Affinage

PPARA

Peroxisome proliferator-activated receptor alpha · UniProt Q07869

Round 2 corrected
Length
468 aa
Mass
52.2 kDa
Annotated
2026-04-28
130 papers in source corpus 26 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PPARα is a ligand-activated nuclear receptor that heterodimerizes with RXR to bind peroxisome proliferator response elements (PPREs) and orchestrate transcriptional programs governing fatty acid oxidation, ketogenesis, lipoprotein metabolism, and inflammatory suppression. Endogenous fatty acids, eicosanoids such as 8(S)-HETE, and the endocannabinoid-like lipid oleoylethanolamide serve as direct ligands, while L-FABP shuttles lipid ligands to nuclear PPARα and coactivators PGC-1α and SIRT1 potentiate its transcriptional output in a ligand-influenced, AF-2-helix-dependent manner (PMID:9113987, PMID:11226238, PMID:10669761, PMID:19356714). Anti-inflammatory transrepression is achieved through direct protein–protein interactions with c-Jun and NF-κB p65, suppressing AP-1- and NF-κB-dependent gene expression independently of PPRE binding, and PPARα additionally attenuates hepatic NLRP3 inflammasome activation via induction of the lncRNA Gm15441 and consequent TXNIP suppression (PMID:10542237, PMID:33203882). Beyond canonical metabolic regulation, PPARα drives autophagy-dependent ciliogenesis and amyloid-β clearance, controls hepatocyte proliferation through an E2F8–UHRF1–CDH1 epigenetic axis, regulates CYP3A4 expression in human liver, and induces FGF21 as a circulating metabolic signal during prolonged fasting (PMID:29771182, PMID:30898012, PMID:35479397, PMID:22510778, PMID:18680716).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1993 High

    Cloning and functional identification of human PPARα resolved whether a peroxisome-proliferator-responsive nuclear receptor existed in humans, establishing that it trans-activates PPREs from acyl-CoA oxidase and CYP4A6 genes in response to fibrate-class drugs.

    Evidence cDNA cloning from human liver library, chromosomal mapping, cotransfection reporter assay with two distinct PPREs

    PMID:7684926

    Open questions at the time
    • Endogenous ligands not yet identified
    • In vivo physiological role not established
  2. 1997 High

    Demonstrating that mono/polyunsaturated fatty acids and 8(S)-HETE bind PPARα directly at physiological concentrations answered the key question of whether PPARα is a bona fide lipid sensor rather than merely a drug target.

    Evidence Radioligand competition binding assay with the high-affinity ligand GW2331 against multiple fatty acid species

    PMID:9113987

    Open questions at the time
    • Structural basis of ligand selectivity versus PPARγ/δ unknown
    • Tissue-specific ligand availability not characterized
  3. 1999 High

    Two contemporaneous advances established PPARα's in vivo metabolic essentiality and its anti-inflammatory transrepression mechanism: PPARα-null mice revealed an indispensable role in fasting-induced fatty acid oxidation and ketogenesis, while biochemical studies showed PPARα physically binds c-Jun, p65/NF-κB, and CBP to repress IL-6 expression independently of PPRE binding.

    Evidence PPARα knockout mouse metabolic phenotyping; GST pull-down of PPARα–c-Jun/p65/CBP complexes with reporter assays and null-mouse aortic explant validation

    PMID:10377439 PMID:10542237

    Open questions at the time
    • Structural basis of transrepression complex not resolved
    • Relative contribution of direct transrepression versus PPRE-mediated gene activation to anti-inflammatory effects unclear
  4. 2000 High

    Identification of PGC-1α as a PPARα coactivator that binds the AF-2 domain in a ligand-influenced manner and cooperatively induces fatty acid oxidation genes resolved how metabolic signals are integrated at the coactivator level to amplify PPARα transcriptional output.

    Evidence Cotransfection reporter assay, GST pull-down mapping LXXLL–AF-2 interaction, palmitate oxidation assay in retrovirally transduced cells

    PMID:10669761

    Open questions at the time
    • Whether SIRT1 modifies PGC-1α to regulate this interaction was unknown
    • Coactivator versus corepressor switching mechanism not yet structurally defined
  5. 2001 High

    Crystal structures of the PPARα ligand-binding domain with an agonist/SRC-1 and later an antagonist/SMRT complex provided the atomic-level framework for understanding ligand selectivity (a single Tyr-vs-His substitution versus PPARγ) and the AF-2-helix-dependent switch between coactivator and corepressor recruitment.

    Evidence X-ray crystallography of PPARα LBD–GW409544–SRC-1 and PPARα LBD–GW6471–SMRT ternary complexes with structure-based mutagenesis

    PMID:11698662 PMID:11845213

    Open questions at the time
    • Full-length PPARα–RXR heterodimer structure on DNA not available
    • Dynamics of coactivator/corepressor exchange in a cellular context unresolved
  6. 2001 High

    Discovery that L-FABP physically interacts with PPARα and colocalizes in hepatocyte nuclei resolved the question of how hydrophobic fatty acid ligands are delivered to a nuclear receptor, establishing L-FABP as a cytosolic ligand shuttle.

    Evidence GST pull-down, co-immunoprecipitation, mammalian two-hybrid, laser-scanning colocalization, HepG2 transactivation assay

    PMID:11226238

    Open questions at the time
    • Whether L-FABP determines ligand selectivity in vivo not tested
    • Mechanism of nuclear import of L-FABP–ligand complex not resolved
  7. 2003 High

    The finding that oleoylethanolamide binds PPARα and induces satiety exclusively in wild-type but not PPARα-null mice revealed an unexpected non-metabolic role for PPARα as a gut-brain signaling integrator regulating feeding behavior.

    Evidence Radioligand binding, PPARα knockout mouse food-intake/body-weight studies, intestinal target gene expression

    PMID:12955147

    Open questions at the time
    • Neural circuit through which PPARα activation in enterocytes signals satiety not defined
    • Whether other endocannabinoid-like ligands use PPARα similarly unknown
  8. 2004 High

    Placing PPARα downstream of ERRα in a PGC-1α–ERRα–PPARα hierarchy, supported by ERRα ChIP at the Ppara promoter and double-null epistasis, established how mitochondrial biogenesis transcriptional programs converge on PPARα in heart and skeletal muscle.

    Evidence ChIP of ERRα on Ppara promoter, ERRα/PPARα double-knockout fibroblasts, fatty acid oxidation assay

    PMID:15456881

    Open questions at the time
    • Whether this hierarchy operates in liver or other tissues not tested
    • Quantitative contribution of ERRα versus other promoter-bound factors unclear
  9. 2009 High

    Demonstrating that SIRT1 physically interacts with PPARα and is required for PGC-1α coactivation resolved how NAD⁺-dependent deacetylation integrates cellular energy status with PPARα-driven fatty acid oxidation in hepatocytes.

    Evidence Liver-specific SIRT1 knockout and overexpression, co-immunoprecipitation, high-fat diet metabolic phenotyping

    PMID:19356714

    Open questions at the time
    • Specific acetylation sites on PPARα or PGC-1α modified by SIRT1 not mapped
    • Whether SIRT1 modulates corepressor displacement not examined
  10. 2015 High

    Identification of KLF5 as a direct activator of the Ppara promoter and c-Jun as a competitive repressor at the same site in cardiac myocytes explained how sepsis-induced c-Jun upregulation suppresses PPARα-driven fatty acid oxidation and causes cardiac metabolic failure.

    Evidence ChIP and EMSA on Ppara promoter, cardiac-specific Klf5 knockout mouse with metabolic and echocardiographic phenotyping

    PMID:26574507

    Open questions at the time
    • Whether KLF5/c-Jun competition operates in hepatocytes or other PPARα-expressing tissues unknown
    • Therapeutic rescue of septic heart by restoring KLF5–PPARα axis not tested
  11. 2017 High

    Conditional deletion of PPARα in hepatocytes versus macrophages resolved the long-standing question of cell-type-specific contributions: hepatocyte PPARα is required for agonist-induced hepatomegaly and proliferation, while macrophage PPARα mediates anti-inflammatory cytokine repression.

    Evidence Hepatocyte- and macrophage-specific Ppara conditional knockout mice, BrdU labeling, histology, inflammatory gene profiling

    PMID:28082284

    Open questions at the time
    • Mechanism of hepatocyte proliferation downstream of PPARα not yet defined
    • Role of PPARα in other immune cell types (e.g. T cells) not addressed
  12. 2018 Medium

    Discovery that PPARα induces ciliogenesis through an autophagy-dependent mechanism, impaired in ppara-null kidneys during fasting, expanded PPARα's functional repertoire beyond metabolic transcription to organelle biogenesis and cellular homeostasis.

    Evidence ppara−/− mouse kidney, pharmacological and genetic autophagy inhibition, cilia quantification, FXR antagonism

    PMID:29771182

    Open questions at the time
    • Specific autophagy targets mediating ciliogenesis not identified
    • Relevance to human ciliopathies not established
    • Single-lab finding awaits independent replication
  13. 2019 Medium

    Two studies extended PPARα's autophagy role: PPARα agonists induced autophagy in microglia to promote Aβ plaque clearance in an Alzheimer model, and lysosomal–TFEB signaling was shown to regulate PPARα/PGC-1α protein levels for peroxisomal biogenesis, positioning PPARα within a lysosome–TFEB–PPARα–peroxisome regulatory circuit.

    Evidence PPARα agonist + siRNA in human microglia/glioma cells, APP-PSEN1ΔE9 mouse behavioral and Aβ assays; bafilomycin A1 treatment, TFEB knockdown, PPARα rescue of peroxisomal genes

    PMID:30898012 PMID:31032705

    Open questions at the time
    • Direct PPARα transcriptional targets mediating autophagosome biogenesis not identified
    • Whether TFEB regulation of PPARα is transcriptional or post-translational not fully defined
    • Translational relevance to human neurodegeneration unconfirmed
  14. 2020 High

    Identification of the lncRNA Gm15441 as a direct PPARα target that suppresses TXNIP and NLRP3 inflammasome activation revealed a non-coding RNA mechanism through which PPARα exerts hepatoprotective anti-inflammatory effects beyond its classical protein–protein transrepression of NF-κB.

    Evidence ChIP confirming PPARα binding at Gm15441 promoter, Gm15441-null mouse with enhanced inflammasome phenotype, CASP1/IL-1β cleavage assays

    PMID:33203882

    Open questions at the time
    • Whether human orthologs of Gm15441 exist and function analogously is unknown
    • Quantitative contribution of Gm15441/TXNIP versus direct NF-κB transrepression to net anti-inflammatory effect not determined
  15. 2022 Medium

    Delineation of the PPARα–E2F8–UHRF1–CDH1 epigenetic cascade explained how PPARα activation drives hepatocyte hyperproliferation: PPARα induces E2F8, which upregulates UHRF1, leading to H3K9me3-mediated silencing of CDH1 and derepression of Wnt/Myc proliferative programs.

    Evidence PPARα agonist treatment, E2F8/UHRF1 knockdown, CDH1 forced expression, ChIP for H3K9me3 at Cdh1 promoter

    PMID:35479397

    Open questions at the time
    • Whether this axis operates in human hepatocytes not shown
    • Contribution relative to other PPARα-driven proliferation signals not quantified
    • Single-lab study awaits independent validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the full-length structure of the PPARα–RXR heterodimer on DNA, the identity of specific PPARα transcriptional targets that directly execute autophagosome biogenesis, the human relevance of lncRNA-mediated inflammasome suppression, and the neural circuitry translating intestinal PPARα activation into satiety signaling.
  • Full-length PPARα–RXR heterodimer structure on chromatin unavailable
  • Direct autophagy effector genes transcribed by PPARα not catalogued
  • Human ortholog of Gm15441 not identified
  • Circuit from gut PPARα to central satiety centers not mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0003677 DNA binding 3 GO:0008289 lipid binding 3
Localization
GO:0005634 nucleus 5
Pathway
R-HSA-1430728 Metabolism 7 R-HSA-74160 Gene expression (Transcription) 6 R-HSA-168256 Immune System 5 R-HSA-9612973 Autophagy 3 R-HSA-162582 Signal Transduction 2 R-HSA-1640170 Cell Cycle 2 R-HSA-9748784 Drug ADME 1
Partners
FABP1JUNNCOA1NCOR2PPARGC1ARELARXRASIRT1
Complex memberships
PPARα–RXR heterodimer

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 Human PPARA was cloned from a liver cDNA library, mapped to chromosome 22q12-q13.1, and shown by cotransfection assays to trans-activate PPAR response elements from two distinct genes (acyl-CoA oxidase and CYP4A6) in response to peroxisome proliferators nafenopin, clofibrate, and WY-14,643. cDNA cloning, chromosomal mapping, cotransfection reporter assay Biochemistry High 7684926
1997 Certain mono- and polyunsaturated fatty acids (e.g., arachidonic acid, linoleic acid) and the eicosanoid 8(S)-HETE bind directly to PPARα at physiological concentrations, as demonstrated by competition binding assays using the high-affinity radioligand GW2331, establishing PPARα as a direct physiological sensor of lipid levels. Radioligand competition binding assay (in vitro ligand binding domain) Proceedings of the National Academy of Sciences of the United States of America High 9113987
1998 PPARα is expressed in undifferentiated human monocytes and monocyte-derived macrophages where it resides constitutively in the cytoplasm (whereas PPARγ is predominantly nuclear). Ligand activation of both PPARα and PPARγ induces apoptosis of TNFα/IFNγ-activated macrophages, and PPARγ inhibits NFκB p65/RelA transcriptional activity, indicating a mechanism for macrophage apoptosis via interference with anti-apoptotic NFκB signaling. Immunocytochemistry, transient transfection, TUNEL assay, caspase-3 activation assay The Journal of biological chemistry High 9748221
1999 PPARα-null mice subjected to short-term fasting develop hepatic steatosis, myocardial lipid accumulation, hypoglycemia, and an inadequate ketogenic response, demonstrating that PPARα is required for the transcriptional induction of fatty acid oxidation genes (MCAD, CPT-I, acyl-CoA oxidase, CYP4A3) during fasting in liver and heart. PPARα knockout mouse model, gene expression analysis, metabolic phenotyping Proceedings of the National Academy of Sciences of the United States of America High 10377439
1999 PPARα physically interacts with the transcription factors c-Jun and p65 (NFκB) and with the coactivator CBP, as shown by GST pull-down experiments. PPARα ligands (fibrates) repress IL-6 gene expression in aortic smooth muscle cells via transcriptional interference with AP-1 and NFκB, independent of promoter context, establishing a mechanism of anti-inflammatory transrepression. GST pull-down, cotransfection reporter assay with Gal4 chimeras, PPARα-null mouse aortic explants, IL-6 ELISA The Journal of biological chemistry High 10542237
2000 PGC-1 coactivates PPARα in the transcriptional control of mitochondrial fatty acid oxidation genes. PGC-1 binds PPARα in a ligand-influenced manner via an LXXLL domain interacting with the PPARα AF-2 region (distinct from the ligand-independent PPARγ–PGC-1 interaction). PPARα and PGC-1 cooperatively induce FAO gene expression and increase cellular palmitate oxidation rates. Cotransfection reporter assay, GST pull-down, retroviral overexpression in 3T3-L1 cells, palmitate oxidation assay Molecular and cellular biology High 10669761
2001 The X-ray crystal structure of the PPARα ligand-binding domain in complex with the agonist GW409544 and an SRC-1 coactivator motif was determined. Comparison with PPARγ and PPARδ structures revealed that a single amino acid difference (Tyr in PPARα vs. His in PPARγ) is a key molecular determinant of ligand subtype selectivity. X-ray crystallography, structure-based mutagenesis, ligand binding assay Proceedings of the National Academy of Sciences of the United States of America High 11698662
2001 Liver fatty acid binding protein (L-FABP) directly interacts with PPARα (and PPARγ but not PPARβ or RXRα) in a ligand-independent manner, colocalizes with PPARα in hepatocyte nuclei, and mediates PPARα transactivation in response to fatty acids and hypolipidemic drugs in a concentration-dependent manner, establishing L-FABP as a cytosolic carrier that shuttles lipid ligands to PPARα. Laser-scanning microscopy colocalization, GST pull-down, co-immunoprecipitation, mammalian two-hybrid system, transactivation assay in HepG2 cells Proceedings of the National Academy of Sciences of the United States of America High 11226238
2002 PPARα and PPARγ bind as heterodimers with RXR to specific response elements (PPREs) and recruit coactivators (e.g., SRC-1/p160 family) in a ligand-dependent fashion, increasing transcription initiation rate. The AF-2 helix conformation is essential for coactivator interaction. Biochemical coactivator interaction assays, reporter gene assays, structural analysis (review consolidating experimental findings) Annual review of medicine High 11818483
2002 Crystal structure of a ternary complex of the PPARα ligand-binding domain bound to the antagonist GW6471 and a SMRT co-repressor motif revealed that the co-repressor adopts a three-turn α-helix that sterically prevents the AF-2 activation helix from assuming the active conformation, and the antagonist reinforces this by blocking AF-2 repositioning. Structure-based mutagenesis confirmed this co-repressor binding mode is conserved across nuclear receptors. X-ray crystallography, structure-based mutagenesis, biochemical co-repressor interaction assays Nature High 11845213
2003 Oleoylethanolamide (OEA) binds with high affinity to PPARα and induces satiety and reduces body weight gain in wild-type mice but not in PPARα-null mice, defining an unexpected role for PPARα in regulating feeding behavior. OEA also regulates expression of PPARα target genes in the small intestine in a PPARα-dependent manner, including repression of iNOS. Radioligand binding assay, PPARα knockout mouse, food intake and body weight measurement, gene expression analysis Nature High 12955147
2004 RXR homodimers can selectively bind to functional PPREs (normally considered PPAR:RXR binding sites) and induce transactivation in vivo in a ligand-dependent manner requiring interaction with coactivators SRC1 or TIF2. This pathway operates even in cells with inactivating PPAR gene mutations and can rescue the hypothermia phenotype of fasted PPARα−/− mice, revealing a PPAR-independent RXR signaling pathway through PPREs. In vivo chromatin immunoprecipitation, cell transfection with PPAR-inactivating mutations, PPARα-null mouse rescue experiment The EMBO journal High 15103326
2004 Estrogen-related receptor alpha (ERRα) directly binds the PPARα gene promoter and activates PPARα expression; in cells null for both PPARα and ERRα, ERRα-driven activation of PPARα target genes and increased fatty acid oxidation were abolished, placing ERRα upstream of PPARα in the PGC-1α–ERRα–PPARα regulatory hierarchy in cardiac and skeletal muscle. Gene expression profiling, ChIP, ERRα/PPARα double-knockout fibroblasts, fatty acid oxidation assay Molecular and cellular biology High 15456881
2006 PPARα controls hepatic and skeletal muscle lipid metabolism by acting as a molecular sensor of endogenous fatty acids and their derivatives, regulating expression of genes encoding enzymes and transport proteins for fatty acid oxidation and lipoprotein metabolism. It also exerts anti-inflammatory effects and prevents cholesterol accumulation in macrophages by stimulating cholesterol efflux. Review consolidating cellular, animal model, and fibrate clinical data The Journal of clinical investigation High 16511589
2008 Prolonged fasting (7 days) and PPARα activation by fenofibrate significantly increase circulating FGF21 levels in humans, demonstrating that FGF21 is a PPARα-regulated circulating metabolic regulator in man (unlike ketosis induced by short-term fasting or ketogenic diet, which is FGF21-independent). Clinical study with serum FGF21 measurement, PPARα agonist (fenofibrate) treatment, controlled fasting protocols Cell metabolism Medium 18680716
2009 SIRT1 physically interacts with PPARα and is required to activate PGC-1α coactivation of PPARα. Hepatocyte-specific deletion of SIRT1 impairs PPARα signaling and decreases fatty acid β-oxidation, while SIRT1 overexpression induces PPARα target gene expression, placing SIRT1 as an upstream positive regulator of PPARα-mediated hepatic lipid homeostasis. Liver-specific SIRT1 knockout mouse, SIRT1 overexpression, co-immunoprecipitation, gene expression analysis, high-fat diet metabolic phenotyping Cell metabolism High 19356714
2011 Activated AMPK inhibits PPARα transcriptional activity in hepatoma cells independently of PPARα/RXR binding to DNA and independently of AMPK kinase activity; the effect instead depends on the activated conformation of AMPK. Both AICAR and metformin (AMPK activators) decreased basal and WY-14,643-stimulated PPARα-driven PPRE-reporter activity, while compound C (AMPK inhibitor) increased it. Transfection reporter assay (PPRE-luciferase), pharmacological AMPK activation/inhibition, constitutively active and dominant-negative AMPK constructs, nuclear localization analysis American journal of physiology. Gastrointestinal and liver physiology Medium 21700905
2012 PPARA SNPs (including rs4253728) are associated with CYP3A4 phenotype in human liver. shRNA-mediated knockdown of PPARA in primary human hepatocytes decreased ACOX1 (a PPARA target) and CYP3A4 expression by >50%, demonstrating that PPARA directly regulates CYP3A4 expression in human liver. Candidate-gene association in human liver bank, shRNA knockdown in primary human hepatocytes, CYP3A4 activity assay, clinical validation in atorvastatin-treated volunteers Clinical pharmacology and therapeutics Medium 22510778
2012 miR-141 represses HBV replication by targeting PPARA: miR-141 reduces PPARA expression post-transcriptionally, and siRNA knockdown of PPARA mimics the effect of miR-141 by reducing HBV promoter activity, indicating that PPARA normally sustains HBV gene expression through interactions with HBV promoter regulatory elements. miRNA library screen, miR-141 mimic transfection, siRNA knockdown, luciferase promoter reporter assay, Western blot PloS one Medium 22479552
2015 KLF5 (Krüppel-like factor 5) directly binds the Ppara promoter and activates Ppara gene transcription in cardiac myocytes. In septic hearts, c-Jun competes with KLF5 for an overlapping binding site on the Ppara promoter and suppresses transcription. Cardiac myocyte-specific Klf5 knockout mice show reduced Ppara expression, decreased fatty acid oxidation, reduced ATP, triglyceride accumulation, and cardiac dysfunction. Promoter binding assay (ChIP, EMSA), cardiac-specific Klf5 knockout mouse, fatty acid oxidation assay, ATP measurement, echocardiography Circulation research High 26574507
2017 Hepatocyte-specific (but not macrophage-specific) PPARA deletion abolishes agonist (Wy-14643)-induced hepatomegaly and hepatocyte proliferation in mice. Macrophage PPARA mediates downregulation of inflammatory cytokines IL-15 and IL-18 in response to PPARA agonism, demonstrating cell-type-specific roles of PPARA. Conditional (hepatocyte- and macrophage-specific) Ppara knockout mice, BrdU labeling, histology, gene expression, serum chemistries American journal of physiology. Gastrointestinal and liver physiology High 28082284
2018 PPARA activates ciliogenesis in cells by inducing autophagy; pharmacological or genetic inactivation of autophagy blocked PPARA-induced ciliogenesis. In ppara-/- mice, starvation-induced ciliogenesis and autophagy were impaired in the kidney, and an NR1H4/FXR agonist (which reciprocally represses ciliogenesis) exacerbated kidney damage in ppara-/- mice, establishing a PPARA–autophagy–ciliogenesis regulatory axis. ppara-/- mouse model, pharmacological autophagy inhibition/activation, genetic knockdown, cilia quantification, kidney histology Autophagy Medium 29771182
2019 Pharmacological activation of PPARA by gemfibrozil or Wy14643 induces autophagy in human microglia and glioma cells in a PPARA-dependent manner (blocked by siRNA knockdown of PPARA), enhances autophagosome biogenesis, promotes microglial recruitment to Aβ plaques, and reduces amyloid pathology and memory deficits in APP-PSEN1ΔE9 mice. PPARA agonist treatment, siRNA knockdown, autophagy flux assay, Alzheimer mouse model (APP-PSEN1ΔE9), behavioral testing, Aβ ELISA, immunofluorescence Autophagy Medium 30898012
2019 Lysosomal inhibition (bafilomycin A1) suppresses PPARA and PPARGC1A protein levels, leading to downregulation of peroxisomal biogenesis and lipid oxidation gene sets. Genetic knockdown of TFEB (a lysosomal regulator) similarly reduces PPARA and PPARGC1A. Ectopic induction of PPARA transcriptional activity rescues peroxisomal gene expression after lysosomal inhibition, establishing a lysosome–TFEB–PPARA–PPARGC1A axis regulating peroxisomal function. Microarray, qPCR, pharmacological lysosomal inhibition, Tfeb siRNA knockdown, PPARA overexpression rescue Autophagy Medium 31032705
2020 Ligand activation of PPARα directly upregulates the lncRNA gene Gm15441 through PPARα binding sites in its promoter. Gm15441 expression suppresses its antisense transcript TXNIP, thereby decreasing TXNIP-mediated NLRP3 inflammasome activation, CASP1 cleavage, and IL-1β maturation. Gm15441-null mice showed enhanced hepatic inflammasome activation in response to PPARα agonism and fasting. ChIP (PPARα binding sites), Gm15441-null mouse generation, NLRP3 inflammasome activation assays, CASP1/IL-1β cleavage, PPARα agonist/fasting in vivo Nature communications High 33203882
2022 PPARA activation induces expression of the transcription factor E2F8 as a novel PPARA target gene, which in turn upregulates the epigenetic regulator UHRF1. UHRF1 methylates (H3K9me3) and strongly represses CDH1 promoter, suppressing CDH1 expression. Forced CDH1 expression inhibited Wnt/Myc target gene expression and suppressed PPARA-driven hepatocyte hyperproliferation. Thus, the PPARA–E2F8–UHRF1–CDH1 axis epigenetically controls hepatocyte proliferation. PPARA agonist treatment, KO/knockdown of E2F8 and UHRF1, CDH1 forced expression, ChIP (H3K9me3 on Cdh1 promoter), gene expression analysis iScience Medium 35479397

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Discovery and refinement of loci associated with lipid levels. Nature genetics 2409 24097068
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2002 The mechanisms of action of PPARs. Annual review of medicine 2053 11818483
1997 Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proceedings of the National Academy of Sciences of the United States of America 1782 9113987
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
1998 PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 1481 9568680
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2009 A census of human transcription factors: function, expression and evolution. Nature reviews. Genetics 1191 19274049
2000 The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Molecular and cellular biology 968 10669761
1999 Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. The Journal of biological chemistry 931 10542237
2009 Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell metabolism 914 19356714
2010 Genetic evidence for high-altitude adaptation in Tibet. Science (New York, N.Y.) 907 20466884
2003 Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha. Nature 901 12955147
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2016 Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-α and -δ, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening. Gastroenterology 848 26874076
2018 VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell discovery 829 29507755
1999 The DNA sequence of human chromosome 22. Nature 808 10591208
1999 A critical role for the peroxisome proliferator-activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha-null mouse as a model of fatty acid oxidation disorders. Proceedings of the National Academy of Sciences of the United States of America 802 10377439
2004 Peroxisome proliferator-activated receptor alpha target genes. Cellular and molecular life sciences : CMLS 794 14999402
1998 Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. The Journal of biological chemistry 787 9748221
2006 Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. The Journal of clinical investigation 783 16511589
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 PPAR control of metabolism and cardiovascular functions. Nature reviews. Cardiology 719 34127848
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2014 PPAR gamma gene--a review. Diabetes & metabolic syndrome 553 25450819
2002 Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha. Nature 543 11845213
2020 The role of peroxisome proliferator-activated receptors (PPAR) in immune responses. Metabolism: clinical and experimental 520 32791172
1997 RAC3, a steroid/nuclear receptor-associated coactivator that is related to SRC-1 and TIF2. Proceedings of the National Academy of Sciences of the United States of America 494 9238002
1993 cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor. Biochemistry 459 7684926
2008 The circulating metabolic regulator FGF21 is induced by prolonged fasting and PPARalpha activation in man. Cell metabolism 450 18680716
2001 Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. Proceedings of the National Academy of Sciences of the United States of America 447 11698662
2001 The role of PPAR-gamma in macrophage differentiation and cholesterol uptake. Nature medicine 445 11135614
2001 Peroxisome proliferator-activated receptor gamma coactivator 1beta (PGC-1beta ), a novel PGC-1-related transcription coactivator associated with host cell factor. The Journal of biological chemistry 439 11733490
2004 Estrogen-related receptor alpha directs peroxisome proliferator-activated receptor alpha signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle. Molecular and cellular biology 413 15456881
2001 Fatty acids and hypolipidemic drugs regulate peroxisome proliferator-activated receptors alpha - and gamma-mediated gene expression via liver fatty acid binding protein: a signaling path to the nucleus. Proceedings of the National Academy of Sciences of the United States of America 402 11226238
2016 An update on PPAR activation by cannabinoids. British journal of pharmacology 360 27077495
2007 Modulation of PPAR activity via phosphorylation. Biochimica et biophysica acta 358 17560826
2019 Activation of PPARA-mediated autophagy reduces Alzheimer disease-like pathology and cognitive decline in a murine model. Autophagy 303 30898012
2004 PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis. Journal of lipid research 271 15489539
2005 Receptor-independent actions of PPAR thiazolidinedione agonists: is mitochondrial function the key? Biochemical pharmacology 241 15925327
2015 Fatty acids, eicosanoids and PPAR gamma. European journal of pharmacology 236 26632493
2000 Regulation of lipid and lipoprotein metabolism by PPAR activators. Clinical chemistry and laboratory medicine 215 10774955
2005 The toxicology of ligands for peroxisome proliferator-activated receptors (PPAR). Toxicological sciences : an official journal of the Society of Toxicology 206 16322072
2016 Localization of PPAR isotypes in the adult mouse and human brain. Scientific reports 203 27283430
2008 Coordination of inflammation and metabolism by PPAR and LXR nuclear receptors. Current opinion in genetics & development 189 18782619
1996 Expression of the peroxisome proliferator-activated receptor (PPAR) in the mouse colonic mucosa. Biochemical and biophysical research communications 187 8651933
2003 A paradigm for gene regulation: inflammation, NF-kappaB and PPAR. Advances in experimental medicine and biology 186 14713228
2006 The PPAR regulatory system in cardiac physiology and disease. Cardiovascular research 172 17010956
2000 Role of the peroxisome proliferator-activated receptors (PPAR) in atherosclerosis. Biochemical pharmacology 167 11007963
2004 In vivo activation of PPAR target genes by RXR homodimers. The EMBO journal 161 15103326
2000 Molecular scanning of the human PPARa gene: association of the L162v mutation with hyperapobetalipoproteinemia. Journal of lipid research 154 10828087
2008 Klotho is a target gene of PPAR-gamma. Kidney international 146 18547997
2022 In vitro activity of a panel of per- and polyfluoroalkyl substances (PFAS), fatty acids, and pharmaceuticals in peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma, and estrogen receptor assays. Toxicology and applied pharmacology 143 35752307
2007 Peroxisome proliferator-activated receptor (PPAR) in metabolic syndrome and type 2 diabetes mellitus. Current diabetes reviews 143 18220654
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