Alternative titles; symbols
HGNC Approved Gene Symbol: PPARD
Cytogenetic location: 6p21.31 Genomic coordinates (GRCh38): 6:35,342,558-35,428,178 (from NCBI)
Peroxisome proliferator-activated receptors (PPARs), such as PPARD, are so named because they bind chemicals that induce proliferation of peroxisomes, organelles that contribute to the oxidation of fatty acids. As members of the nuclear receptor superfamily, PPARs act by controlling networks of target genes. PPARs can be activated by both dietary fatty acids and their metabolic derivatives in the body, and thus serve as lipid sensors that, when activated, can markedly redirect metabolism. Whereas PPARA (170998) and PPARG (601487) are predominantly expressed in liver and adipose tissue, respectively, PPARD is abundantly expressed throughout the body, but at only low levels in liver. Consistent with their expression profiles, the PPARs each have unique functions in the regulation of energy metabolism. PPARD is a powerful regulator of fatty acid catabolism and energy homeostasis, with a broad role in fat burning (review by Evans et al., 2004).
By cDNA cloning from a human osteosarcoma cell library, Schmidt et al. (1992) identified a novel member of PPAR superfamily, PPARD, which they called NUCI (or NUC1), that is predicted to encode a 441-amino acid protein. Northern blot analysis with rat PPARD RNA showed highest expression in heart, kidney, and lung.
Xing et al. (1995) cloned the rat Ppard gene and demonstrated that it contains a 14 CGG triplet repeat in the 5-prime untranslated region.
Yoshikawa et al. (1996) mapped the PPARD gene to human chromosome 6 by a PCR-based analysis of a somatic cell hybrid panel. By fluorescence in situ hybridization analysis, they narrowed the assignment to chromosome 6p21.2-p21.1.
Schmidt et al. (1992) showed that the PPARD protein was experimentally activated by arachidonic and oleic acids as well as the peroxisome proliferator activator WY14643.
PPAR-alpha and PPAR-gamma were shown by Green and Wahli (1994) to be activated by a variety of fatty acids and hypolipidemic compounds that induce peroxisome proliferation in the liver. Human PPARD and mouse Ppard are known to be activated by C18 unsaturated fatty acids (Schmidt et al., 1992).
He et al. (1999) identified PPARD as a target of APC (611731) through the analysis of global gene expression profiles in human colorectal cancer (CRC; 114500) cells using SAGE (serial analysis of gene expression). PPARD expression was elevated in CRCs and repressed by APC in CRC cells. This repression was mediated by beta-catenin (116806)/TCF4 (TCF7L2; 602228)-responsive elements in the PPARD promoter. The ability of PPARs to bind eicosanoids suggested that PPARD might be a target of chemopreventive nonsteroidal antiinflammatory drugs (NSAIDs). Reporters containing PPARD-responsive elements were repressed by the NSAID sulindac. Furthermore, sulindac was able to disrupt the ability of PPARD to bind its recognition sequences. These findings suggested that NSAIDs inhibit tumorigenesis through inhibition of PPARD, the gene for which is normally regulated by APC.
To evaluate the role of PPARD in colorectal carcinogenesis, Park et al. (2001) created a Ppard-null cell line by targeted homologous recombination. When inoculated as xenografts in nude mice, Ppard -/- cells exhibited a decreased ability to form tumors compared with Ppard +/- and wildtype controls. These data suggested that suppression of PPARD expression contributes to the growth-inhibitory effects of the APC tumor suppressor.
Kersten et al. (2000) reviewed the roles of PPARs in health and disease.
Shi et al. (2002) demonstrated that PPARD functions as a potent transcriptional repressor with 2 interrelated properties. First, on its own it is able to repress basal transcription. Second, coexpression of PPARD with PPARA or PPARG leads to dramatic inhibition of PPAR target gene expression. Consequently, PPARD is able to block the expression of acyl-CoA oxidase and PPARG-mediated adipogenesis in cultured cells. This anti-lipid oxidation and anti-adipogenic feature of PPARD may represent a useful strategy to gate the activities of PPARA and PPARG and could be exploited as a potential therapeutic approach in the control of obesity and related type II diabetes. The results suggested that PPARD functions as a gateway receptor whose relative levels of expression can be used to modulate PPARA and PPARG activity.
Di-Poi et al. (2002) showed that PPARB modulates AKT1 (164730) activation via transcriptional upregulation of ILK (602366) and PDPK1 (605213), revealing a mechanism for the control of AKT1 signaling. The resulting higher AKT1 activity led to increased keratinocyte survival following growth factor deprivation or anoikis. PPARB also potentiated NFKB (164011) activity and MMP9 (120361) production, which could regulate keratinocyte migration. Together, these results provided a molecular mechanism by which PPARB protects keratinocytes against apoptosis and may contribute to the process of skin wound closure.
Lee et al. (2003) found that PPARD controls the inflammatory status of foam cells in atherosclerotic lesions. Deletion of PPARD from foam cells increased the availability of inflammatory suppressors, which in turn reduced the atherosclerotic lesion area by more than 50%. Lee et al. (2003) proposed an unconventional ligand-dependent transcriptional pathway in which PPARD controls an inflammatory switch through its association and dissociation with transcriptional repressors.
Because the PPARD and PPARGC1A (604517) genes are determinants of mitochondrial function in animals and in vitro, Stefan et al. (2007) investigated whether SNPs in these genes modulate the effect of exercise training on change in aerobic physical fitness and insulin sensitivity and whether they affect mitochondrial function in human myotubes in vitro. After 9 months of lifestyle intervention (Tuebingen Lifestyle Intervention Program), the minor G allele of rs2267668 in PPARD and the gly482-to-ser polymorphism in PPARGC1A were independently associated with less increase in individual anaerobic threshold (n = 136, p = 0.002 and p = 0.005), a precise measurement of aerobic physical fitness. Moreover, individual anaerobic threshold (+11%) and insulin sensitivity (+4%) increased less in subjects carrying the minor alleles at both SNPs (X/G-X/ser), compared with homozygous carriers of the major alleles (A/A-gly/gly, +120% and +40%; p less than 0.0001 and p = 0.015), suggesting an additive effect of the SNPs. Low skeletal muscle mitochondrial function in vitro was detected in young carriers of the G allele of rs2267668 in PPARD (n = 19, p = 0.02).
Peters et al. (2000) constructed Ppard null mice by targeted disruption of the ligand binding domain of Ppard, which they called PPAR-beta. Homozygous Ppard-null term fetuses were smaller than controls, and this phenotype persisted postnatally. Peters et al. (2000) reported smaller gonadal adipose stores and higher constitutive mRNA levels of CD36 (173510) in Ppard null mice than in controls. Myelination of the corpus callosum was altered in the brain of Ppard null mice. Peters et al. (2000) concluded that Ppard plays a significant role in development, myelination of the corpus callosum, lipid metabolism, and epidermal cell proliferation.
Using RNase protection and in situ hybridization, Michalik et al. (2001) showed that the alpha, delta (which they called beta), and gamma isotypes of Ppar are expressed in the mouse epidermis during fetal development and that they disappear progressively from the interfollicular epithelium after birth. They detected significant levels of reexpression of Ppard in the adult epidermis after various stimuli, resulting in keratinocyte proliferation and differentiation such as tetradecanoylphorbol acetate topical application, hair plucking, or skin wound healing. Michalik et al. (2001) generated Ppard mutant mice and observed incomplete but very high penetrance of a lethal phenotype in the Ppard null mice which they reported as similar to the phenotype described by Peters et al. (2000). By studying skin wound healing in Ppard heterozygous mutant mice, Michalik et al. (2001) demonstrated that Ppard is important for the rapid epithelialization of a skin wound and plays a specific role in this process distinct from that of Ppara. They observed an increased keratinocyte proliferative response in Ppard heterozygous mutant mice and a delay during the wound healing process. Michalik et al. (2001) concluded that Ppard plays a role in adult mouse epidermal repair and is implicated in the control of keratinocyte proliferation.
Gupta et al. (2004) treated Apc-min mice, which are predisposed to intestinal polyposis, with a selective synthetic agonist of PPARD. The treated mice showed a significant increase in the number and particularly the size of intestinal polyps, with a 5-fold increase in the number of polyps larger than 2 mm. The results implicated PPARD in the regulation of intestinal adenoma growth.
Harman et al. (2004) examined the role of PPARD in colon carcinogenesis using Ppard null mice. In both a Min mutant and a chemically induced (azoxymethane) model, colon polyp formation was significantly greater in mice nullizygous for Ppard. Harman et al. (2004) concluded that PPARD attenuates colon carcinogenesis.
Miura et al. (2009) found that GW501516, a PPARD agonist, stimulated utrophin A (UTRN; 128240) mRNA levels in muscle cells from the Duchenne muscular dystrophy (DMD; 310200) mdx mouse, through an element in the utrophin A promoter. Expression of PPARD was greater in skeletal muscles of mdx versus wildtype mice. Over a 4-week trial, treatment increased the percentage of muscle fibers expressing slower myosin heavy chain isoforms and stimulated utrophin A mRNA levels, leading to its increased expression at the sarcolemma. Expression of alpha-1-syntrophin (SNTA1; 601017) and beta-dystroglycan (DAG1; 128239) was also restored to the sarcolemma. The mdx sarcolemmal integrity was improved, and treatment also conferred protection against eccentric contraction-induced damage of mdx skeletal muscles.
Metabolic Studies
Using combinatorial chemistry and structure-based drug design, Oliver et al. (2001) generated a subtype-selective PPARD agonist, GW501516, which increased cholesterol efflux from cells, in part by increasing expression of the reverse cholesterol transporter ATP-binding cassette A1 (ABCA1; 600046). Treatment of middle-aged insulin-resistant obese rhesus monkeys with GW501516 caused a dramatic dose-dependent increase in serum high density lipoprotein (HDL) cholesterol, while lowering the levels of low density lipoprotein (LDL), fasting triglycerides, and fasting insulin.
In transgenic mice with targeted activation of Ppard in adipose tissue, Wang et al. (2003) observed decreased lipid accumulation in both adipose tissue and serum, consistent with fatty acid consumption. The transgenic animals were resistant to both high-fat diet-induced and genetically predisposed (db/db; 601007) obesity; treatment of db/db mice with the Ppard agonist GW501516 also reversed obesity. The most striking changes were found in metabolically active brown fat, and Northern blot analysis showed increased expression of genes involved in fatty acid catabolism, including hydrolysis, oxidation, and uncoupling of oxidative phosphorylation. In vitro studies in adipocytes and skeletal myocytes showed similar results. There was an association between Ppard and Pgc1a (604517), suggesting that thermogenic effects of Pgc1a are mediated through Ppard.
Tanaka et al. (2003) found that the Ppard agonist GW501516 increased fatty acid oxidation in mouse skeletal muscle by inducing activation of genes involved in fatty acid transport, beta-oxidation, and mitochondrial respiration. Similar results were achieved with rat myocytes in vitro. Administration of the agonist to mice fed a high-fat diet and to genetically obese ob/ob (164160) mice ameliorated obesity, diabetes, and insulin resistance.
Wang et al. (2004) generated transgenic mice with targeted expression and activation of Ppard in skeletal muscle. Compared to wildtype mice, the transgenic mice showed an average 2-fold increase in type I (slow oxidative) mitochondria-rich skeletal muscle fibers, as measured by mRNA, DNA, and protein expression of myoglobin and mitochondrial components. Wildtype mice became obese on a high-fat diet, whereas transgenic mice maintained a normal body weight and fat mass composition and showed increased muscle oxidative capacity. Finally, transgenic mice showed a 67% and 92% increase in running time and distance, respectively, on a treadmill, indicating increased endurance strength. Wang et al. (2004) concluded that genetic manipulation and activation of Ppard induces a switch to type I skeletal muscle fibers, which confer resistance to obesity and result in increased physical endurance.
Cheng et al. (2004) demonstrated that cre-loxP-mediated cardiomyocyte-restricted deletion of Ppard in mice downregulated constitutive expression of key fatty acid oxidation genes and decreased basal myocardial fatty acid oxidation. The conditionally deleted mice had cardiac dysfunction, progressive myocardial lipid accumulation, cardiac hypertrophy, and congestive heart failure with reduced survival. Cheng et al. (2004) concluded that chronic myocardial PPARD deficiency leads to lipotoxic cardiomyopathy, and that PPARD is a crucial determinant of constitutive myocardial fatty acid oxidation and is necessary to maintain energy balance and normal cardiac function.
Lee et al. (2006) showed that Ppard-null mice were metabolically less active and glucose intolerant, whereas receptor activation in db/db mice improved insulin sensitivity. Euglycemic-hyperinsulinemic-clamp experiments demonstrated that a Ppard-specific agonist suppressed hepatic glucose output, increased glucose disposal, and inhibited free fatty acid release from adipocytes. Gene array and functional analyses suggested that Ppard ameliorated hyperglycemia by increasing glucose flux through the pentose phosphate pathway and enhancing fatty acid synthesis.
Using FACS analysis, Mukundan et al. (2009) showed that Ppard, but not Ppara or Pparg, was upregulated in mouse macrophages after apoptotic cell feeding. Ppard -/- macrophages exhibited downregulated expression of opsonin genes, such as C1qa (120550) and C1qb (120570). Female Ppard -/- mice developed a systemic lupus erythematosus (SLE; 152700)-like autoimmune disease. Mukundan et al. (2009) proposed that Ppard -/- mice with defective clearance of apoptotic cells, lower opsonin expression, and increased macrophage inflammatory responses are a good model system for studying SLE.
In mice, Liu et al. (2013) identified a Ppard-dependent de novo lipogenic pathway in the liver that modulates fat use by muscle via a circulating lipid. The nuclear receptor Ppard controls diurnal expression of lipogenic genes in the dark/feeding cycle. Liver-specific Ppard activation increases, whereas hepatocyte-Ppard deletion reduces, muscle fatty acid uptake. Unbiased metabolite profiling identified phosphatidylcholine (PC) 18:0/18:1 as a serum lipid regulated by diurnal hepatic Ppard activity. PC(18:0/18:1) reduces postprandial lipid levels and increases fatty acid use through muscle Ppara (170998). High-fat feeding diminished rhythmic production of PC(18:0/18:1), whereas PC(18:0/18:1) administration in db/db (601007) mice improved metabolic homeostasis. Liu et al. (2013) concluded that their findings revealed an integrated regulatory circuit coupling lipid synthesis in the liver to energy use in muscle by coordinating the activity of 2 closely related nuclear receptors. The data implicated alterations in diurnal hepatic PPARD-PC(18:0/18:1) signaling in metabolic disorders, including obesity.
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