liver [57]. Furthermore, phloroglucinol compounds of the aerial parts of Potentilla longifolia Wild. Ex Schlecht. protected 3T3-L1 adipocyte cells against lipid accumulation by downregulating SREBP1c, fatty acid synthase (FAS), stearoyl CoA desaturase-1 (SCD1), glycerol-3-phosphate acyltransferase (GPAT), PPARγ, and CCAAT-enhancer-binding protein α (C/EBPα) adipogenesis-related proteins [58]. Although phlorotannins demonstrated several beneficial effects, there was evidence of side effects or toxicity in cell lines, both in animal and human studies. However, further studies should evaluate safety and toxicity of phlorotannins for use as functional foods and pharmaceuticals (Table 1) [59].
4.5. Quercetin
Quercetin is a common and important flavonoids that is widely distributed in tea, onions, peppers, plums, mangos, and various types of berries, fruits, and vegetables [60–62]. Quercetin plays an important role in anti-inflammation, antioxidation, antiviral, anticancer, antiatherosclerotic, cardioprotection, and other biological activities in the prevention and treatment of diseases [60–62]. Quercetin can inhibit atherosclerosis-induced myocardial infarction (MI), heart failure, and hypertension by upregulation of PPARγ and the signaling cascades involved, including the antioxidant pathway and the downregulation of inflammatory cytokines (Table 1) [60–66]. However, the PPARγ2 chemically activated luciferase gene expression (CALUX) culture study showed that quercetin (10 μM) co-incubated with vitamin C (500μM, to prevent auto-oxidation) can potentially increase the effect of PPARγ ligands and expression of PPARγ-cellular receptors leads to synergistic effects with endogenous PPARγ agonists [67].
In metabolic disorders such as obesity and metabolic syndrome, quercetin can enhance WAT browning and brown adipose tissue (BAT) activation due to activation of β3-adrenergic receptor (β3AR)/PKA/AMPK/PPARγ/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) pathways, by this means inducing expression of uncoupling protein 1 (UCP1) and ABCA1 to promote adenosine triphosphate (ATP) and inhibit fat accumulation [68–70]. Owing to its relevance in adipogenesis, it appears that the inhibition of PPARγ, C/EBPα, or SREBP plays a pivotal role in obesity treatment. Furthermore, quercetin may exert its antidiabetic and glucose uptake effects through activating SIRT1/ PPARγ/AMPK signal cascades to improve the complications of insulin resistance and diabetes [71]. The combination of quercetin (0.1 μM) and pioglitazone (0.1 μM, a PPARγ agonist) inhibited the angiotensin II (Ang II)-induced contractile effect in fructose-streptozotocin (FSTZ)-diabetic rats via antioxidant and NO release properties [72]. In another study, quercetin showed anti-diabetic effects more than antiobesity effects in high-fat high-sucrose diet (HFHSD) animals which consumed quercetin (30 mg/kg/BW/day) for 6 weeks. Likewise, lipogenic enzymes and lipoprotein lipases, including acyl-coenzyme A oxidase (ACO), CD36, carnitine palmitoyltransferase-1b (CPT-1b), PPARα, PGC-1α, uncoupling protein 3 (UCP3), transcription factor A mitochondrial (TFAM) and cyclooxygenase-2 (COX-2), remained unchanged in adipose tissue, while quercetin treatment reduced fructosamine, basal glucose, insulin and homeostatic model assessment for insulin resistance (HOMA-IR), as accepted diabetic markers in rat models [73].
PPAR isoforms have gained significant attention in CVD treatment. Quercetin exhibited antiatherosclerosis effect by upregulating PPARγ/LXRα/ ABCA1 and promoting cholesterol efflux in THP-1 derived foam cells [62]. Moreover, the administration of quercetin reduces ischemia/reperfusion injury by upregulating SIRT1//PPARγ/PGC-1α, activating PI3K/Akt pathway, suppressing myonecrosis, increasing Bcl-2/Bax (pro-apoptotic protein), inhibiting the inflammatory cascade, scavenging ROS, and enhancing cardiac function [61, 66]. Therefore, quercetin, by increasing or activating PPARγ and associated signaling cascades in the heart, exerts cardioprotective effects in CVDs, including hypertension, heart failure, ischemia, and atherosclerosis due to antioxidant, anti-inflammatory, and antiapoptotic disease [60–66]. Also, quercetin inhibited activation of all three isoforms of PPAR through its anti-inflammatory and antioxidant properties in obesity-related disorders and inflammatory diseases and an enhanced immune system [74]. Likewise, quercetin displayed its beneficial effects such as lipid lowering and suppression of the lipid accumulation-induced chronic inflammation by the PPARα cascade in cultured chicken hepatocytes [75]. Furthermore, quercetin treated neurodegenerative dysfunction in the mouse Parkinson’s disease model through up-regulating PPARγ, PGC-1α, and TFAM to activate the polycystin 1 (PKD1)/Akt pathway [75].
4.6. Kaempferol
Kaempferol is a flavonol that is abundant in fruits, vegetables, and various medical plants, such as grapefruit, tea, and berries [76, 77]. Numerous studies have supported diverse beneficial properties of kaempferol, including antioxidant, anti-inflammatory, anticarcinogenic, antiobesity, antiatherosclerotic, cardioprotective, antihyperlipidemia, antiosteoporotic, and antidiabetic and estrogenic/antiestrogenic activities [76–79]. In addition, it reduced cholesterol, glucose, and TG levels through liver X receptor (LXR) activation and inhibition of sterol regulatory element-binding proteins (SREBPs), and without the side effect of hepatic steatosis [76–80]. Kaempferol also enhanced the expression of ACO, cytochrome P450 - family4 – subfamily a - polypeptide 1 (CYP4A1) and PPARα, thereby reducing fat and lipid accumulation in obesity [79]. Published data revealed that in metabolic disorders, especially obesity and fat, kaempferol increased PPARα, PPARδ, and target genes, thereby inducing autophagy and fatty acid uptake as well as decreasing PPARγ and SREBP-1c expression via activation/inhibition of related signaling pathways regulating obesity and metabolic dysfunctions (Table 1) [76–82]. Although beneficial antioxidant and anti-inflammatory effects of kaempferol have been reported, the precise molecular target and mechanism of kaempferol in the treatment of diseases remains unclear. Therefore, further study is needed to investigate the kaempferol mechanisms of action.
4.7. Rutin
Rutin, quercetin-3-O-rutinoside, is a flavonol with significant beneficial properties, such as antioxidant capacity, anticarcinogenic, cardioprotective, antiatherosclerotic, antiadipogenic, neuroprotective, and antihyperuricemia activities [83–89]. A number of in vitro and in vivo studies indicated that rutin can improve glucose uptake, hyperlipidemia, insulin resistance, lipid accumulation, obesity, and metabolic dysfunction through modifying the expression of PPARγ and SREBP-1cin adipose tissue, thereby promoting AMPK and Akt activities to regulate body fat deposition [83–87]. Also, rutin attenuated NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome activation through its anti-inflammatory and antioxidant effects in response to fructose-induced renal hyperlipidemia and injury [88]. Likewise, rutin, by stimulating insulin (Akt and ERK1/2) pathways and inhibiting leptin (JAK2/STATE3) cascades, triggered PPARα, carnitine palmitoyl-transferase 1 (CPT1), and organic cation transporter 2 (OCTN2) up-regulation, resulting in renal urate and lipid lowering [88]. Moreover, rutin exhibited neuroprotective effects due to its ability to retard oxidative stress in brain tissue by stimulating PPARδ (an abundant PPAR isoform in neural tissue and brain), leading to a promotion of antioxidant systems, including glutathione peroxidase (GPX), GSH, and paraoxonase (PON-1, PON-3) and a reduction of PON-2 in the cisplatin-neurotoxic rat model [89]. Taken together, rutin attenuated the metabolic dysfunction or other diseases induced by oxidative/inflammation stress through stimulation or inhibition of molecular mechanisms associated with a regulation of PPARα/PPARγ/PPARδ levels (Table 1).
4.8. Hesperetin
Hesperidin and its aglycone hesperetin, a methoxylated flavanone known as citrus flavonoid, have particular pharmacological activities associated with high permeability in cell membranes, such as anti-inflammatory, antioxidant, antihypertensive, cardioprotective, vasodilation, anticancer, immunomodulator, antiallergic, neuroprotective, antiepileptic, antidepressant, lipid lowering, capillary fragility-reducing, antiadipogenic, and PPARγ agonist properties (Table 1) [81, 90–98]. Furthermore, hesperidin/hesperetin exerted their beneficial effects through PPARγ activation and subsequently modulating both PPARγ-dependent/independent pathways in targeted tissue [90, 98].
These studies indicated that hesperidin restored oxidative stress and inflammation-induced hepatotoxicity via boosting hepatic PPARγ expression and antioxidant markers, as well as reducing liver function enzymes and inflammation cytokines [92, 97]. Also, hesperidin/hesperetin stimulated PPARγ, which is centrally involved in the mediation of antiapoptotic (diminishing JNK, caspase-3/9, p53, Bax), anti-inflammatory (attenuating TNF-α, IL-1β, IL-6, monocyte chemoattractant protein-1 (MCP-1), intracellular adhesion molecule-1 (ICAM-1)), and antioxidant (increasing superoxide anion dismutase (SOD), catalase (CAT), GSH) effects and improving inotropic and lusitropic cardiac function (rate of left ventricular systolic pressure (+dP/dt), rates of pressure fall (-dP/dt), mean arterial pressure (MAP)) in rat heart hypertrophy and IR models [93–95].
Interestingly, hesperidin showed antiadipogenic and delipidating effects by inhibiting PPARγ, CCAAT-enhancer-binding protein β (C/EBPβ), SREBP1-C, and perilipin, that are involved in different stages of adipogenesis (lipolysis and lipogenesis). In addition, it increased adipose triglyceride lipase in preadipocytes derived from human mesenchymal stem cells but also acted as a PPARγ agonist and increased C/EBPα to decrease insulin and lipid in the 3T3-L1 adipocytes model [81, 90, 91]. It can be postulated that hesperidin/hesperetin, as a PPARγ agonist, leads to attenuation of the inflammatory response and is thus ultimately protective against diseases through activation of radical scavenging activity.
4.9. Apigenin
Apigenin, a flavone abundant in foods injested daily, such as fruits, vegetables, and some medicines, possesses various biological activities including antioxidant, anti-inflammatory, anticancer, antihyperglycemic, antiadipogenic, antiobesity, cardioprotective, antifibrotic, antidepressant, antidiabetic, and hepatoprotective actions [99–103]. Moreover, apigenin can also downregulate PPARγ and CEBP-α in the early phase of adipogenesis in 3T3-L1 adipocytes and protect against high-fat diet- (HFD-) induced metabolic syndrome in rats. Apigenin also prevents lipid accumulation and enhances adipocyte differentiation, thereby having hepatoprotective effects [99–103]. Recent research has established that apigenin is a PPAR modulator that inhibits obesity-induced metabolic syndrome via suppressing PPARγ and PPARα, resulting in activation/inhibition of upstream or downstream targets, such as STAT3, C/EBP-α, SREBP-1c, CD36, and Nrf2 in adipose tissues [99, 100, 103]. In addition, another study showed that apigenin provoked expression of PPARγ in the macrophage to reduce metabolic abnormality and liver/muscular steatosis in HFD and diabetic rat [101]. Likewise, apigenin attenuated carbon tetrachloride (CCl4)– and bile duct ligature (BDL)–induced liver fibrosis by alleviating autophagy and activated hepatic stellate cells (HSCs) and extracellular matrix (ECM) formation via activating PPARα and inhibiting TGF-β1/Smad3 and p38 pathways [102]. However, to further confirm the precise underlying mechanisms of apigenin on PPARs specifically in adipose, macrophage, or other tissues, in vivo models of obesity and ob/ob in vitro studies are needed.
In the cardioprotective effects of apigenin, previous studies reported that PPARα and PPARγ were involved in ameliorating cardiac hypertrophy and myocardial abnormality [104, 105]. Herein, apigenin in diabetic rats increased PPARγ to attenuate MI-induced myonecrosis and cardiac dysfunction [105]. In renovascular hypertensive rats, it improved cardiac hypertrophy and glucolipid metabolism by directly inhibiting angiotensin II and hypoxia inducible factor-lα (HIF-1α), and subsequently diminishing PPARγ and increasing PPARα led to modulation of myocardial CPT-1, pyruvate dehydrogenase lipoamide kinase isozyme 4 (PDK-4), glycerol-3-phosphate acyltransferase (GPAT),and glucose transporter-4 (GLUT-4) proteins [104]. Furthermore, apigenin by its antioxidant and anti-inflammatory properties activated PPARγ to protect against depression or mice pulmonary fibrosis by decreasing NLRP3 inflammasome, microglia, malondialdehyde (MDA), and apoptosis [106] or TGF-β1, matrix metallopeptidase 9 (MMP-9), and vimentin [107] in rat depression or mouse pulmonary fibrosis models, respectively. Therefore, the pharmacological effect of apigenin on PPARs suggests a novel approach in the treatment of cardiovascular, brain/nervous system, and immunity complications (Table 1).
4.10. Naringenin
Naringin (a flavanone glucoside) and naringenin (its aglycone) are major flavonoids of citrus fruit, grapefruit, tomato, and orange with various pharmacological activities, such as antioxidant, anti-inflammatory and antihypercholesterolemia, antiobesity, hypotensive, cardioprotective, neuroprotective, and metabolic syndrome therapy [108–113]. Naringenin improved metabolic disturbances via PPARα and/or PPARγ up-regulation and stimulation (PGC1α, CPT-1, UCP1, UCP2)/suppression (LXRα, adipogenic, lipogenic) of its related underling up/downstream kinases, enzymes, genes, and receptors, thereby providing antioxidant and anti-inflammatory effects in diabetic, hypercholesterolemia, obesity, and lipid metabolism liver dysfunction models, as shown in Table 1 [109–111, 114–117]. Some researchers have reported naringenin as a PPARα/γ agonist [108, 111], but using naringenin supplementation had no significant effect on PPARα/γ (slightly decreased) in ovariectomy-induced metabolically disturbed female mice. Interestingly, it increased fatty acid oxidation (CPT1α) and lipogenesis de novo (SREBF1) but decreased acyl-CoA oxidase 1 (ACOX1), another fatty acid oxidation target [108]. Also, in a further study, naringenin blocked expression of adipogenic and lipogenic activity by inhibiting LXRα/SREBP1c/PPARγ signaling cascade to restore hepatic lipid accumulation and liver dysfunction in HBx-induced hepatic steatosis [118].
PPAR isoforms (α, β, and γ) seem to have pivotal actions in cardiac and renal injuries. Naringenin, through the activation of PPARα, PPARβ, and PPARγ, ameliorated diabetic nephropathy and cardiomyocyte hypertrophy, which was associated with an increase in CYP4A-20-Hydroxyeicosatetraenoic acid (20-HETE), cytochrome P450-family2-subfamily j-polypeptide 3 (CYP2J3), and 14,15-epoxyeicosa-5,8,11-trienoic acid (14,15-EET) levels, respectively [112–119]. Thus, naringin/naringenin may be effective as a potential complementary/alternative medicine PPAR modulator in the treatment of immune, brain, cardiac, metabolic, and renal diseases.
4.11. Catechins
Catechins are a large group of flavonoids, with flavan-3-ol structure, including catechin, epi-catechin, epigallocatechin, epigallocatechin-3-gallate, and proanthocyanidins found in many plants and also dietary foods such as apples, tea, cocoa beans, grape seed, and red wines [120–130]. Notably, catechins have multibeneficial biological effects, for instance antiobesity, lipid lowering, antioxidant, anti-inflammatory, antidiabetic, anticancer, antiatherosclerotic, cardioprotective, neuroprotective, and nephroprotective [120–130]. (-)-Epigallocatechin-3-gallate (EGCG), a green tea catechin, exhibited PPARα and PPARγ agonist properties in subcutaneous adipose tissues, but PPARγ antagonist activity in epididymal adipose tissue to reduce obesity and epididymal white adipose tissue weight in HFD mice via activation of AMPK [120]. In addition, EGCG and catechins suppressed differentiation of adipocyte by reducing ROS, inflammation, insulin signaling, and the stress-dependent mitogen-activated protein kinase (MAPK) kinase, (MEK)/ERK, and PI3K/Akt pathways. Additionally, increasing cyclic adenosine monophosphate (cAMP)/PKA signaling led to inactivation of PPARγ, C/EBPα, and forkhead transcription factor O1 (FoxO1) as clonal expansion-related genes in 3T3-L1 cells or preadipocyte models [121, 123–126]. Interestingly, procyanidin B2 (a catechin type) activated PPARγ to regulate macrophage M2 polarization and manipulation of M1/M2 macrophage homeostasis in metabolic inflammatory diseases. Likewise, it induced M2 macrophage markers, including arginase (Arg1), Ym1, found in inflammatory zone (Fizz1) and cluster of differentiation 206 (CD206+) as well as PPARγ targets (CD36, ABCG1), but inhibited the M1 markers in diabetic mice macrophages [122].
EGCG exerted its beneficial anticancer effects via PPARα activation and inactivation of HO-1/Nrf2 pathway on some cancer cell lines, including pancreatic, esophageal, MCF-7, and ovarian. However, as a consequence of EGCG-induced PPARα expression, HO-1 is negatively regulated by PPARα as its direct target, depending on cell type and ligand stimulation. Therefore, PPARα activation attenuates EGCG-induced HO-1 up-regulation and sensitizes cancer cells to EGCG [127]. In addition, catechins activated PPARγ via their anti-inflammatory, antioxidant, and antiapoptotic effects to ameliorate cardiac, renal, brain, and nervous system injuries induced by their related diseases [128–130]. Additionally, catechins appeared to be critical regulators of PPARs (PPARα, PPARγ, PPARα/γ, and PPARδ) (Table 1) that are involved in protection of organs, and by inhibiting/stimulating their upstream or downstream targets improved each of the organ functions [129–131].
4.12. Berberine
Berberine is an isoquinoline alkaloid, which exists in plants such as Berberis spp. and Rhizoma coptidis. In addition, several previous studies have reported that berberine is considered anti-inflammatory, antidiabetic, cardioprotective, neuroprotective, antihyperlipidemic, antioxidant, hepatoprotective, and antiadipogenic potential [132–138]. Berberine exhibited its pharmacological effects through PPARs, especially as selective PPARα agonist in regulation of metabolic, liver, renal, cardiac, and brain dysfunctions (Table 1) [135, 137, 139–142]. Berberine affects upstream or downstream signaling targets, resulting in activation of PPARα, thereby reducing lipogenesis and promoting β-oxidation in animal metabolic dysfunction models [133–135, 137]. Interestingly, berberine activated PPARα/nitrous oxide systems (NOS)/NO signaling pathway in cardiac animal experiments, which indicated that NO is a pivotal downstream target of PPARα signaling cascade in cardiachypertrophy [140, 141].
4.13. Cinnamic Acid
Cinnamic acid is an organic and aromatic unsaturated plant-based carboxylic acid (with two cis and trans isoforms) exerting beneficial therapeutic effects such as antitumoral activity, antioxidant, anti-inflammation, antiatherogenic, hepatoprotection, cardioprotection, and neuroprotection [143–145]. Cinnamic acid exhibited a PPARα agonist role to reduce lipid accumulation and neurodegeneration in cellular and animal models [143–145]. Interestingly, it acted as PPARγ antagonist, resulting in inhibition of hepatic lipogenesis and fatty acid intake in HepG2 cells and db/db mice (Table 1) [144]. A recent study indicated that poly lactic-co-glycolic acid (PLGA) nanoparticle of cinnamic acid at concentration of ≥25 μM inhibited MCF-7 cellular proliferation via PPARγ signaling pathway, leading to a drop of metabolic activity and Ki-67 antigen to exert its cytotoxic effects on breast cancer [146]. Thus, cinnamic acid can act as agonist or antagonist of PPARs to regulate abnormality of various diseases.
4.14. Glycyrrhizic Acid
Glycyrrhizic acid (Glycyrrhizin) is a bioactive triterpenoid that was extracted from Glycyrrhizaglabra L. roots [147, 148]. Previous studies reported beneficial effects of glycyrrhizinin treatment of diseases and some research investigated the relationship of glycyrrhizic acid and PPARs (Table 1) [147–149]. In addition, new synthetic derivatives of glycyrrhizic acid, 2-cyano-substituted analogues, and 19 glycyrrhetic acid exhibited promising potential for PPARγ activation to inhibit HT-29, HCT-15, MCF-7, and HepG2 carcinogen cell lines [150]. In addition, 19 glycyrrhetic acid derivative increased PPARγ and reduced MMP-2/MMP-9 to act as antitumor agent against MCF-7 cells [150]. In another study, intraperitoneal injection of 50mg/kg glycyrrhetic acid in male Sprague-Dawley rats fed ad libitum with standard diet improved insulin sensitivity, reduced lipid (total cholesterol (TC), LDL, and triacylglycerol (TAG)), up-regulated PPARα and PPARγ in the liver, and revealed antiglucocorticoid effects [151]. Finally, glycyrrhetic acid exerts a role as PPARα/γ agonist due to its antioxidant and anti-inflammatory properties.
4.15. Oleanolic Acid
Oleanolic acid is a natural pentacyclic triterpenoid found in medicinal plants, fruits, and vegetables [152, 153]. It showed some pharmacological potential through its dual agonist actions on PPAR in tissues [153, 154]. Likewise, oleanolic acid simultaneously activated PPARγ/α, leading to an increase of fatty acid transport protein 1 (FATP-1) and long-chain acyl-CoA synthetase (ACSL) to regulate metabolic dysfunction in 3T3-L1 and C2C12 cells [154]. Also, oleanolic acid operated as a ligand of PPARγ-1 or PPARδ for management of obesity or high glucose-induced metabolic abnormality in animal and cell line models [152, 153]. However, in the in vivo studies, it had cardioprotective and hepatoprotective effects by stimulation of PPARα and PPARγ, respectively [155, 156]. In another study, isolated oleanane-type triterpenoid of Pulsatilla koreana root showed anti-inflammatory effects via activation of PPAR binding to PPRE luciferase reporter, thereby inducing an inhibition of NF-κB, iNOS, and ICAM-1in HepG2 cells (Table 1) [157]. However, future studies are needed to identify the precise mechanism of the PPARs agonist role of oleanolic acid.
4.16. Ursolic Acid
Ursolic acid (UA), a pentacyclic triterpenoid that is found in bark, root, leaves, and fruits of numerous medicinal plants, showed a wide range of biological activities such as anti-inflammatory, anticancer, antioxidant, cardioprotective, antiviral, and metabolic disorders [158–161]. In addition, UA functioned as a PPARα agonist to regulate metabolic syndrome, liver diseases, respiratory dysfunction, and exaggerated inflammatory response in the animal and cell line experiments [158, 160, 162–164]. Likewise, UA improved cerebral ischemia/reperfusion injury, central nervous system (CNS) neural dysfunction, remyelination, multiple sclerosis (brain/central nervous system irregularities), and also airway inflammation of allergic asthma via promotion of PPARγ signaling by its PPARγ agonist potential in in vivo studies [159, 165, 166]. A recent study showed that UA (0-50 μM) may exert antiskin cancer effects by promoting AMPK and PPARα in Ca3/7 and MT1/2 premalignant and malignant skin cancer cell lines [166]. Also, ursolic acid in combination with artesunate suppressed hyperlipidemia and atherosclerosis due to increasing low density lipoprotein receptor (LDLR), apolipoprotein A-I (apoA-I), and PPARα, as well as SREBP1 reduction in a hyperglycemic rabbit model [7]. Therefore, UA, a PPAR ligand and coactivator (Table 1), could play a role in management of multiple diseases, but future animal or clinical studies are needed to prove its promising properties related to PPARs.
4.17. Shogaol
6-Shogaol, the dehydrated form of 6-gingerols from dried Zingiber officinale (ginger) rhizomes, is a phenolic pungent compound which possesses numerous pharmacological properties, including anticancer, anti-inflammatory, and neuroprotective effects [167–169]. A number of studies reported that 6-shogaol acted as a PPARγ agonist in its anti-inflammatory, antitumor, and neuroprotective effects (Table 1) [167–169]. These studies suggest that 6-shogaol may have a role as a novel PPARγ agonist ligand to manage diseases such as inflammation, cancer, and neurodegeneration.
4.18. Oleic Acid
Oleic acid (OA) is the most abundant cis omega-9 monounsaturated fatty acid with 18 carbon atoms in olive oil, which exhibits antioxidant, cardioprotective, anti-inflammatory, antibacterial, and hepatoprotective effects [170, 171]. It has been reported that OA acts to enhanced PPARγ to reduce TNF-α, IL-6, IL-1β, iNOS, and MMP-9 in monocytes or macrophages [171, 172]. Interestingly, OA repressed expression of PPARγ and SIRT1 to protect coronary arteries in smooth muscle cells [170]. Also, OA boosted PPARδ in HepG2 cells by provoking the G protein-coupled receptor 40-phospholipase C- (GPR40-PLC-) calcium pathway to regulate lipid metabolism and insulin sensitivity [172]. Thus, these results suggested that OA can function as a potential PPAR agonist (Table 1) and future work will be needed to investigate the relationship between PPARs and oleic acid on animal models and clinical trials.
4.19. Polyunsaturated Fatty Acid
Polyunsaturated fatty acids (PUFA) or essential fatty acids, known as n-3, n-6, or n-9, are found in fish and vegetable oils and have been shown to exert beneficial effects on human or animal health [173, 174]. Polyunsaturated fatty acids can act as PPAR signaling activators in the regulation of abnormalities in liver, cancer, cardiovascular, and inflammatory diseases (Table 1) [175–178]. In goats feeding with α-linolenic acid enhanced PPARα in the liver [172]. While a number of studies have investigated PUFA effects on PPARs results were contradictory, and therefore more studies are warranted to determine their precise effects.
4.20. Other Phytochemicals
In addition to the compounds mentioned above, other natural phytochemicals showed potential PPARs ligand activity in research studies (Table 1). Terpenoids such as 1,8-cineole [7, 179], gingerol [7], cinnamaldehyde [180], carvacrol [181], zerumbone [182], oridonin [183], tanshinone IIA [184], pedunculoside [185], and lycopene and β-carotene [186] acted as dual PPARs activators for exhibiting antiatherosclerotic, antiadipogenic, anti-inflammatory, anticancer, hepatoprotective, and antihyperlipidemia effects. Interestingly, betulinic acid (a triterpenoid) had PPARγ and PPARα antagonist activity in 3T3-L1 cells to boost glucose uptake and osteogenesis, along with adipogenesis inhibition [187]. Also, fucosterol (a triterpenoid) [188], umbelliferone (a coumarin) [189], and chelerythrine (an alkaloid) [190] demonstrated PPARγ activation in remediation of liver injury, liver fibrosis, and diabetes in animal models, respectively. The phytochemical ligands of PPARs and their biological targets are shown in (Figure 2).
5. Clinical Finding
Although numerous in vitro and in vivo studies demonstrated beneficial therapeutic effects of phytochemicals via their PPARs activation/suppression roles on a wide range of diseases (Table 1), there are few clinical studies on the impact of phytochemicals on PPARs and their implications in diseases. Limited clinical evidence for some phytochemicals associated with PPARs and disease remediation is available and is mainly on metabolic syndrome (Table 2). For polyunsaturated fatty acids (PUFAs), known to be PPAR ligands, most clinical trials have reported the role of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and α-linolenic acid (n-3 PUFAs) on PPARs activation/suppression to modulate disease [191–200]. Additionally, blood sampling or gene assay of subjects demonstrated single nucleotide polymorphisms (SNPs) associated with impacts of PPARs and PUFAs on metabolic syndrome [202, 204]. Moreover, curcumin and resveratrol increased expression of PPARγ gene for regulation of metabolic syndrome and associated diabetes, coronary heart disease, and polycystic ovary syndrome [201–203]. In addition, administration of naringen into a diabetic 53-year-old African American female (a case study) showed that naringenin exerted its regulatory effects on insulin resistance and metabolic rate via activation of PPARα and PPARγ, leading to promotion of UCP1 and CPT1β [204]. In another study, effects of epigallocatechin gallate (EGCG) evaluated on Thai obese subjects (=15) that reported consumption of 300 mg/day EGCG for 4 and 8 weeks did not affect expression of UCP1 and PPARγ in browning white adipocytes, but interestingly EGCG reduced TG, blood pressure, and kisspeptin levels in these obese human subjects (Table 2) [205]. Given the sparsity of such clinical studies, the exact activation/suppression effects of phytochemicals on PPARs in diseases warrant more clinical trial investigations with larger sample size with attention to pharmacokinetic, dosage, frequency, and treatment duration protocols.
6. Limitations
There are some limitations to this review which are highlighted here. The most important limitation for therapeutic evaluation is the lack of sufficient clinical studies on the majority of PPAR natural agonists to date. In addition, there is insufficient evidence of safety or adverse side effects and possible drug interactions in oral administration of phytochemicals both in clinical and animal studies. Thus, further studies are needed to evaluate pharmacokinetic characteristics and bioavailability of phytochemicals as PPAR agonists. Likewise, as genetic polymorphisms in different individuals may modify the phytochemical effects on PPARs and their dosage and treatment regimes, there are only genetic polymorphic considerations of PUFAs in the available studies. While a wide range of natural phytochemicals have been suggested as candidate PPAR regulators from in vitro and in vivo studies, the greatest number of clinical trials have been performed on polyunsaturated fatty acids.
7. Conclusions
Overall, based on adjunct therapy with natural products in numerous diseases, this review has highlighted the interplay between phytochemicals and PPARs in multiple regulatory mechanisms of disease (Table 1). Here, we have focused on regulation by phytochemicals of disease abnormalities through PPAR-targeted molecular mechanisms, mainly from available in vitro and in vivo experimental models. However, clinical trials which were reported on the impact of phytochemicals in management of diseases via PPARs activation or suppression pathways are summarized in Table 2.
Based on the information presented in this review, it is noteworthy that phytochemicals have demonstrated promising potential, with acceptable safety, as agonists or antagonists of PPAR subtypes in several diseases associated with PPAR signaling cascades. In addition, phytochemicals not only can act as PPAR ligands but also they are able to impact on interactions with coactivators and corepressors in order for PPARs to target gene activation or suppression. Furthermore, phytochemicals also affect RXR activity and pre- and post-transcription regulators by inducing the obligatory heterodimer PPARs/RXR interaction, thereby instituting binding to PPRE and the consequent DNA binding site.
To conclude, it can be proposed that further studies warrant evaluation of more details of phytochemical formulations mentioned on their pharmacokinetic parameters, oral administration dosage, frequency, and absorption to enhance and expand clinical applications. As natural phytochemicals may represent favorable PPAR agonist/antagonist effects, it is expected that an understanding of phytochemical-mediated molecular mechanisms of PPAR-associated diseases will contribute to a safe approach to the therapeutic use of PPAR-targeted agents in the future.
Abbreviations
| Aβ: | β-Amyloid peptides |
| ABCA1: | ATP-binding cassette transporter A1 |
| ABCG1/5/8: | ATP-binding cassette transporters G1/5/8 |
| ACAA2: | Acetyl-coenzyme A acyltransferase 2 |
| ACACA: | Acetyl-CoA carboxylase alpha |
| ACADL: | Acyl-CoA dehydrogenase long chain |
| ACAT: | Acyl-CoA cholesterol acyl transferase |
| ACC: | Acetyl-CoA carboxylase |
| AChE: | Acetyl cholinesterase |
| ACOT: | Acyl-CoA thioesterase |
| ACOX1: | Acyl-CoA Oxidase 1 |
| ACSL: | Long-chain acyl-CoA synthetase |
| AdGFP: | AdCMV-GFP control vector |
| Agpat2: | 1-Acylglycerol-3-Phosphate O-Acyltransferase 2 |
| AIF: | Apoptosis-inducing factor |
| Akt: | Protein kinase B |
| ALB: | Albumin |
| ALOX5: | Arachidonate 5-lipoxygenase |
| ALP: | Alkaline phosphatase |
| ALT: | Alanine transaminase |
| AMPK: | AMP-activated protein kinase |
| ANF: | Atrial natriuretic factor |
| Ang II: | Angiotensin II |
| ANP: | Atrial natriuretic peptide |
| AP-1: | Activator protein 1 |
| APG-7: | Autophagy protein 7 |
| APOC3: | Apolipoprotein C3 |
| Arg1: | Arginase |
| AOPP: | Advanced oxidation protein product |
| AOX: | Acyl-CoA oxidase |
| Apo-AI: | Apolipoprotein A-I |
| Apo-AII: | Apolipoprotein A-II |
| apoE−/−: | Apolipoprotein E-defcient |
| β3AR: | β3-Adrenergic receptor |
| ASC: | Apoptosis-associated speck-like protein |
| Atgl: | Adipose triglyceride lipase |
| ATGL: | Adipose triglyceride lipase |
| ATP: | Adenosine triphosphate |
| AUC: | Area under curse |
| BACE1: | β-Site amyloid precursor protein-cleaving |
| BAT: | Brown adipose tissue |
| BDL: | Bile duct ligature |
| BDNF: | Brain-derived neurotrophic factor |
| BMI: | Body mass index |
| BNP: | Brain natriuretic peptide |
| BSP: | Bone sialoprotein |
| BUN: | Blood urea nitrogen |
| cAMP: | Cyclic adenosine monophosphate |
| CaMKII: | Ca+2/Calmodulin-dependent protein kinase II |
| CAT: | Catalase |
| CatB/L: | Cathepsin B/L |
| CD36: | Scavenger receptor (class B) |
| CD11c: | Scavenger receptor |
| CD206: | Cluster of differentiation 206 |
| cdk1: | Cyclin-dependent kinase 1 |
| C/EBPα: | CCAAT-enhancer-binding protein α |
| CE: | Esterified cholesterol |
| Cel: | Carboxyl ester lipase |
| CETP: | Plasma cholesterol ester transferase |
| Cfd: | Complement factor D |
| ChAT: | Cholineacetyltransferase |
| ChE: | Cholesterol efflux |
| CHOP: | C/EBP-homologous protein |
| Cidea: | Cyclic adenosine monophosphate |
| CK-MB: | Creatine kinase on myocardial bundle |
| CNTF: | Ciliary neurotrophic factor |
| Col1α1/2: | Collagen type I alpha-1/2 |
| COX1: | Cytochrome C oxidase subunit 1 |
| COX-2: | Cyclooxygenase-2 |
| CPT1β: | Carnitine palmitoyl-transferase 1 β |
| CREB: | cAMP response element-binding |
| CRP: | C-reactive protein |
| CTGF: | Connective tissue growth factor |
| CVD: | Cardiovascular disease |
| CVF: | Collagen volume fraction |
| cTnT: | Cardiac troponin T |
| Cyt C: | Cytochrome CDAB |
| CUMS: | Chronic unpredictable mild stress |
| DAP: | Diastolic arterial pressure |
| DCF: | 2,7-Dichlorofluorescein |
| DGAT1/2: | Diacylglycerol O-Acyltransferase 1/2 |
| DsbA-L: | Disulfide-bond A oxidoreductase-like protein |
| EAT: | Epididymal adipose tissues |
| ECM: | Extracellular matrix |
| eGFR: | Estimated glomerular filtration rate |
| Ehhadh: | Enoyl-CoA hydratase and 3-Hydroxyacyl CoA dehydrogenase |
| EMT: | Epithelial-to-mesenchymal transition |
| ER: | Endoplasmic reticulum |
| ERK: | Extracellular signal-regulated kinase |
| eIF2α: | Phosphorylation of eukaryotic initiation factor-2α |
| eNOS: | Endothelial nitric oxide synthase |
| ERR-1α: | PPARα–estrogen-related receptor |
| FABP1/4: | Fatty acid binding protein 1/4 |
| FAS: | Fatty acid synthase |
| FBG: | Fasting blood glucose |
| FC: | Free cholesterol |
| FEUA: | Fractional excretion of uric acid |
| FFA: | Free fatty acid |
| FINS: | Fasting insulin |
| FN: | Fibronectin |
| Fitm1/2: | Fat-induced transcript 1/2 |
| Fizz1: | Found in inflammatory zone |
| FoxO1: | Forkhead transcription factor O 1 |
| FPG: | Fasting plasma glucose |
| FSI: | Fasting serum insulin |
| FSP27: | Fat-specific protein 27 |
| FS: | Fractional shortening |
| GA: | Glycyrrhizic acid |
| GCLC: | Glutamatecysteine ligase catalytic subunit |
| GCLm: | Glutamyl cysteine ligase Modifier Subunit |
| GIR60–120: | Glucose infusion rate between the 60th and 120th minute |
| GFAP: | Glial fibrillary acidic protein |
| GK: | Glycerol Kinase |
| GLUT-4: | Glucose transporter-4 |
| GOT: | Glutamic-oxaloacetic transaminase |
| GPAT: | Glycerol-3-phosphate acyltransferase |
| G3PDH: | Glyceraldehyde-3-phosphate dehydrogenase |
| GPR120: | G protein-coupled receptor 120 |
| G6Pase: | Glucose 6-phosphatase |
| GPT: | Glutamate pyruvate transaminase |
| GPX3: | Plasmatic glutathione peroxidase |
| GRP78: | 78 kDa glucose-regulated protein |
| GSH: | Glutathione |
| G0S2: | G0/G1 switch gene 2 |
| GST: | Glutathione S-transferase |
| γGT: | Gamma glutamyl transferase |
| HbA1c: | Hemoglobin A1c |
| HDL-C: | High-density lipoprotein cholesterol |
| HFHS-D: | High-fat high-sucrose diet |
| HGF: | Hepatocyte growth factor |
| HIF-1α: | Hypoxia inducible factor-lα |
| HK-2: | Normal human kidney epithelial |
| HMGCR: | 3-Hydroxy-3-methylglutaryl-CoA reductase |
| 4-HNE: | 4-Hydroxynonenal |
| HO-1: | Heme oxygenase-1 |
| H2O2: | Hydrogen peroxide |
| HOMA-IR: | Homeostatic model assessment-insulin resistance |
| HR: | Heart rate |
| HSCs: | Hepatic stellate cells |
| hs-CRP: | High-sensitivity C-reactive protein |
| HSL: | Hormone-sensitive lipase |
| Hsp70: | Heat shock protein70 |
| HUVECs: | Human umbilical vein endothelial cells |
| iAUC: | Incremental AUC |
| ICAM-1: | Intracellular adhesion molecule-1 |
| IFN-γ: | Interferon gamma |
| IKK: | IκB kinase |
| IL-1: | Interleukin-1 |
| IL-6: | Interleukin-6 |
| IL-10: | Interleukin-10 |
| IL-13: | Interleukin-13 |
| iNOS: | Inducible nitric oxide synthase |
| iROS: | Intercellular reactive oxygen species |
| IS: | Infarct size |
| IVSd: | End-diastolic interventricular septal thickness |
| JNK: | c-JUN N-terminal kinase |
| Keap1: | Kelch-like ECH-associated protein 1 |
| LAMP-1/2: | Lysosome-associated membrane protein 1/2 |
| LC3: | Protein light chain 3 |
| LDH: | Lactate dehydrogenase |
| LDL-C: | Low-density lipoprotein cholesterin |
| LDLR-/-: | Lack the LDL receptor |
| LPAATθ: | Lysophosphatidic acid acyltransferase-θ |
| LPL: | Lipoprotein lipase |
| LPIN1: | Lipin1 |
| L-PK: | L-Pyruvate kinase |
| LSR: | Lipolysis-stimulated receptor |
| LXR: | Liver X receptor |
| +LVdp/dtmin: | Maximal positive rate of left ventricular pressure |
| −LVdp/dtmin: | Maximal negative rate of left ventricular pressure |
| LVIDd: | Left ventricular end-diastolic internal diameter |
| LVEDP: | Left ventricular end diastolic pressure |
| LVPWd: | Left ventricular end-diastolic posterior wall thickness |
| MAP: | Mean arterial pressure |
| MAPK: | Mitogen-activated protein kinase |
| MALAT1: | Metastasis-associated lung adenocarcinoma transcript 1 |
| MBP: | Myelin basic protein |
| MCAD: | Mitochondrial medium-chain acyl-CoA dehydrogenase |
| MCP-1: | Monocyte chemoattractant protein-1 |
| MDA: | Malondialdehyde |
| ME: | Malic enzyme |
| MI: | Myocardial infarction |
| MMPs: | Matrix metalloproteinases |
| mTOR: | Mammalian target of rapamycin |
| MUFA: | Monounsaturated fatty acids |
| NEFAs: | Nonesterifed fatty acids |
| NF-κB: | Nuclear factor-κB |
| NLRP3: | NOD-like receptor family pyrin domain containing 3 |
| NO: | Nitric oxide |
| NOX: | NADPH oxidase |
| NPT: | Non-protein thiol |
| NQO-1: | NADPH quinone oxidoreductase |
| Nrf2: | Nuclear factor erythroid 2-related factor 2 |
| NRF-1: | Nuclear respiratory factor-1 |
| NRK-49F: | Rat renal interstitial fibroblasts |
| O1: | Immature OL |
| O4: | Pre-OL |
| OAT1: | Organic anion transporter 1 |
| OCN: | Osteocalcin |
| OCTN2: | Organic cation transporter 2 |
| OP: | Oligodendrocyte progenitor |
| oxLDL: | Oxidized low-density lipoprotein |
| PAI-1: | Plasminogen activator inhibitor |
| PBEF: | Pre-B cell colony enhancing factor |
| PCNA: | Proliferating cell nuclear antigen |
| PcSK9: | Proprotein convertase subtilisin/kexin type 9 |
| PDE/cAMP: | Phosphodiesterase/Cyclic adenosine monophosphate |
| PDGF-β: | Platelet-derived growth factor subunit B |
| PDK-4: | Pyruvate dehydrogenase kinase-4 |
| PERK: | Prospective evaluation of radial keratotomy |
| PGC-1α: | Peroxisome proliferator-activated receptor gamma coactivator 1-alpha |
| PGE2: | Prostaglandin E2 |
| PI3K: | Phosphatidylinositol-3 kinase |
| PKA: | Protein kinase A |
| Plin2: | Perilipin 2 |
| Pnpla2: | Adipose triglyceride lipase |
| PON-1/2/3: | Paraoxonase-1/2/3 |
| PPARα: | Peroxisome proliferator-activated receptor alpha |
| PPARγ: | Peroxisome proliferator-activated receptor gamma |
| PPARδ: | Peroxisome proliferator-activated receptor delta |
| PP2C-α: | Protein phosphatase 2C-α |
| PPRE: | Peroxisome proliferator response elements |
| Prdm16: | PR domain containing 16 |
| PT: | Protein thiol |
| P-TEFb: | Positive transcription elongation factor b |
| PTEN: | Phosphatase and tensin homolog |
| PUFA: | Polyunsaturated fatty acids |
| QUICKI: | Quantitative insulin sensitivity check index |
| RAGE: | Advanced glycosylation end products receptor |
| rIR: | Insulin receptor |
| ROS: | Reactive oxygen species |
| RST: | Renal-specific transporter |
| RUNX2: | Runt-related transcription factor 2 |
| RXR: | Retinoid X receptor |
| SAH: | Subarachnoid hemorrhage |
| SAP: | Systolic arterial pressure |
| SAT: | Subcutaneous adipose tissue |
| SBP: | Systolic blood pressure |
| SCD-1: | Stearoyl CoA desaturase-1 |
| Scr: | Serum creatinine |
| SFA: | Saturated fatty acids |
| SIRT1: | NAD-dependent protein deacetylase |
| S6K1: | Ribosomal S6 kinase 1 |
| α-SKA: | α-Skeletal actin |
| SLU: | Selective lipid uptake |
| α-SMA: | Alpha smooth muscle actin |
| SOCS3: | Suppressors of cytokine signaling 3 |
| SOD: | Superoxide anion dismutase |
| SR-A: | Scavenger receptor-A |
| SR-BI: | Scavenger receptor class B type I |
| SQI: | Subcutaneous injection |
| SREBP-1: | Sterol regulatory element-binding protein-1 |
| STAT3: | Signal transducer and activator of transcription 3 |
| Surf: | Surfeit locus protein |
| sVCAM-1: | Soluble vascular cell adhesion molecule-1 |
| TAG: | Triacylglycerol |
| T-AOC: | Total antioxidative capability |
| TBARS: | Thiobarbituric acid reactive substances |
| 3T3-L1 cells: | Mouse preadipocytes |
| TC: | Total cholesterol |
| TERT: | Antitelomerase reverse transcriptase |
| Tfam: | Transcription factor A |
| TG: | Triglyceride |
| TGF: | Transforming growth factor |
| TIMP-2: | Tissue inhibitor of metalloproteinase |
| TH: | Tyrosine hydroxylase |
| TNF-α: | Tumor necrosis factor alpha |
| Tmem26: | Transmembrane protein 26 |
| TPP1: | Tripeptidyl-peptidase 1 |
| TRAF2: | TNF receptor associated Factor 2 |
| Treg: | Regulatory T cells |
| TR-FRET: | Time-resolved fluorescence resonance energy transfer |
| TXNIP: | Thioredoxin interacting protein |
| UA: | Uric acid |
| UCP 1/2: | Uncoupling protein 1/2 |
| VAT: | Visceral adipose tissue |
| VLDL-cholesterol: | Very low-density lipoprotein-cholesterol |
| VSMCs: | Vascular smooth muscle cells |
| XDH: | Xanthine dehydrogenase |
| XO: | Xanthine oxidase |
| XOR: | Xanthine oxidoreductase |
| ZO-1: | Zonula occludens-1. |
Data Availability
There is no raw data associated with this article.
Conflicts of Interest
The authors have no conflicts of interest.