Alternative titles; symbols
HGNC Approved Gene Symbol: PPARA
Cytogenetic location: 22q13.31 Genomic coordinates (GRCh38): 22:46,150,526-46,243,756 (from NCBI)
Peroxisome proliferators are a diverse group of chemicals which includes hypolipidemic drugs, herbicides, leukotriene antagonists, and plasticizers. Two major categories of peroxisome proliferator chemicals play a significant role in current society: the fibrate class of hypolipidemic drugs, which are used to reduce triglycerides and cholesterol in patients with hyperlipidemia; and phthalate ester plasticizers, which are used in the production of highly versatile, flexible vinyl plastics. Peroxisome proliferators induce hepatomegaly as a result of liver hyperplasia and an increase in the size and number of peroxisomes. Sher et al. (1993) cloned a cDNA for human peroxisome proliferator-activated receptor from a human liver cDNA library. The PPAR cDNA exhibited 85% and 91% DNA and deduced amino acid sequence identity, respectively, with mouse PPAR.
Vohl et al. (2000) determined that the PPARA gene spans 83.7 kb and contains 8 exons.
By Southern analysis of DNAs from a panel of human/rodent somatic cell hybrids and by linkage analysis in a CEPH family using a RFLP, Sher et al. (1993) assigned the PPAR gene to chromosome 22q12-q13.1, slightly telomeric to a linkage group that includes MYH9 (160775), IL2RB (146710), PDGFB (190040), CYP2D (124030), and G22P1 (152690).
Kersten et al. (2000) reviewed the roles of PPARs in health and disease.
Using RNase protection and in situ hybridization, Michalik et al. (2001) showed that the alpha, delta (PPARD; 600409) (which they called beta), and gamma (PPARG; 601487) isotypes of PPAR are expressed in the mouse epidermis during fetal development and that they disappear progressively from the interfollicular epithelium after birth. A low level of Ppara expression was reactivated 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.
In human cell lines, Jung et al. (2002) found that PPARA bound to and activated a DR1 motif in the 5-prime untranslated region of the apical ileal sodium/bile salt transporter (SLC10A2; 601295). Treatment of cholangiocytes with ciprofibrate, a PPARA ligand, increased ASBT mRNA levels. The studies identified a link between PPARA, which is known to play a role in lipid metabolism, and ileal bile salt absorption.
Fu et al. (2003) presented evidence that oleylethanolamide (OEA), a naturally occurring lipid that regulates satiety and body weight, is a natural endogenous ligand for PPARA. In vitro, OEA showed high affinity binding to PPARA. In vivo, OEA reduced total food intake and suppressed body weight gain in wildtype mice, whereas it had no effect in Ppara-null mice. In the small intestine of wildtype mice, OEA regulated the expression of several PPARA target genes, initiating the transcription of proteins involved in lipid metabolism and repressing inducible nitric oxide synthase (iNOS; 163730), an enzyme which may contribute to feeding stimulation.
Using protein pull-down and immunoprecipitation analyses, Patel et al. (2005) found that recombinant human CAP350 (CEP350; 617870) interacted with several nuclear receptors, including PPAR-alpha. Binding between CAP350 and nuclear receptors was independent of receptor ligands. When coexpressed, PPAR-alpha colocalized with CAP350 at nuclear foci and centrosomes, perinuclear region, and intermediate filaments. An N-terminal domain of CAP350 that included an LxxLL motif was sufficient for CAP350 to recruit PPAR-alpha to nuclear foci. CAP350 inhibited PPAR-alpha transactivation of a reporter gene in an LxxLL-dependent manner.
Tateishi et al. (2009) demonstrated that JHDM2A (611512) is critically important in regulating the expression of metabolic genes through disruption of the Jhdm2a gene in mice. The authors showed that Jhdm2a expression is induced by beta-adrenergic stimulation, and that it directly regulates PPARA and Ucp1 (113730) expression. Furthermore, Tateishi et al. (2009) demonstrated that beta-adrenergic activation-induced binding of Jhdm2a to the PPAR responsive element (PPRE) of the Ucp1 gene not only decreases levels of dimethylation of lys9 of histone H3 (H3K9me2; see 602810) at the PPRE, but also facilitates the recruitment of Pparg and Rxr-alpha (180245) and their coactivators Pgc1-alpha (604517), CBP/p300 (see 600140), and Src1 (602691) to the PPRE.
Sengupta et al. (2010) showed that mTORC1 (see 601231) controls ketogenesis in mice in response to fasting. The authors found that liver-specific loss of TSC1 (605284), an mTORC1 inhibitor, led to a fasting-resistant increase in liver size, and to a pronounced defect in ketone body production and ketogenic gene expression on fasting. The loss of raptor (regulatory associated protein of mTOR, complex 1, 607130), an essential mTORC1 component, had the opposite effects. In addition, Sengupta et al. (2010) found that the inhibition of mTORC1 is required for the fasting-induced activation of PPAR-alpha and that suppression of NCoR1 (600849), a corepressor of PPAR-alpha, reactivates ketogenesis in cells and livers with hyperactive mTORC1 signaling. Like livers with activated mTORC1, livers from aged mice have a defect in ketogenesis, which correlates with an increase in mTORC1 signaling. Moreover, Sengupta et al. (2010) showed that suppressive effects of mTORC1 activation and aging on PPAR-alpha activity and ketone production are not additive, and that mTORC1 inhibition is sufficient to prevent the aging-induced defect in ketogenesis. Thus, Sengupta et al. (2010) concluded that their findings revealed that mTORC1 is a key regulator of PPAR-alpha function and hepatic ketogenesis and suggested a role for mTORC1 activity in promoting the aging of the liver.
Lee et al. (2014) showed that both Ppara and Fxr (603826) regulated hepatic autophagy in mice. Pharmacologic activation of Ppara reverses the normal suppression of autophagy in the fed state, inducing lipophagy. This response is lost in Ppara-knockout mice, which are partially defective in the induction of autophagy by fasting. Pharmacologic activation of the bile acid receptor Fxr strongly suppresses the induction of autophagy in the fasting state, and this response is absent in Fxr-knockout mice, which show a partial defect in suppression of hepatic autophagy in the fed state. PPARA and FXR compete for binding to shared sites in autophagic gene promoters, with opposite transcriptional outputs. Lee et al. (2014) concluded that these results revealed complementary, interlocking mechanisms for regulation of autophagy by nutrient status.
Lee et al. (2015) demonstrated that activation of PPAR-alpha by PPAR-alpha agonists synergizes with the glucocorticoid receptor (GR, or GCCR; 138040) to promote burst-forming unit erythroid (BFU-E) self-renewal. Over time these agonists greatly increased production of mature red blood cells in cultures of both mouse fetal liver BFU-Es and mobilized human adult CD34+ peripheral blood progenitors, with a new and effective culture system being used for the human cells that generated normal enucleated reticulocytes. Although Ppara-null mice showed no hematologic difference from wildtype mice in both normal and phenylhydrazine (PHZ)-induced stress erythropoiesis, PPAR-alpha agonists facilitated recovery of wildtype but not Ppara-null mice from PHZ-induced acute hemolytic anemia. Lee et al. (2015) also found that PPAR-alpha alleviated anemia in a mouse model of chronic anemia. Finally, both in control and corticosteroid-treated BFU-E cells, PPAR-alpha cooccupies many chromatin sites with the GR. When activated by PPAR-alpha agonists, additional PPAR-alpha is recruited to GR-adjacent sites and presumably facilitates GR-dependent BFU-E self-renewal. Lee et al. (2015) concluded that their results suggested a novel function of PPAR-alpha in self-renewal of early committed erythroid progenitors.
Aljada et al. (2001) examined the possibility that troglitazone may modulate the expression of PPARA and PPARG. Seven obese hyperinsulinemic subjects were administered 400 mg troglitazone daily for 4 weeks. Fasting blood samples were obtained before and during troglitazone therapy at 1, 2, and 4 weeks. Fasting insulin concentrations fell at week 1 and persisted at lower levels until 4 weeks. PPARG expression fell significantly at week 1 and fell further at weeks 2 and 4. In contrast, PPARA expression increased significantly at week 2 and further at week 4. Two products of linoleic acid peroxidation and agonists of PPARG, 9- and 13-hydroxyoctadecanoic acid, decreased during troglitazone therapy. The authors concluded that troglitazone, an agonist for both PPARA and PPARG, has significant but dramatically opposite effects on PPARA and PPARG. They also concluded that these effects may be relevant to its insulin sensitizing and anti-inflammatory effects.
Crystal Structure
Xu et al. (2002) reported the crystal structure of a ternary complex containing the peroxisome proliferator-activated receptor-alpha ligand-binding domain bound to the antagonist GW6471 and an SMRT (600848) corepressor motif. In this structure, the corepressor motif adopts a 3-turn alpha-helix that prevents the carboxy-terminal activation helix (AF-2) of the receptor from assuming the active conformation.
Several lines of evidence suggest that PPAR-alpha is involved in the metabolic control of the expression of the genes encoding fatty acid oxidation enzymes. First, PPAR-alpha is necessary for the induction of peroxisomal biogenesis in response to peroxisome proliferators. Second, most known PPAR-alpha target genes encode enzymes involved in cellular fatty acid oxidation including the peroxisomal, mitochondrial, and cytochrome p450 pathways. Third, PPAR-alpha is activated by fatty acids or inhibitors of mitochondrial long-chain fatty acid import. These facts suggest that PPAR-alpha serves as a cellular 'lipostat,' transducing changes in cellular lipid levels to the transcriptional regulation of target genes involved in fatty acid utilization. To test the hypothesis that PPAR-alpha is activated as a component of the cellular lipid homeostatic response, Djouadi et al. (1998) characterized the expression of PPAR-alpha target genes in response to a perturbation in cellular lipid oxidative flux caused by pharmacologic inhibition of mitochondrial fatty acid import. Inhibition of fatty acid oxidative flux caused a feedback induction of PPAR-alpha target genes encoding fatty acid oxidation enzymes in liver and heart. In mice lacking PPARA (Ppara -/-), inhibition of cellular fatty acid flux caused massive hepatic and cardiac lipid accumulation, hypoglycemia, and death in 100% of male, but only 25% of female Ppara -/- mice. The metabolic phenotype of male Ppara -/- mice was rescued by a 2-week pretreatment with beta estradiol. These results demonstrated a pivotal role for PPAR-alpha in lipid and glucose homeostasis in vivo and implicated estrogen signaling pathways in the regulation of cardiac and hepatic lipid metabolism.
PPAR-alpha is a nuclear transcription factor activated by structurally diverse chemicals referred to as peroxisome proliferators. Activators can be endogenous molecules (fatty acids or steroids) or xenobiotics (e.g., fibrate lipid-lowering drugs). (The fibrate class of lipid-lowering drugs derive their name, by contraction, from 'phenoxyisobutyrate.') Upon pharmacologic activation, PPAR-alpha modulates target genes encoding lipid metabolism enzymes, lipid transporters, or apolipoproteins, suggesting a role in lipid homeostasis. Transgenic mice deficient in PPAR-alpha lack hepatic peroxisomal proliferation and have an impaired expression and induction of several hepatic target genes. Young adult males show hypercholesterolemia but normal triglycerides. Using a long-term experimental set up, Costet et al. (1998) identified these mice as a model of monogenic, spontaneous, late-onset obesity with stable caloric intake, and marked sexual dimorphism. Serum triglycerides, elevated in aged animals, were higher in females that developed a more pronounced obesity than males. The males showed a marked and original centrilobular-restricted steatosis and a delayed occurrence of obesity. Fat cells from the liver of these animals expressed substantial levels of PPAR-gamma-2 (PPARG2; 601487) transcripts when compared with lean cells. Studies in rodents demonstrated the involvement of PPAR-alpha nuclear receptor in lipid homeostasis, with a sexually dimorphic control of circulating lipids, fat storage, and obesity.
The nuclear receptor PPAR-alpha plays a role in regulating mitochondrial and peroxisomal fatty acid oxidation, suggesting that it is involved in the transcriptional response to fasting. Kersten et al. (1999) subjected PPAR-alpha-null mice to a high fat diet or to fasting, and their responses were compared with those of wildtype mice. PPAR-alpha-null mice chronically fed a high fat diet showed a massive accumulation of lipid in their livers. The researchers noted a similar phenotype in PPAR-alpha-null mice fasted for 24 hours, who also displayed severe hypoglycemia, hypoketonemia, hypothermia, and elevated plasma-free fatty acid levels, indicating a dramatic inhibition of fatty acid uptake and oxidation. It was shown that to accommodate the increased requirement for hepatic fatty acid oxidation, PPAR-alpha mRNA is induced during fasting in wildtype mice. The data indicated that PPAR-alpha plays a pivotal role in the management of energy stores during fasting. By modulating gene expression, PPAR-alpha stimulates hepatic fatty acid oxidation to supply substrates that can be metabolized by other tissues.
Leone et al. (1999) hypothesized that the lipid-activated transcription factor, peroxisome proliferator-activated receptor-alpha, plays a pivotal role in the cellular metabolic response to fasting. In rodents, short-term starvation caused hepatic steatosis, myocardial lipid accumulation, and hypoglycemia, with an inadequate ketogenic response in adult mice lacking PPAR-alpha, a phenotype that bears remarkable similarity to that of humans with genetic defects in mitochondrial fatty acid oxidation enzymes. In homozygous normal mice, fasting induced the hepatic and cardiac expression of PPAR-alpha target genes encoding key mitochondrial and extramitochondrial enzymes. In striking contrast, the hepatic and cardiac expression of most PPAR-alpha target genes was not induced by fasting in homozygous deficient mice. These results defined a role for PPAR-alpha in a transcriptional regulatory response to fasting and identified the homozygous deficient mouse as a potentially useful murine model of inborn and acquired abnormalities of human fatty acid utilization. The clinical manifestations of genetic defects in enzymes of fatty acid oxidation are 'stress'-induced; affected children are usually asymptomatic until faced with a dietary or physiologic condition that dictates an increased reliance on the oxidation of fats for energy. For example, during a period of fasting, affected children often develop a clinical episode or 'crisis' characterized by the precipitous onset of symptoms related to multiorgan toxicity.
To gain insight into the function of PPAR isoforms in rodents, Lee et al. (1995) disrupted Ppara in mice using homologous recombination. The homozygous mutant mice were viable and fertile with no detectable gross phenotypic defects. The mutant mice do not display the peroxisome proliferator pleiotropic response when challenged with classic peroxisome proliferators. Lee et al. (1995) concluded that Ppara is the major isoform required for mediating the pleiotropic response resulting from the actions of peroxisome proliferators.
By observing skin wound healing in Ppara mutant mice generated by Lee et al. (1995), Michalik et al. (2001) demonstrated that Ppara plays a role in the rapid epithelialization of a skin wound and that this role is distinct from that of Ppard. Ppara-null mice have a transient and initial delay in wound healing which Michalik et al. (2001) hypothesized is due to uncontrolled inflammation at the wound site. Michalik et al. (2001) concluded that Ppara plays a role in adult mouse epidermal repair and is mainly involved in the early inflammation phase of healing.
Adenovirus-induced hyperleptinemia (see leptin; 164160) causes rapid disappearance of body fat in normal rats, presumably by upregulating fatty acid oxidation within white adipocytes. To determine the role of PPARA expression, which was increased during the rapid loss of fat, Lee et al. (2002) infused adenovirus-leptin into Ppara-null and Ppara-wildtype mice. Despite similar degrees of hyperleptinemia and reduction in food intake, epididymal fat pad weight declined 55% in wildtype but only 6% in null mice; liver triacylglycerol fell 39% in the wildtype group but was unchanged in the null group. Carnitine palmitoyltransferase-1 (600528) mRNA rose 52% in the wildtype mice but did not increase in the null mice. The most striking transcription difference was the 3-fold rise in PGC1-alpha (PPARGC1; 604517) mRNA in white adipose tissue that occurred in Ppara-wildtype but not in Ppara-null mice. Moreover, baseline expression of PGC1-alpha in the null mice was below normal. The role of the PGC1 coactivator in mitochondrial biogenesis, thermogenesis, and gluconeogenesis is well established. Lee et al. (2002) found the most plausible interpretation of the findings in white adipose tissue to be that leptin induces, through upregulation of PGC1-alpha expression, a PPARA-dependent increase in mitochondrial biogenesis that increases fatty acid oxidation sufficiently to deplete triglyceride stores with a relatively modest increase in the transcription and/or activities of the enzymes of fatty acid oxidation. During the sustained hyperleptinemia induced by adenovirus transfer of the leptin gene, white adipocytes acquire features of brown adipocytes and are converted from fat-storing to fat-burning cells, in large part through upregulation of PGC1-alpha.
Hypertension and diabetes are common side effects of glucocorticoid treatment. To determine whether PPAR-alpha mediates these sequelae, Bernal-Mizrachi et al. (2003) treated chronically with dexamethasone mice deficient in low-density lipoprotein receptor (Ldlr -/-; 606945), with (Ppara +/+) or without (Ppara -/-) PPAR-alpha. Ppara +/+, but not Ppara -/-, mice developed hyperglycemia, hyperinsulinemia, and hypertension. The Ppara +/+, but not Ppara -/-, mice developed hypertension. Adenoviral reconstitution of PPAR-alpha in the livers of nondiabetic, normotensive, dexamethasone-treated Ppara -/- mice induced hyperglycemia, hyperinsulinemia, and increased gluconeogenic gene expression. It also increased blood pressure, renin (179820) activity, sympathetic nervous activity, and renal sodium retention. Human hepatocytes treated with dexamethasone and a PPAR-alpha agonist showed induction of PPARA and gluconeogenic gene expression. These results identified hepatic activation of PPAR-alpha as a mechanism underlying glucocorticoid-induced insulin resistance.
To clarify the role of PPAR signaling in tumor development, Saez et al. (2003) generated strains of mice with defined loss-of-function mutations in the Ppar genes. Mice devoid of Pparg (601487) die in utero, whereas heterozygotes are viable. To assess how Pparg haploinsufficiency influences the development of prostate cancer, Saez et al. (2003) crossed heterozygous mice with the transgenic adenocarcinoma mouse prostate (TRAMP) model, in which the probasin promoter drives prostate-specific expression of SV40 T antigen, thus recapitulating the progressive stages associated with clinical prostate cancer. TRAMP mice have also been used to examine the role of Ppara, as this Ppar is androgen-responsive and is highly expressed in prostatic adenocarcinoma. Saez et al. (2003) crossed Ppara and Pparg mutants with TRAMP mice to generate mice carrying the TRAMP transgene in a Ppara-null or Pparg-hemizygous background. They detected no increase in tumor predisposition in any of the Ppar mutant colonies, even after monitoring enough mice for enough time to be able to detect age-dependent tumor development. No differences in tumor incidence (complete in all cases), latency, size, histopathology, or disease progression were observed in animals carrying any of the Ppar loss-of-function mutations in addition to the TRAMP transgene. Saez et al. (2003) concluded that neither complete loss of Ppara nor hemizygous deletion of Ppara or Pparg has a significant effect on tumor development in this experimental model.
Yu et al. (2003) found that overexpression of Pparg in Ppara -/- mice induced hepatic steatosis. Northern blot analysis and gene expression profiling showed that adipocyte-specific genes and lipogenesis-related genes were highly induced in livers from these mice. In contrast, hepatic steatosis induced in Ppara -/- mice either by feeding a choline-deficient diet or by fasting failed to induce expression of these Pparg-regulated adipogenesis-related genes. Yu et al. (2003) concluded that a high level of Pparg in mouse liver is sufficient for adipogenic transformation of hepatocytes.
Using microarray analysis with RNA from the livers of fasted wildtype and Ppara-null mice, Patsouris et al. (2004) demonstrated that genes involved in the hepatic metabolism of glycerol, including cytosolic (138420) and mitochondrial (138430) glycerol-3-phosphate dehydrogenase, glycerol kinase (300474), and glycerol transporters aquaporin-3 (600170) and aquaporin-9 (602914), are upregulated by fasting in wildtype but not null mice. Furthermore, expression of these genes was induced by the synthetic PPAR-alpha agonist Wy14643 in wildtype but not Ppara-null mice. Administration of synthetic PPAR-alpha agonists in mice and humans decreased plasma glycerol, consistent with a stimulating role of PPAR-alpha in hepatic glycerol utilization. Finally, hepatic glucose production was decreased in Ppara-null mice simultaneously fasted and exposed to Wy14643, suggesting that the stimulatory effect of PPAR-alpha on gluconeogenic gene expression was translated at the functional level. Patsouris et al. (2004) concluded that these data indicated that PPAR-alpha directly governs glycerol metabolism in liver.
This variant, formerly titled HYPERAPOBETALIPOPROTEINEMIA, SUSCEPTIBILITY TO, has been reclassified as a polymorphism. The variant was present in 12,192 of 282,868 alleles and in 345 homozygotes, with an allele frequency of 0.04310, in the gnomAD database (v2.1.1) (Hamosh, 2023).
In 1 of 12 patients with type 2 diabetes (125853), Vohl et al. (2000) identified a 484C-G transversion in exon 5 of the PPARA gene, resulting in a leu162-to-val (L162V) substitution in the DNA-binding domain of the protein. Additional studies of 121 patients with type 2 diabetes and 193 nondiabetics found no association between the V162 allele and type 2 diabetes. However, carriers of the V162 allele had significantly higher concentrations of plasma LDL cholesterol and total and LDL apolipoprotein B (107730) levels compared to those homozygous for the L162 allele. The findings suggested that PPARA is a regulator of lipid metabolism.
Tai et al. (2002) evaluated the L162V polymorphism in 2,373 individuals from the Framingham Offspring Study. In men, the V162 allele was associated with significantly increased serum concentrations of total and LDL cholesterol, apoB, and apoC3 (107720). A similar trend was seen in women, but only the increase in apoB reached significance. The association of the V162 allele with LDL cholesterol was greatest in those who also carried the APOE (107741) E2 allele and the APOC3 3238G allele, both of which are associated with decreased clearance of triglyceride-rich lipoproteins.
Among 632 men, Robitaille et al. (2004) found increased frequency of the V162 allele among those with abdominal obesity, hypertriglyceridemia, high plasma apoB, and low HDL plasma levels, which are components of the metabolic syndrome (605552). The frequency of the V162 allele was approximately 10% in their group.
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