Resources

PPAR Signaling Pathway

Figure 1. PPAR signaling pathway.

PPAR signaling pathway overview

Like other nuclear receptor super families, PPAR is essentially a class of ligand-dependent transcriptional regulators, all of which are single subunits with an N-terminal region (A/B region), a highly conserved DNA-binding region (C region), and the hormone binding region of the C-terminus (region E). It includes three subtypes: PPARα, PPAR β/δ and PPARγ. The classical pathway by which PPARs regulate gene transcription involves its heterodimerization with RXR through initial activation of binding to a ligand. The PPAR-RXR dimer binds to a DNA response element (PPRE) located in the promoter or intragenic region. At the same time, the nuclear receptor coactivator (co-activator) synergizes with PPAR-RXR and complements and stabilizes the active transcriptional complex. Upon activation of PPARs and ligands, a heterodimer is formed with the retinoid X receptor (RXR), and the formed PPARγ/RXR heterodimer binds to the PPAR response element (PPRE) upstream of the target gene promoter, and finally regulates the transcription of the target gene. The ligand is a fat-soluble molecule, and after binding to the ligand, the receptor mainly produces a biological effect by regulating the expression of the target gene. The binding of PPARs to their respective ligands causes a change in their conformation, promoting or inhibiting the expression of the target gene. Unmatched PPARβ binds to co-repressors such as SMRT, SHARP, NCo and HDACs to inhibit genes. In this inactive state, PPARβ inhibits several PPARα and PPARγ target genes by competing for PPRE. Therefore, PPARβ exists as a transcriptional inhibitor of intrinsic properties. In contrast, the activated PPARβ releases a co-inhibitor that inhibits other genes that do not contain PPRE. This physiologically relevant mode of action needs to continue to be studied in vivo. The initial activation state of PPARs is caused by peroxisome proliferators. PPAR2α is highly expressed in the liver, skeletal muscle, kidney, heart and blood vessel walls, and is relatively low in fat and cartilage. PPARβ is widely expressed in vivo and is expressed at relatively high levels in the brain, stomach, and colon. PPARγ is an important cell differentiation transcription factor expressed in mammalian adipose tissue, vascular smooth muscle tissue, and myocardial tissue.

PPAR family

PPARA is a member of the receptor-activated nuclear transcription factor superfamily, including PPARα, PPAR β/δ, PPARγ, a family of important transcriptional factors that regulate metabolic balance, sugar, lipid and energy metabolism, and insulin sensitivity in humans. In vivo, there are four isoforms, PPAR-γ mRNA, PPAR-γ1, PPAR-γ2, PPAR-γ3 and PPAR-γ4. PPAR-γ1, PPAR-γ3, and PPAR-γ4 mRNA produce the same gene product PPAR-γ. PPAR-γ2 mRNA produces a protein of 28 amino acids at the NH2 end. The four PPAR-γ mRNA isoforms are not identically expressed in different tissues. PPAR-γ1 is expressed in different degrees in all tissues, and PPAR-γ3 is expressed in adipose tissue, colon, macrophages, and T lymphocytes, while the expression of PPAR-g4 is not clear. The PPAR-γ gene is located on chromosome 3p25. The non-ligand-dependent transcriptional activation domain (A/B region) is also known as activation function-1 (6), and phosphorylation of this region may result in inhibition of PPAR-γ transcriptional activation; 2C region is a region that binds to the promoter and the target gene; The C-terminal E/F domain or activation function-2 (activation function -2) is a ligand binding region (LBD) that forms a dimer with the ligand. Both PPAR-g and other nuclear receptor super families must be combined with the corresponding ligand to be activated. Once activated by binding to the ligand, PPARγ binds to the retinoid X receptor (RXR) to form a heterodimer, and then recruits a series of synergistic factors. The promoter region binds to the heterodimer and regulates transduction; PPAR-γ can also directly activate specific genes, such as CD 36; PPAR-γ can also be transgenic by non-DNA binding-dependent models. PPARα regulates lipid metabolism by regulating genes involved in fatty acid metabolism, including β oxidation of fatty acids and transportation processes, thereby reducing TG, free fatty acid and VLDL synthesis. PPARβ regulates gene expression involved in cell energy metabolism, lipid and glucose utilization, and maintains body energy balance. PPAR-γ regulates the transcription of multiple genes involved in the differentiation of adipose precursor cells, regulates insulin-mediated uptake of glucose by peripheral tissues, and increases insulin sensitivity. Research on PPAR-α is still relatively rare.

PPAR signaling pathway

  1. PPAR signaling pathway Cascade

    The PPARγ-related signal transduction pathways include the following: 1. PPARγ activation pathway. PPARγ binds directly to the ligand; ligand regulates PPAR-g phosphorylation status and participates in the regulation of MARK and PI3K activity; 2. PPARγ activation and regulation of target gene transcriptional expression pathways, including ligand-activated PPAR-γ, activation of PPAR-γ interaction with PPRE, involvement in lipid metabolism, cell proliferation, differentiation, apoptosis etc. By regulating biological effects such as gene transcription and translation, 3PPAR-γ affects other transcription factors and signaling pathways, such as competitive inhibition of NF-kB, activator protein-1 (AP-1), JAK-STAT and other pathways in the inflammatory response. PPAR-α is most expressed in tissues that rapidly oxidize fatty acids. In rodents, the highest levels of PPAR-alpha mRNA expression were found in liver and brown adipose tissue, followed by heart and kidney. Lower PPARα expression levels were found in the small intestine, large intestine, skeletal muscle, and adrenal gland. Human PPARα appears to be more evenly expressed in different tissues and higher in the liver, intestine, heart and kidney. PPARα has four functional domains, the transcriptional activation regulatory region (A/B region), the DNA binding region (C region), the variable hinge region (D region), and the ligand binding region (E/F region). The ligand of PPARα includes saturated, unsaturated fatty acids such as arachidonic acid, leukotriene B4, and fibrate lipid-lowering drugs. Among them, polyunsaturated fatty acids have the highest affinity with PPARα. PPARα is a reaction element that is activated by a ligand to form a heterodimer with a nuclear receptor retinoid X receptor (RXR) or a glucocorticoid, and a peroxisome proliferator that binds to a promoter region of a target gene. PPRE regulates the expression of target genes and exerts biological functions. PPARα can be activated by binding to ligands, regulating liver lipid synthesis, lipid transport, fatty acid oxygen and by regulating the transcription level of liver lipid metabolism-related genes. Ketone body formation and cholesterol metabolism play an important role in lipid metabolism, such as fatty acid binding protein (Fabps), fatty acid binding protein (aP2), and apolipoprotein (Apo-A1), which is also regulated by PPARα at the transcriptional level. Fabps has a high affinity for fatty acids, and participates in the absorption and transport of triglycerides, phospholipids and cholesterol, and the transport of long-chain fatty acids in cells by increasing the intracellular diffusion of fatty acids. Experiments have shown that agonists of PPARα can induce the expression of Fabps, resulting in increased Fabps synthesis, and promoting lipid absorption and transport. CYP450A is involved in the oxidation and utilization of fatty acids, and the long-chain fatty acid β-oxidation key enzyme carnitine-palmitoyl transferase 1 (Cpt-1), as well as the rate-limiting enzyme LPL that scavenges triglycerides in plasma lipoproteins, which is also a target of PPARα gene. PPARα also promotes fatty acid ω-oxygen by directly enhancing CYP4A expression. In recent years, a variety of natural PPARα agonists have been reported to activate PPARα to enhance fatty acid oxidation and treat fatty liver disease. The expression level of PPARα and its signaling pathway-related genes are disordered, which may cause a decrease in the transcription level of a series of genes involved in lipid metabolism, which leads to a decrease in fatty acid oxidation and a disorder in lipoprotein anabolism, resulting in lipid deposition in the liver, thereby causing liver injury. PPARα is involved in the regulation of ketone body formation while stimulating fatty acid oxidation in the liver. Hydroxy methylglutaryl acid CoA (HMG-CoA) synthase is the rate-limiting enzyme produced by ketone bodies. PPRE was found in the upstream promoter region of the HMG-CoA synthase gene in pigs and rats, indicating that PPARα can participate in the formation of ketone bodies by regulating the gene expression of HMG-CoA synthetase. Hepatic fatty acids are oxidized to acetyl-CoA by HMG-CoA synthetase, and then ketone bodies such as acetoacetate and β-hydroxybutyric acid are synthesized under the control of PPARα. PPARα also interacts with HMG-CoA reductase to increase the transcriptional activity of HMG-CoA reductase. PPARα is involved in many aspects of cholesterol metabolism regulation. 7α-hydroxylase, a sterol 12α-hydroxylase that catalyzes the metabolism of bile acids, is regulated by PPARα. PPARα also reduces low-density lipoprotein levels, increases HDL production, and hydrolyzes triglyceride-rich very low-density lipoproteins, affecting the transport of cholesterol in plasma and promoting liver metabolism of cholesterol. PPARα is also involved in the regulation of glucose metabolism. Deng reported that the expression of PPARα was significantly decreased in the liver of diabetic mice, and serum transaminase increased in 46% of mice. Clinically, it has also been confirmed that the expression of PPARα is decreased in diabetic patients, and an agonist of PPARα such as fenofibrate is used to treat diabetic lipid metabolism disorder. Although the specific mechanism of the effect of PPARα expression on diabetes is unclear, the experimental results indicate that PPARα plays an important role in the regulation of glucose metabolism.

  2. Regulation

    Due to the complexity of the PPAR signaling pathway, many proteins and factors can effectively regulate this signaling pathway. For example, in the inflammatory response, PPARγ can inhibit the inflammatory response through competitive inhibition of inflammatory signaling pathways and inflammatory mediators. The roles of related inflammatory signaling pathways include 1JAK-STAT; 2NF-κB; nuclear factor of activated T cell (NFAT); 4AP-1,and so on. JAK-STAT signal transduction pathway starts from JAK-2 activation after phosphorylation, and the activated JAK-2 reactivates JAK-1, and then STAT1 and STAT2 are activated by JAK-1, respectively. The former forms a homodimer and is required to cooperate with the coactivator CREB binding protein (CBP). Or p300 binds to exert its biological activity in the nucleus. When PPAR-γ binds to and activates with a ligand, PPARγRXR heterodimer competes and recruits a limited number of synergistic activators CBP and p300, resulting in a decrease in the number of synergistic activators capable of binding to STAT1, thereby inhibiting STAT1. It activates and blocks the production of STAT-associated pro-inflammatory cytokines (IL-6, IL-1, TNF-α). In the inflammatory response, INF-γ is closely related to PPARγ-related signals. It has been reported that IFN-γ stimulation induces and activates the JAK/STAT pathway, resulting in increased production of TNF-α and IL-1β. In rat macrophages and human DLD1 cells, IFN-γ enhances the expression of nitric oxide synthase (iNOS) and aggravates the inflammatory response by activating JAK2 and the downstream STAT1 and STAT3. In the above reaction, iNOS induces over-expression of NO under endotoxin stimulation, which directly damages the cellular DNA and causes it to rupture, resulting in apoptosis. PPAR-γ blocks the pro-inflammatory action of IFN-γ by inhibiting the JAK-STAT pathway.

  3. Relationship with disease

    Due to the breadth and complexity of the PPAR signaling pathway, this pathway is known to be associated with many diseases, including the following:

    Liver cancer

    Hepatocellular carcinoma peroxisome proliferator (PP) is a non-hereditary carcinogen that can proliferate peroxisomes in the liver, leading to the proliferation of hepatocytes and thus the development of liver cancer. PPARα is a major regulator of PP activity in the liver and plays a central role in the development of liver cancer caused by PP. PPARα agonists can cause abnormal expression of enzymes that modulate cell proliferation activity in rodents, with varying degrees of proliferation in the liver. Kurokawa et al. found that the expression of PPARα mRNA and target gene mRNA was elevated in liver cancer tissues. However, it has been reported that PP does not cause liver cancer in humans. It may be due to the fact that the expression of PPARα in human liver tissue is significantly lower than that in rodents. Humans react differently to rodents in response to PP. The exact mechanism of PPARα in the development of liver cancer remains to be further studied.

    Fatty liver disease

    PPAPα regulates the expression of lipid metabolism-related genes in the liver and plays an important role in liver lipid absorption, transport, and fatty acid oxidation. The expression of PPAR alpha is inhibited and the expression of the downstream target gene of PPAR alpha related to fatty acid synthesis, lipid transport, fatty acid oxidation and cholesterol metabolism in the PPAR alpha signaling pathway is disorganized. The transcriptional level of protein and enzyme genes related to fatty acid metabolism in the liver, the use of lipid in the liver and the oxygen of fatty acids in the liver is reduced. It causes the occurrence and development of fatty liver disease by reducing the oxidation of fatty acids in the liver, and reducing the self-removal of triglycerides and the presence of fatty deposits and inflammatory reactions in the liver cells.

References:

  1. Wilbanks M S, Gust K A, Atwa S, et al. Validation of a genomics-based hypothetical adverse outcome pathway: 2,4-dinitrotoluene perturbs PPAR signaling thus impairing energy metabolism and exercise endurance. Toxicological Sciences. 2014, 141(1):44-58.
  2. Wang S, Awad K S, Elinoff J M, et al. G Protein-coupled Receptor 40 (GPR40) and Peroxisome Proliferator-activated Receptor γ (PPARγ). Journal of Biological Chemistry. 2015, 290(32):19544-19557.
  3. Huang L, Cheng Y, Huang K, et al. Ameliorative effect of Sedum sarmentosum Bunge extract on Tilapia fatty liver via the PPAR and P53 signaling pathway. Scientific Reports. 2018, 8(1).
  4. Wagner K D, Wagner N. Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) acts as regulator of metabolism linked to multiple cellular functions. Pharmacol Ther. 2010, 125(3):423-435.

Return to Resources

Inquiry Basket