Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Peroxisome Proliferator-Activated Receptor Alpha (PPAR-Alpha)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101552


Historical Background

The first peroxisome proliferator-activated receptor or PPAR was discovered as hormone receptor that was activated by rodent hepatocarcinogens that induced peroxisome proliferation (Issemann and Green 1990). PPARs are now known as a group of transcription factors that are able to induce transcription of genes that contain PPAR responsive elements (PPREs). The PPAR family of transcription factors consist of PPARα, β of δ (or nuclear receptor subfamily 1, group C, member 2 (NR1C2)), and γ (or nuclear receptor subfamily 1, group C, member 3 NR1C3). Here the focus is on PPARα that, in humans, is mainly expressed in tissue with high fatty acid oxidation like liver, muscle, heart, and kidney though also many other tissues do show expression of this family member. PPARα is thought to be a master regulator of lipid metabolism. It does so by acting as a “fat” sensor that modulates fatty acid metabolism in response to diet. The transcription factor is therefore also highly linked to glucose metabolism and metabolism related diseases such as the metabolic syndrome, cardiovascular disease, insulin resistance, diabetes, and is recently also linked to cancer. The general protein structure is shared among all PPARs (Fig. 1a). They all have a ligand-binding domain (LBD) where they can bind to for instance the fatty acids or fibrates that act as ligands. Furthermore, they have a DNA-binding domain (DBD) that is comprised of two zinc fingers through which the transcription factor can bind to the DNA. This DBD binds specifically to the PPRE consensus site which is slightly different depending on the PPAR (Bragt and Popeijus 2008) (Fig. 1b). The gene of human PPARα (reference sequence number: NC_000022.11) is located at chromosome 22 position q13.31 and spans approximately 93 kbp while the coding sequence is just 1,407 bp long (including stop codon) resulting in a 468 amino acid long 52 kb protein. Upon PPARα activation in human liver, Janssen et al. investigated the expression profile of the genes involved (Janssen et al. 2015). They showed that classic PPARα-responsive genes are transcribed like CPT1a PDK4, PLIN2, VLDLR, and ANGPTL4. Furthermore, PPARα was found to be involved in the upregulation of many other genes involved in lipid and xenobiotic metabolism and in the downregulation of many genes involved in inflammation-related genes including chemokines, interferon-gamma-induced genes, and others (Janssen et al. 2015).
Peroxisome Proliferator-Activated Receptor Alpha (PPAR-Alpha), Fig. 1

General structure of PPARs (a) and their preferred consensus binding sites (b) (Adapted in modified form with permission from Bragt and Popeijus (2008))

Regulation of PPARα

mRNA of full length PPARα comprises of six exons and an alternative spliced mRNA that lacks the sixth exon thereby introducing a premature stop codon. This results in a smaller, truncated PPARα variant that misses the LBD (Fig. 2c). This PPARα splice variant is therefore unable to activate PPARα-mediated transcription and acts as negative regulator of PPARα transcription (Fig. 2b). This is because it is able to dimerize with the PPARα dimeric partners and as such prevent them to bind to the full length splice variant. And upon binding inhibits the ability of the heterodimer to act as active transcription factor. However, current research indicates that the role of the truncated form of PPARα may also elicit specific functions of its own. It seemed to regulate, independently of the full length PPARα, genes involved in proliferation and proinflammation using splice variant specific overexpression and RNAi (Thomas et al. 2015). Furthermore, upon ligand binding there are two main mechanism that enable PPARα to transactivate genes, PPRE dependent through binding of PPARα with the retinoid X receptor (RXR) or PPRE independent by capturing other transcription factors and as such prevent them to transactivate (Fig. 1b). These mechanisms of transactivation and PPARα regulation are extensively reviewed by Pawlak, Lefebvre, and Staels and are suggested for further reading on the molecular mechanism of PPARα regulation (Pawlak et al. 2015).
Peroxisome Proliferator-Activated Receptor Alpha (PPAR-Alpha), Fig. 2

Normal transcriptional activity of PPARα and RXR (a). PPARα binding with other transcription factors is reported to inhibit their transcriptional activity (b). Truncated PPARα (PPARα tr.) inhibits transactivation as it cannot be activated by ligands probably due to heterodimerization with PPARα dimer partner RXR (c, right panel) though PPARα tr. may also have other transcriptional activities (c, left panel)

PPAR Agonist

Fatty acids are the natural ligands of the PPARs. Binding assays show that especially for polyunsaturated fatty acids (PUFAs). In addition, also monounsaturated fatty acids (MUFAs) bind readily to PPARα. The most potent MUFAs are (C18:1, n-12), oleic (C18:1, n-9), and elaidic (C18:1, n-9-trans) acids though the PUFAs, docosahexaenoic acid (C22:6, n-3), eicosapentaenoic acid (C20:5, n-3), linolenic acid (C18:3, n-3), linoleic acid (C18:2, n-6), and arachidonic acid (C20:4, n-6) were slightly better in binding bases on a coactivator-dependent receptor ligand assay (CARLA) (Krey et al. 1997). In agreement with these results, fatty acids with 18–20 carbons and 3–5 double bonds appeared to be strong PPARα transactivators using a GAL4 fusing system (Mochizuki et al. 2006). Furthermore, medium-chain fatty acids like lauric acid (C12:0) were reported to induce PPARα dose dependently. As expected both longchain fatty acids EPA (20:5(n-3)), and DHA (C22:6(n-3)), were able to induce transactivation dose dependently at low dose range. However at higher concentrations they gradually, dose dependently, decreased and eventually even inhibited PPARα transactivation Popeijus et al. (2014) showed that for the fatty acids ranging from 8 carbons to 22 carbons including various degrees of desaturation that the transactivation depends on the specific fatty acid. Interestingly, palmitic acid (C16:0) and stearic acid (C18:0) were both found to be poor PPARα transactivators while their desaturated cousins palmitoleic acid (C16:1) and oleic acid (C18:1) both dose dependently increased PPARα (ranging from ±1–100 μM) (Popeijus et al. 2014). This implies that stearoyl Co-a desaturase (SCD) within the cell that introduces double bounds in saturated fatty acids can play indirectly a modulating role in PPARα transactivation. This is supported by ample evidence where SCDs are linked to metabolic disturbances (Popeijus et al. 2008). The human SCD is in turn also regulated by PPARα, showing that metabolism is tightly regulated (Pawlak et al. 2015). Beside the natural PPARα ligands, there are many other ligands including thiazolidinediones (TZDs) and fibrates (for instance gemfibrozil, fenofibrate, and ciprofibrate). Though the TZDs are no longer in use because of their negative side effects, increased risk for myocardial infarction, heart failure, and death, there is still discussion with regard to the certainty of these data (Bilandzic et al. 2016). Fibrates are currently widely used to treat metabolic disturbances such as primary hypertriglyceridemia or dyslipidemia. However, although fibrates are considered relatively safe, increasing data shows that careful decision making is in place whether or not to prescribe these drugs (Shipman et al. 2016).

PPARα and Metabolic Disease and NAFLD

As PPARα is known to play a crucial role in energy metabolism, it is also logic to postulate involvement of the transcription factor in metabolic diseases and nonalcoholic fatty liver disease (NAFLD). This is indeed so for PPARα and is already reviewed in several papers (Bragt and Popeijus 2008; Mansour 2014; Pawlak et al. 2015). Activation of PPARα has been shown to positively influence metabolic disturbances like improvement of the lipid profile in humans and improved cholesterol status. Currently, people are also successfully treated with fibrates to increase PPARα activity. Evidence for a positive effect of PPARα is still increasing. For instance, sustained PPARα activation in mice that are deficient of leptin (ob/ob mice) resulted in increase of fatty acid oxidation in the liver (Gao et al. 2015). However, also an increased liver cancer risk was observed, probably due to increased oxidative stress following increased fat burning. Interestingly, when PPARα was knocked out in these mice (PPARα(Δ)ob/ob), the obesity and liver steatosis became more severe due to decreased fat oxidation while there was no increase in liver tumor development. Yan et al. showed that PPARα activation by the agonist fenofibrate may enhance liver steatosis through increased expression of sterol regulatory element-binding protein 1c (SREBP-1c) and observed an increased liver triglyceride accumulation in mouse and human liver cells (Yan et al. 2014). However, they did not investigate whether these negative effects could be (partly) countered by increased fat oxidation. The effects of PPARα stimulation and increased risk of cancer is, in the light of metabolic disease treatment, a new variable that needs careful further investigation. Furthermore, the effect of increased SREBP-1c seemed not sufficient to counter the increased uptake of fatty acids in the liver, so that improving the lipid status in blood results in increased fattening of the liver. This might eventually result in increased nonalcoholic fatty liver disease disease (NAFLD), to which increased PPARα activity is also linked as reviewed by Ballestrio et al. and references herein (Ballestri et al. 2016).

PPARα and Inflammation

One of the important factors that induce and regulate inflammation is nuclear factor-kappa B (NF-κB). NF-κB is able to switch on cells to an inflammatory status. It does so by binding with coactivators and inducing the transcription of many inflammation-related genes. PPARα prevents this inflammatory action of NF-κB as it is able to bind to the same coactivators, thereby inhibiting NF-κB-induced gene transcription. For instance, the PPARα agonist WY-14643 has been shown to inhibit lipopolysaccharide (LPS)-induced inflammation in synovial fibroblasts from patients with osteoarthritis. They showed that NF-κB translocation followed by LPS induction was significantly reduced. In addition, inflammation-related gene expression of,for instance, proinflammatory cytokines, interleukin-6 (IL-6), IL-1β, tumor necrosis factor-α (TNF-α), and monocyte chemotactic protein-1 (MCP-1) was reduced too. Silencing of PPARα using RNAi reversed these effects of WY-14643 (Huang et al. 2016). This shows a typical example of the important role of PPARα within inflammation. The review by Agarwal, Yadav, and Chaturvedi also clearly describes that PPARs, including PPARα, play a strong role in the inflammatory response in neurodegenerative disorders (Agarwal et al. 2016).


PPARα has shown to be a main regulator of metabolism and therefore to be a valuable candidate to treat metabolic syndrome and related diseases. Currently, fibrates are in many cases important drugs used to counter the negative effects of the metabolic syndrome through the activation of PPARs. Furthermore, it is long known that fatty acids act as ligands for PPARα. It has been shown that the type, carbon chain length and saturation status of the fatty acid, and its dose determines the ability of the fatty acid to activate or even inhibit PPARα transactivation. Many studies show for instance that eating fatty fish and nuts are protective to cardiovascular disease. Interestingly, there are also other studies that do not see these protective effects. Although it is still difficult to properly assess, combining these data suggest that the mixture of fatty acids in the diet in combination with the amount eaten might be more important to study instead of investigating the separate compounds effects alone. Beside their role in metabolism, there is also ample evidence that links PPARα to the immune system, cancer, and cognitive disease. The involvement of PPARα within the immune system, cancer, and cognitive disease is also linked to cellular metabolism. Furthermore, PPARα potentially influences the vast amount of genes that contain a PPRE or genes that are prevented to be transcribed by the inhibitory role of PPARα following dimerization. However, to fully understand the role of PPARα within these diseases, more long-term studies are likely required as most current studies that determine the protective role of PPARα have a relatively short-term focus.

Furthermore, the truncated form of PPARα is studied in only a few occasions. The current view was that the truncated PPARα acted as a dominant negative form. Therefore, the balance between the full-length PPARα and the truncated PPARα was presumed to be of importance. Interestingly, the truncated form of PPARα seems to possess also regulatory functions of its own. As the evidence supporting this new role is just emerging, more research is needed to set light on a third new role of the truncated PPARα, adding even more complexity to the already highly interconnected protein family of the PPARs.

Taken together, PPARα is an important player within human metabolism, growth, and development that still has many yet unknown secrets.


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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Human BiologyMaastricht UniversityMaastrichtThe Netherlands